bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2026–11–01
57 papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Lipid acyl chain remodeling governs KRAS nanoclustering and oncogenic functions through membrane composition control.
  2. Engaging the host adaptive response to nutrient limitation delays cancer cachexia.
  3. Intravital Multiphoton Microscopy of Schwann Cells in Mouse Models of Pancreatic Disease.
  4. Cryo-EM structures reveal the mechanism of phosphatidylserine remodeling by membrane-bound glycerophospholipid O-acyltransferase 1.
  5. Respiration-deficient cells require pyruvate carboxylase to suppress asparagine auxotrophy.
  6. Ferritinophagy ignites GSDMD activation: selective autophagy links iron metabolism to innate immunity.
  7. Behavioral dysfunction but not wasting in cancer cachexia is driven by altered tryptophan metabolism.
  8. Resistance to membrane damage enhances metastatic potential of breast cancer cells via dysregulated phospholipid profiles and annexin-mediated repair.
  9. Plasma Membrane Lipid Asymmetry Dynamically Regulates Passive Diffusion.
  10. Cancer cells have got 'MoVes'.
  11. Energetics of stalk intermediates elucidated from hydrostatic pressure effects on membrane fusion.
  12. Macrophages iron out cancer cells' vulnerability.
  13. Epithelial-to-mesenchymal transition confers mechanical resistance to hemodynamic stress during hematogenous dissemination.
  14. ANO6-mediated trogocytosis of cancer-associated fibroblasts promotes pancreatic cancer cell growth and immune suppression.
  15. An Optimized Cancer Cachexia Research Model.
  16. Opening the window for immunotherapy in pancreatic cancer.
  17. Rethinking Radiation Therapy in the Era of RAS Inhibition for Pancreatic Cancer.
  18. Survey of the human proteostasis network: the autophagy-lysosome pathway.
  19. Visualization of Disseminated Tumor Cells and Metastatic Outgrowth in the Lung at Single Cell Resolution via Intravital Imaging.
  20. Motile vesicles (MoVes) are a cancer cell migration-associated extracellular vesicle population.
  21. A Dissociation-Based Seahorse XF Workflow for Quantifying Averaged Bioenergetics in Anchorage-Independent Cancer Cell Clusters.
  22. Integrated single-cell and proteomic profiling of pancreatic neoplasia identifies tissue markers that outperform established diagnostic markers in distinguishing cancer from precursor lesions.
  23. Bacterial Peptidoglycan Extends Lifespan by Activating Lysosomal Activity through V-ATPase Binding.
  24. A guide to autophagy-dependent cell death: concepts, criteria, and mechanisms.
  25. Autophagy and intratumoral bacteria abundance influence the prognosis of patients with pancreatic carcinoma.
  26. Employing High-Resolution Microscopy to Identify Dormant Disseminated Tumor Cells in the Brain.
  27. Influence of hemin on biophysical properties of membranes.
  28. Optimizing first-line NALIRIFOX and exploring the role of the microbiota in second-line pancreatic cancer treatment: the PRODIGE 105-GERCOR 116 PANORAMIX trial.
  29. scGlycoAI: machine learning analysis of single-cell glycan and RNA sequencing data for cell-type annotation and malignancy-associated glycan discovery.
  30. Quantitative Mapping of Organelle Positioning in Cultured Cells Using Semi-Automated Image Analysis Pipeline.
  31. Lipid Defect Analyzer (LipiDeA): A Python Framework for Quantifying Lipid Packing Defects in Curved and Neutral Lipid-Containing Membranes.
  32. Dual targeting of DHODH and SLC29A1 overcomes metabolic resistance and enhances antitumor immune responses in PDAC.
  33. The Spliceosome Scaffold Component BCAS2 Promotes Pancreatic Cancer Progression through Weak 5' Splice Site-Dependent Splicing Regulation.
  34. RAStoERK: A reference interaction atlas for insights into signaling and disease.
  35. Adipocyte lipolysis is a determinant of skeletal muscle size during fasting and feeding.
  36. Cellquant: a vibecoder's guide to image analysis.
  37. Ionic liquid-mediated cellular loading for whole tumor cell vaccines.
  38. Selective AUTAC-mediated ATP7B degradation unlocks cuproptosis vulnerability in pancreatic ductal adenocarcinoma.
  39. Nanotherapy targets senescent cells.
  40. Impaired autophagy and lysosome function in human fibroblast aging.
  41. Histopathological growth patterns represent a dynamic biological and clinically-relevant terminus of the metastatic cascade.
  42. Oncogenic KRAS Suppresses IFNγ Signaling in Tumor Cells.
  43. An ECM-driven mechanotransductive signaling module promotes NKX6.1-enriched human pancreatic progenitor formation.
  44. Augmenting intercellular mitochondrial transfer for tissue repair and rejuvenation.
  45. Addressing complex autofluorescence signatures in solid tissue samples to enhance full spectrum flow cytometry of non-immune cells.
  46. Intrinsic resistance to KRAS inhibition: Interfering with interferon.
  47. Nobel 2026: Optogenetics - how we can control the nerve cells of others!
  48. Quantitative Colocalization Analysis in Fluorescence Microscopy.
  49. A fluorescence-based assay to measure chaperone-mediated autophagy in cell and tissue lysates.
  50. Exercise against cancer: recent advances and open questions.
  51. Tumor-educated macrophages promote ferroptosis inhibition in pancreatic cancer via activating the p62-KEAP1-NRF2 pathway.
  52. Lysosomal biophysics in CLN3 disease: Connecting membrane transport, molecular homeostasis, and tissue dysfunction.
  53. The impact of sex and ancestry on the molecular landscape of pancreatic adenocarcinoma.
  54. Isoenzyme-specific determination of glutathione peroxidase activity in cell lysates and GPX1/GPX4-HiBiT cellular target engagement.
  55. E-cadherin-mediated neighborhood surveillance dictates pre-malignant outcomes.
  56. A nanoscale map of the human cell surface proteome reveals spatial and functional organization.
  57. ATAD2B governs epigenetic silencing of the epithelial program to fuel cancer metastasis and neuronal migration.
  1. bioRxiv. 2026 Oct 07. pii: 2026.10.06.757084. [Epub ahead of print]
    Lipid acyl chain remodeling governs KRAS nanoclustering and oncogenic functions through membrane composition control.
    Neha Arora, Rafael S Bravo, Hong Liang, Jeffrey T Chang, Alex Reed, Junchen Liu, Benjamin F Cravatt, Haoqiang Ying, Claudia Pedroza, Yong Zhou.
      KRAS signaling is spatially organized within the dynamic proteolipid nanoclusters on the plasma membrane (PM) that selectively concentrate anionic phospholipids, yet the molecular determinants governing this lipid sorting remain incompletely defined. Here we identify phospholipid acyl chain composition as a critical regulator of KRAS spatial organization and signal output. Using genetic and pharmacological perturbation of lysophosphatidylcholine acyltransferase 3 (LPCAT3), a key enzyme that incorporates polyunsaturated fatty acids into phospholipids, we demonstrate that remodeling of membrane acyl chain unsaturation alters the phosphatidylserine (PS) lipidome without changing total PS abundance. Loss of LPCAT3 depletes polyunsaturated PS species, disrupts KRAS PM association and nanoclustering, and attenuates downstream MAPK signaling and oncogenic activity across multiple KRAS mutant contexts. Acute restoration of polyunsaturated, but not saturated, lipids rescue KRAS nanoclustering, establishing a direct requirement for lipid unsaturation in sustaining signaling-competent assemblies. Mechanistically, these findings define membrane acyl chain composition as a determinant of proteolipid organization that encodes KRAS signaling capacity. Consistent with this model, LPCAT3 inhibition selectively impairs KRAS-dependent proliferation and sensitizes tumor cells to direct KRAS inhibition. Together, this work uncovers lipid acyl chain remodeling as a fundamental regulator of membrane-associated signaling and identifies membrane composition as an exploitable vulnerability in oncogenic KRAS systems.
    DOI:  https://doi.org/10.64898/2026.10.06.757084
  2. bioRxiv. 2026 Oct 09. pii: 2026.10.08.757672. [Epub ahead of print]
    Engaging the host adaptive response to nutrient limitation delays cancer cachexia.
    Maria Gomez-Jenkins, Trishna Das, Maria Ibrahim, Damon Fard, Sereno Lopez-Darwin, Justine Raeber, Jesse Powers, Zhixian Hu, Hirak Sarkar, Eduardo CararoLopes, Akshada Sawant, Gabriela Reyes-Castellanos, Wenyun Lu, Hantao Qiang, Aslihan Sen, Young-Yon Kwon, Selina Wadhera, Honiyah Armughan, Shang Shi, Joshua D Rabinowitz, Sheng Hui, Tracy G Anthony, Michael A Skinnider, Benjamin J Raphael, Marcus D Goncalves, Tobias Janowitz, Eileen White.
      Cancer cachexia is a debilitating wasting syndrome associated with involuntary weight loss, reduced appetite and food intake, adipose and muscle atrophy, and systemic inflammation with induction of a myriad of candidate cachexia factors. Using a multi-omic approach in a genetically engineered mouse model of lung cancer cachexia, we found that early circulating metabolic alterations preceded overt weight loss. Although both cachexia and fasting are characterized by a reduction in food intake, we show that the systemic metabolic changes in cachexia are distinct, indicating a lack of induction in the normal protective response to negative energy balance during cachexia. Cancer cachexia causes profound hepatic reprogramming, and activation of inflammatory programs, alongside muscle atrophy and elevation of circulating cytokines. However, targeting individual candidate cachectic factors such as IL-6, TNF-α, GDF15, CCL2, LIF, and IL17A failed to rescue weight loss or prolong survival. In contrast, caloric restriction initiated prior to tumor induction elicited a program of protection during tumor progression that attenuated multi-tissue inflammatory and catabolic transcriptional responses, preserved lean mass, and prolonged survival. Together, these findings suggest that metabolic preconditioning broadly dampens systemic inflammation and delays the onset and progression of cancer cachexia.
    HIGHLIGHTS: Despite both fasting and cachexia involve reduced nutrient intake, the metabolic alterations are distinct.Cachexia induces a systemic inflammatory response.Single targeting of implicated cachectic factors fails to rescue weight loss or survival in cancer cachexia.Caloric restriction pre-conditioning to enforce the protective response to nutrient limitation attenuates cachexia.
    DOI:  https://doi.org/10.64898/2026.10.08.757672
  3. Methods Mol Biol. 2027 ;3085 95-107
    Intravital Multiphoton Microscopy of Schwann Cells in Mouse Models of Pancreatic Disease.
    Pavel Stupakov, Ines Velazquez-Quesada, Golbahar Sadatrezaei, Francesca Gaino, Richard J Wong, Sylvie Deborde, Bojana Gligorijevic.
      Over the past decade, the important role of nerves in the growth and progression of pancreatic cancer has been increasingly recognized. The most abundant cell type present in the nerves, Schwann cells (SCs), can be reprogrammed by cancer cells and fibrotic extracellular matrix (ECM), facilitating perineural invasion of cancer cells in the pancreatic ductal adenocarcinoma (PDAC). Activated SCs form tracks, which are then populated and used by cancer cells for invasion. Intravital microscopy of the pancreas under the pathological conditions holds the potential to visualize and decipher real-time interactions of SCs with the cancer cells, ECM, and host cells in the tumor microenvironment and to delineate SC activation dynamics and the responses to targeted therapies. Here, we describe a protocol for high-resolution intravital microscopy of Schwann cells, ECM, and cancer cells using mouse models of PDAC or pancreatitis.
    Keywords:  Collagen fibers; Intravital microscopy; Pancreas; Pancreatic cancer; Pancreatitis; Schwann cells; Tumor microenvironment
    DOI:  https://doi.org/10.1007/978-1-0716-5591-7_6
  4. bioRxiv. 2026 Sep 02. pii: 2026.09.01.748671. [Epub ahead of print]
    Cryo-EM structures reveal the mechanism of phosphatidylserine remodeling by membrane-bound glycerophospholipid O-acyltransferase 1.
    Leehyeon Kim, Siyoung Kim, Ritchie Ly, Luke Cohen-Abeles, Pei Liu, Xuejun Jiang, Dohoon Kwon, Robert V Farese, Tobias C Walther.
      Lands cycle remodeling of glycerophospholipid acyl chains is crucial for cells to maintain appropriate membrane composition. Glycerophospholipids are cleaved at the glycerol sn2-position by phospholipase A. The lysophospholipids are reacylated by enzymes of the membrane-bound O-acyltransferase (MBOAT) family to incorporate specific fatty-acyl chains to adjust membrane properties. How MBOAT enzymes recognize specific acyl-CoA donors, select lysophospholipid acceptors, and release products is unclear. Phosphatidylserine (PS), a critical anionic phospholipid, controls membrane surface charge, signaling-protein recruitment, and cell-death-associated membrane recognition, and PS acyl-chain remodeling is linked to ferroptosis resistance. Here, we showed that MBOAT1 preferentially generates monounsaturated fatty acid-containing PS from lyso-PS. High-resolution cryo-electron microscopy structures of human MBOAT1 captured distinct binding poses of the fatty acyl donor, lyso-PS acceptor, and PS product. With lipidomics, enzymology and molecular dynamics simulations, these structures reveal the mechanism and pathway of MBOAT1-dependent PS remodeling.
    DOI:  https://doi.org/10.64898/2026.09.01.748671
  5. Nat Metab. 2026 Oct 27.
    Respiration-deficient cells require pyruvate carboxylase to suppress asparagine auxotrophy.
    Ruobing Cui, Keun Woo Ryu, Yi Fu, Ziad Bakouny, Dayi Li, Tamar Kavlashvili, Agnel Sfeir, Craig B Thompson.
      Mutations in mitochondrial DNA (mtDNA) impair ETC activity and oxidative phosphorylation, but their phenotypic consequences vary with heteroplasmy levels. Whether increasing mtDNA heteroplasmy creates metabolic dependencies not present in respiratory-competent cells remains unknown. Here, we show that low pyruvate carboxylase (PC) expression creates an asparagine dependency in high-mtDNA-heteroplasmy, respiration-compromised cells. In isogenic cells carrying similar mtDNA deletions, respiration declines linearly with increasing heteroplasmy, whereas redox imbalance emerges only above 50% heteroplasmy. Above 70% heteroplasmy, integrated stress-response-associated translational defects emerge, which can be reversed by either exogenous asparagine or PC overexpression. Asparagine dependence inversely correlates with PC expression across respiration-deficient cells. Consistent with this pattern, patient-derived thyroid tumour cells harbouring a high-heteroplasmy complex I mutation and low PC levels exhibit asparagine auxotrophy and sensitivity to L-asparaginase. Together, these findings demonstrate a role for mitochondrial PC in cellular asparagine synthesis under conditions of compromised respiratory activity.
    DOI:  https://doi.org/10.1038/s42255-026-01651-4
  6. Autophagy. 2026 Nov;22(11): 2981-2983
    Ferritinophagy ignites GSDMD activation: selective autophagy links iron metabolism to innate immunity.
    Daolin Tang, Rui Kang, Daniel J Klionsky.
      
    DOI:  https://doi.org/10.1080/15548627.2026.2698911
  7. bioRxiv. 2026 Oct 09. pii: 2026.10.08.757616. [Epub ahead of print]
    Behavioral dysfunction but not wasting in cancer cachexia is driven by altered tryptophan metabolism.
    Damon Fard, Edisa Pirani, Maria Gomez-Jenkins, Sereno Lopez-Darwin, Maria Ibrahim, Lilia Schell, Charlotte Larkin, Clara Gorgui, Clara Berdasco, Zhixian Hu, Trishna Das, Jesse Powers, Tracy G Anthony, Joshua D Rabinowitz, Benjamin J Raphael, Jessie Yanxiang Guo, Marcus D Goncalves, Tobias Janowitz, Eileen White.
      Cancer cachexia causes pathological weight loss, anorexia, and depressive symptoms, culminating in increased mortality. Using mouse models of pancreatic cancer cachexia, we identify tumor and hepatic inflammatory signaling, multi-organ energy charge depletion, and altered tryptophan metabolism. Metabolomic profiling and stable isotope tracing revealed altered tryptophan fates: serotonin depletion and kynurenine accumulation across tumor, liver, muscle and spleen. Kynurenine accumulation involved accelerated conversion of tryptophan to kynurenine with slowed downstream conversion to kynurenic acid. Restoring serotonin activity pharmacologically or metabolically normalized feeding, locomotion, and depression-like behavior, but wasting, tumor burden, and survival remained unchanged. Blocking kynurenine production or kynurenine-mediated AhR activation pharmacologically produced similar results. Thus, in cancer cachexia, the tryptophan pathway is subverted to deplete serotonin and accumulate kynurenine. This subversion contributes to cachexia-associated behavioral and feeding defects but not lethal systemic catabolism.
    Highlights: Tumors divert tryptophan from serotonin toward kynurenine accumulation in cachexiaSerotonin depletion contributes to behavioral alterations in cancer cachexiaKynurenine accumulation reduces feeding and activity via aryl hydrocarbon receptorCombined pathway targeting preserves fat mass but wasting remains unaltered.
    DOI:  https://doi.org/10.64898/2026.10.08.757616
  8. Cell Mol Life Sci. 2026 Jul 29. pii: 398. [Epub ahead of print]83(1):
    Resistance to membrane damage enhances metastatic potential of breast cancer cells via dysregulated phospholipid profiles and annexin-mediated repair.
    Jonathan Wei Bao Chua, Mette Niemann, Kenji Maeda, Jianzhou Cui, Jesper Nylandsted, Lina Hsiu Kim Lim.
      During cancer metastasis, invading cancer cells are required to navigate through various biophysical barriers. In the process of intravasation, circulation and extravasation, cancer cells which successfully overcome and survive these tremendous biophysical stressors can establish themselves as circulating tumour cell (CTC) precursors to secondary metastatic niches. Although metastatic processes have been well described by current literatures, the determining characteristics for invading cancer cells to withstand these stressors in the tumour microenvironment, remains poorly understood. Using isogenic breast cancer cells of varying metastatic propensities, we demonstrate that breast cancer cells of increasing metastatic propensity possess dysregulated membrane phospholipid profiles and differential recruitment of key membrane repair proteins like Annexin A1 (ANXA1). The dysregulation of key membrane structural phospholipids like phosphatidylcholine (PC), phosphatidylethanolamine (PE) and sphingomyelin (SM) influences membrane structure and integrity. Cumulatively, our investigation revealed that breast cancer cells with higher metastatic potential possessed greater PC/PE ratio, indicative of an enhanced membrane integrity. The simultaneous upregulation of membrane repair calcium-dependent phospholipid-binding ANXA1 and ANXA2 suggests an interplay between membrane repair and phospholipid dysregulation in governing its membrane integrity and subsequent resistance against damage. These findings identify membrane lipid remodelling and annexin-mediated repair as coupled processes that confer metastatic breast cancer cells with resistance to membrane damage, highlighting therapeutic vulnerabilities which could be exploited.
    Keywords:  Annexin-A1/A2; Cancer metastasis; Circulating tumor cells; Membrane damage; Membrane integrity; Membrane phospholipid dysregulation; Membrane repair; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s00018-026-06258-2
  9. Adv Sci (Weinh). 2026 Oct 25. pii: e78435. [Epub ahead of print]
    Plasma Membrane Lipid Asymmetry Dynamically Regulates Passive Diffusion.
    Jieming Ping, Wenliang Wang, Jinnuo Xu, Mengyun Yang, Ning Wu.
      Plasma membrane (PM) phospholipid asymmetry is a fundamental feature of eukaryotic cells that regulates signaling, trafficking, and cell fate. Whether it also controls passive diffusion across the PM remains unknown. Here, we show that phospholipid asymmetry is a critical determinant of PM permeability to hydrophobic molecules. Using genetic and biochemical approaches, we demonstrate that disruption of lipid asymmetry by the Ca2 +-activated scramblase TMEM16F or apoptotic scramblase XKR8 profoundly alters the permeation and intracellular accumulation of diverse hydrophobic compounds, including widely used fluorescent probes, while preserving the barrier to membrane-impermeable molecules. Lipid scrambling is sufficient to remodel membrane permeability to lipophilic molecules, alter membrane biophysical properties, and differentially affect their intracellular accumulation, suggesting selective regulation of passive diffusion rather than nonspecific membrane leakage. Physiological lipid scrambling during T cell activation was also accompanied by altered membrane permeability. Moreover, lipid asymmetry regulates the cellular entry of doxorubicin, 17β-estradiol, and all-trans retinoic acid. Together, our findings identify PM lipid asymmetry as a previously unrecognized regulator of membrane permeability and establish a link between membrane organization and molecular transport.
    Keywords:  ROS; TMEM16F; XKR8; hydrophobic molecules; passive diffusion; phospholipid asymmetry; scramblase; scrambling
    DOI:  https://doi.org/10.1002/advs.78435
  10. Nat Cell Biol. 2026 Oct 30.
    Cancer cells have got 'MoVes'.
      
    DOI:  https://doi.org/10.1038/s41556-026-02108-2
  11. Biophys J. 2026 Oct 30. pii: S0006-3495(26)00742-3. [Epub ahead of print]
    Energetics of stalk intermediates elucidated from hydrostatic pressure effects on membrane fusion.
    Daniel Milshteyn, Jacob R Winnikoff, Joel E Morgan, Gonen Golani, Itay Budin.
      Membrane fusion is an essential process in cells that requires a balance of lipid composition to establish biophysical properties conducive to topology changes. During fusion, lipids of opposing membranes must invert and overcome energy barriers associated with forming highly curved stalk and pore intermediates. While theoretical work has modeled the effect of lipid intrinsic curvature on stalk formation, quantifying the relationship experimentally has proven to be a challenge due to the inability to vary lipid curvature without concomitantly changing other properties that affect fusion. Here we address this hurdle by using hydrostatic pressure to modulate lipid intrinsic curvature independently of chemical composition. Using high-pressure stopped-flow fluorimetry, we measured rates of calcium-mediated lipid mixing between populations of vesicles, a process that is strongly inhibited by pressure. We correlated mean lipid intrinsic curvature across pressure with lipid mixing rates by incorporating complementary small-angle x-ray scattering measurements for each individual lipid component. This analysis showed that lipid mixing rates, a proxy for hemifusion, correlated with mean monolayer spontaneous curvature as we varied either lipid composition or pressure. Consistent with previous theoretical models, we find a linear relation between lipid monolayer spontaneous curvature and the energy barrier to lipid mixing; the slope magnitude of this relation supports the stalk hypothesis.
    DOI:  https://doi.org/10.1016/j.bpj.2026.10.025
  12. Cell Rep. 2026 Oct 30. pii: S2211-1247(26)01222-2. [Epub ahead of print]45(11): 118143
    Macrophages iron out cancer cells' vulnerability.
    Alessandro Carrer.
      Surviving despite accumulating toxic metabolites inside the cell is a defining feature of cancer evolution. In the current issue of Cell Reports, Eric Cheung and coworkers identify a mechanism that enables the survival of malignant pancreatic ductal adenocarcinoma (PDAC) cells through the sequestration of reactive iron.1.
    DOI:  https://doi.org/10.1016/j.celrep.2026.118143
  13. J Cell Sci. 2026 Oct 23. pii: jcs.265092. [Epub ahead of print]
    Epithelial-to-mesenchymal transition confers mechanical resistance to hemodynamic stress during hematogenous dissemination.
    Ismael Ortiz, Victor L Dunagan, Joshua D Greenlee, Paul V Taufalele, Maria Lopez-Cavestany, Wenjun Wang, Francois Bordeleau, Michael R King, Cynthia A Reinhart-King.
      Metastatic dissemination requires circulating tumor cells (CTCs) to survive hemodynamic forces, yet the biological traits that enable survival under fluid shear stress (FSS) remain poorly defined. While current paradigms suggest that fluid shear stress (FSS) broadly induces an epithelial-to-mesenchymal transition (EMT), we investigated an alternative mechanism: FSS acts as a mechanical bottleneck that selectively enriches for pre-existing mesenchymal cancer cells by destroying more epithelial-like phenotypes prior to detectable changes in EMT marker expression. Using epithelial and mesenchymal subpopulations isolated from the same cell lines, we exposed single cells in suspension to pulsatile FSS to demonstrate that mesenchymal cells exhibit significantly higher survival rates and lower membrane rupture following pulsatile FSS. Immediate post-shear single-cell analysis revealed stable vimentin-to-cytokeratin (VIM/KRT) ratios in mesenchymal populations, whereas epithelial-like populations showed a selective loss of low-VIM/KRT cells, consistent with immediate mechanical depletion prior to biological induction of EMT. Direct manipulation of EMT states confirmed this causal relationship: TGFβ-induced EMT rescued survival in epithelial cells, while E-cadherin overexpression sensitized mesenchymal cells to mechanical rupture. To validate these findings clinically, we analyzed single-cell RNA-seq data from three patient-derived CTC datasets and found that higher VIM/KRT ratios significantly correlate with increased CTC abundance in the bloodstream. Together, these results demonstrate that hemodynamic forces impose a deterministic mechanical selection pressure on CTCs, identifying epithelial-associated biophysical traits as a primary therapeutic vulnerability in the metastatic cascade.
    Keywords:  Cancer mechanobiology; Circulating tumor cells; Epithelial-mesenchymal transition; Fluid shear stress
    DOI:  https://doi.org/10.1242/jcs.265092
  14. Nat Cancer. 2026 Oct 30.
    ANO6-mediated trogocytosis of cancer-associated fibroblasts promotes pancreatic cancer cell growth and immune suppression.
    Charline Ogier, Akino Mercy Charles Solomon, Elena Bondarenko, Zhijing Wu, Zhen Lu, Quoc Thang Bui, Mayura R Dhamdhere, Yingying Tang, Ludmila Recoules, Alena Klochkova, Linara Gabitova-Cornell, Battuya Bayarmagnai, Diana Restifo, Aizhan Surumbayeva, Débora B Vendramini-Costa, Alexander Y Deneka, Ralph Francescone, Anna C Lilly, Alyssa Sipman, Jaye C Gardiner, Tiffany Luong, Janusz Franco-Barraza, Aleksandr Dolskii, Mariia Dmitrieva, Kathy Q Cai, Margret B Einarson, Emmanuelle Nicolas, Andrei Efimov, Emily Megill, Nathaniel W Snyder, Sven Miller, Mark Andrake, Natalie Phinney, Rolf Brekken, Jérôme Cros, Erica A Golemis, Yunyun Zhou, Bojana Gligorijevic, Corinne Bousquet, Jonathan Soboloff, Serge Y Fuchs, Edna Cukierman, Igor Astsaturov.
      In pancreatic ductal adenocarcinoma (PDAC), the fibroblastic stroma constitutes most of the tumor mass and is remarkably devoid of functional blood vessels, leaving unresolved how PDAC cells obtain essential metabolites and water-insoluble lipids. We find that cancer-associated fibroblasts (CAFs) acquire and transfer lipids from blood-borne particles to PDAC cells through trogocytosis of CAF plasma membranes, a process requiring the CAF-expressed phospholipid scramblase anoctamin 6 (ANO6) to promote PDAC cell survival. Cancer cells and CAFs form synapse-like contacts that induce cytosolic calcium influx in CAFs through Orai channels, activating ANO6 and driving phosphatidylserine exposure on CAF membranes, which initiates trogocytosis and transfer of membrane lipids, including cholesterol, to PDAC cells. This ANO6-dependent phosphatidylserine externalization also supports CAF-mediated immunosuppression of cytotoxic T cells through trogocytosis. Blockade of ANO6 antagonizes tumor growth, partly by disrupting cholesterol delivery to cancer cells, and attenuates immune suppression, identifying ANO6 as a candidate therapeutic target in PDAC.
    DOI:  https://doi.org/10.1038/s43018-026-01265-5
  15. Curr Protoc. 2026 Nov;pii: e70506. [Epub ahead of print]6(11):
    An Optimized Cancer Cachexia Research Model.
    Yushan Wan, Dongfang Li, Chen Chen, Yirong Xu, Bo Yuan, Fangyi Ding, Jian Peng, Zhehan Ma, Huike Zhang, Zhixiang Zhang.
      Cancer cachexia (CC) is a severe and frequently irreversible systemic syndrome marked by significant weight loss, primarily affecting skeletal muscle and adipose tissue. Cachexia occurs in 50% to 80% of patients with cancer and accounts for up to 20% of cancer-related deaths. While various factors interact to induce cachexia, the precise mechanisms underlying this clinical condition are not fully understood. Currently, there are no approved pharmacological treatments for CC, highlighting the urgent need for developing novel experimental models. Here, we developed an optimized protocol for CC research by injecting HT1080 cells into BALB/c nude female mice and observed a body weight loss, fat and muscle decrease, worsened physical performance, and a trend of increased proinflammatory cytokines. © 2026 Wiley Periodicals LLC. Basic Protocol 1: Generation of a cancer cachexia model Basic Protocol 2: Cancer cachexia mice monitoring, behavior test, and sample processing.
    Keywords:  HT1080 tumor model; cachexia; cancer; cell‐line derived xenograft models; tumor; tumor complications
    DOI:  https://doi.org/10.1002/cpz1.70506
  16. Cancer Res. 2026 Oct 29.
    Opening the window for immunotherapy in pancreatic cancer.
    Margaret E Haerr, Katelyn T Byrne.
      KRAS inhibitors (KRASi) are reshaping the treatment of aggressive tumors such as pancreatic ductal adenocarcinoma (PDAC), but it is appreciated that patients will eventually acquire resistance through multiple pathways. To avoid this outcome, there is much effort to identify combination therapies that take advantage of the 'window-of-opportunity' permitted from KRAS inhibition. Tumor cell-intrinsic targeting - as a result of KRASi - results in altered immune and stromal features within the PDAC tumor site that could allow for improved, non-KRAS-targeted, treatment efficacy. Qiang and colleagues investigate the potential of pairing KRASi with immunotherapy - here, an IL-21 mimic - for therapeutic benefit during this 'open window' phase of the KRASi-induced tumor debulking. IL-21 promotes a CD4 T cell response that requires both conventional type 2 dendritic cells (cDC2s) and interferon (IFN)-γ, but not direct tumor cell recognition via major histocompatibility complex (MHC). This work fits in a series of studies highlighting the ability to drive PDAC tumor rejection through cytokines derived from CD4, but not CD8, T cells. These findings highlight a divergence from more 'traditional' immunotherapeutic responses, where cytotoxic CD8 T cells have historically dominated tumor control. Identifying alternative paths towards targeting PDAC may be beneficial - and points towards cell types and modalities that could be leveraged for clinical benefit as the field identifies potential combinatorial partners for KRASi and more patients start receiving these drugs.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-4570
  17. Oncologist. 2026 Oct 28. pii: oyag433. [Epub ahead of print]
    Rethinking Radiation Therapy in the Era of RAS Inhibition for Pancreatic Cancer.
    Michael D Chuong, Eileen M O'Reilly.
      
    Keywords:  KRAS; RAS inhibition; daraxonrasib; pancreatic cancer; radiation therapy; stereotactic body radiation therapy
    DOI:  https://doi.org/10.1093/oncolo/oyag433
  18. Autophagy. 2026 Oct 28. 1-14
    Survey of the human proteostasis network: the autophagy-lysosome pathway.
    Evan T Powers, Suzanne Elsasser, Ee Phie Tan, Christian M Cole, Qiang Xiao, Thomas Stoeger, Xiaojing Sui, Roy D Kurtzbard, Patricia Martínez-Botía, Reese A K Richardson, T Kelly Rainbolt, Ching-Chieh Chou, Vincent B Masto, Beatrice Costa, Bianca Herting, Lynée A Massey, Maher Budron, Rajshri G Iyer, Shijie Wang, Zachary Tokuno, Alejandro Rodriguez Gama, Eric Mockler, Dan Garza, Jason E Gestwicki, Eugenia M Clerico, Judith Frydman, Miguel A Prado, Jeffery W Kelly, Daniel Finley, Ralph A Nixon, Lisa P Elia, Steven Finkbeiner, Richard I Morimoto.
      The condition of having a healthy, functional proteome is known as protein homeostasis, or proteostasis. Establishing and maintaining proteostasis is the province of the proteostasis network, a highly interconnected system of over 3000 components that regulate protein synthesis, folding, localization, and degradation. The proteostasis network is a fundamental functional unit in biology that is essential for cellular health and has direct relevance to many diseases of protein conformation. However, it is not well defined or annotated, hindering its functional characterization in health and disease. In this series of manuscripts, we aim to operationally define the human proteostasis network by providing a comprehensive, annotated list of its components. In the other manuscripts in this series, we survey the components of the proteostasis network that make up (1) the machineries for protein synthesis, protein folding, protein trafficking into and out of organelles, and organelle-specific degradation pathways and (2) the ubiquitin-proteasome system. Here, we have compiled a curated list of over 850 unique high-confidence components of the autophagy-lysosome pathway, the other major protein degradation system in human cells. This resource will facilitate the rigorous investigation of autophagy-lysosome pathway dysfunction as a driver of proteostasis imbalance in aging and disease.
    Keywords:  Aging; annotation; degradation; lysosomal catabolism; neurodegenerative disease; systems
    DOI:  https://doi.org/10.1080/15548627.2026.2741038
  19. Methods Mol Biol. 2027 ;3085 157-172
    Visualization of Disseminated Tumor Cells and Metastatic Outgrowth in the Lung at Single Cell Resolution via Intravital Imaging.
    Katherine Dalton, John S Condeelis, David Entenberg, Lucia Borriello.
      Most cancer-related deaths are due to metastases. These metastases originate from disseminated tumor cells (DTCs) that detach from the primary tumor and spread to distant organs, where they proliferate and lead to metastatic lesions. Across all cancer types, one of the most frequent sites of metastasis is the lung. Thus, targeting DTCs in the lung would represent a promising therapeutic strategy to prevent and block metastatic relapse. Despite many advances, the biology of DTCs is still largely unknown. This is because technologies able to detect single DTCs in preclinical animal models are lacking. High-resolution intravital imaging has become a powerful tool for understanding the biological process of cancer metastasis. Indeed, recent advances enable direct visualization of DTCs at single-cell resolution in an intact lung. We present here a method for intravital imaging DTCs in the lung through a surgically implanted optical imaging window, called Window for High-Resolution Imaging of the Lung (WHRIL). The WHRIL allows longitudinally tracking the fate of each individual DTC in living lungs for weeks, through all stages of metastatic seeding, including tumor cell arrival; extravasation; growth and progression to micrometastases. The WHRIL will allow us to elucidate the mechanisms of metastasis and other lung diseases, such as lung fibrosis.
    Keywords:  Dormancy; Intravital imaging; Lung; Metastasis
    DOI:  https://doi.org/10.1007/978-1-0716-5591-7_10
  20. Nat Cell Biol. 2026 Oct 28.
    Motile vesicles (MoVes) are a cancer cell migration-associated extracellular vesicle population.
    Thupten Tsering, Amélie Nadeau, Masoud Ghasemi, Felippe Mousovich-Neto, Gabriel Tobias, Yunxi Chen, Laura Kienzle, Kyle Dickinson, Noélie Douanne, Inna Serganova, Roberta Zappasodi, Irina Matei, David Lyden, Julia V Burnier.
      Migrating cancer cells release diverse extracellular vesicles (EVs) that carry cargo capable of influencing tumour progression and intercellular communication. However, the mechanisms by which intracellular components are incorporated into EVs remain poorly understood. Here we identify and characterize a previously undescribed population of large EVs (2-5 μm), termed motile vesicles (MoVes), that are generated during active cancer cell migration and associated with epithelial-mesenchymal transition. Comparative analyses across EV populations show that MoVes display distinct ultrastructural features, molecular composition and sedimentation behaviour. Live-cell imaging and scanning electron microscopy reveal that MoVes arise from trailing-edge retraction during mesenchymal migration and are actively shed by cancer cells but rarely by non-transformed cells. MoVes contain genomic DNA spanning the genome of the parent cell, recapitulating its mutational landscape, as well as organelles and proteins associated with epithelial-mesenchymal transition. Moreover, MoVes-associated mitochondrial cargo can enhance oxidative phosphorylation in recipient cells. Together, these findings identify MoVes as a cancer cell migration-associated EV population capable of disseminating genomic DNA and organelles.
    DOI:  https://doi.org/10.1038/s41556-026-02097-2
  21. Bio Protoc. 2026 Oct 20. 16(20): e5849
    A Dissociation-Based Seahorse XF Workflow for Quantifying Averaged Bioenergetics in Anchorage-Independent Cancer Cell Clusters.
    Ranae Lindeque, Jacobus L Visagie, Belinda R Fouché, Christiaan F Labuschagne.
      Cell clustering during anchorage-independent growth (AIG) is a key hallmark of malignant progression, supporting survival under detachment during metastatic dissemination. However, bioenergetic profiling of cell clusters grown under AIG conditions remains technically challenging, in part because of steep nutrient and oxygen gradients and irregular cell cluster shapes that complicate Seahorse XF assay normalization. Here, we present a dissociation-based Seahorse XF96/XF Pro method that enables high-throughput quantification of the average bioenergetic state of anchorage-independent cancer cell clusters. In this workflow, clusters generated in ultra-low adherent plates are enzymatically and mechanically dissociated into a single-cell suspension immediately prior to Seahorse XF Mito Stress Test analysis on poly-D-lysine-coated 2D microplates. This approach ensures that all viable cells throughout each cluster contribute equally to oxygen consumption rate (OCR) measurements and reduces the need for complex post hoc normalization. We further apply this workflow to an in vitro metastasis model in which A549 lung cancer cells are studied as attached, detached (anchorageindependent), and reattached populations, mimicking primary tumor cells, circulating/clustered cells, and secondary lesions, respectively. Detached cells exhibit reduced mitochondrial membrane potential and diminished basal and maximal OCR, whereas reattached cells largely restore membrane potential and respiratory capacity to levels comparable to attached cells, demonstrating that detachment-induced mitochondrial dysfunction is reversible upon reattachment. These findings align with previous work showing that anchorage-independent and clustered cancer cells undergo reversible metabolic reprogramming, including suppression of oxidative metabolism, engagement of reductive pathways to support redox homeostasis, and altered ROS handling to facilitate metastatic colonization. Collectively, this dissociation-based Seahorse workflow provides a practical and accessible platform to interrogate metabolic adaptations to anchorage-independent growth and cell clustering and identify bioenergetic vulnerabilities of metastasis-relevant cancer cell states. Key features • Dissociation-based Seahorse XF Mito Stress Test enabling per-cell bioenergetic profiling of anchorage-independent cancer cell clusters grown in ultra-low adherent plates. • Overcomes structural heterogeneity by enzymatically dissociating clusters into single-cell suspensions immediately before analysis, ensuring each viable cell contributes equally to OCR measurements. • Compatible with adherent monolayer, anchorage-independent, and reattached cell populations, enabling direct bioenergetic comparison across conditions that model primary tumor, circulating, and metastatic colonization states. • Validated in the A549 lung adenocarcinoma cell line; includes PDL coating, in-house DMEM preparation, and BAM15 concentration optimization steps adaptable to other cancer cell lines.
    Keywords:  Anchorage-independent growth; Cancer cell clusters; Mitochondrial respiration; Oxygen consumption rate (OCR); Seahorse XF Mito Stress Test
    DOI:  https://doi.org/10.21769/BioProtoc.5849
  22. medRxiv. 2026 Oct 07. pii: 2026.10.02.26364030. [Epub ahead of print]
    Integrated single-cell and proteomic profiling of pancreatic neoplasia identifies tissue markers that outperform established diagnostic markers in distinguishing cancer from precursor lesions.
    Thoa T Tran, Phuong-Uyen Nguyen-Hoang, Johannes F Fahrmann, Duy Truong Pham, Huy Bui, Loan Bui, C Max Schmidt.
      Pancreatic ductal adenocarcinoma (PDAC) arises within an extensively remodeled microenvironment, yet tissue markers that distinguish invasive carcinoma from precursor lesions remain limited. Integrating four single-cell RNA-sequencing atlases comprising 324,662 cells from 26 patients, we identified cancer-associated fibroblast expansion, accumulation of C1QA+ immunoregulatory macrophages, and depletion of a dendritic-cell compartment expressing plasmacytoid markers. Fibroblasts were enriched for extracellular-matrix and PI3K-AKT programs and macrophages for an antigen-presentation program. We then examined the protein-level correlates of these populations in a tissue proteomic reference framework of 356 samples spanning non-diseased pancreas, normal-adjacent tissue, low- and high-grade intraductal papillary mucinous neoplasms (IPMNs), IPMN-associated invasive carcinoma, and PDAC, prioritizing proteins that changed monotonically across the six histopathologic reference groups or marked tumor-enriched cell types. Despite depletion of plasmacytoid dendritic cells, the principal source of type I interferon, the interferon-stimulated protein ISG15, expressed by both fibroblasts and macrophages, increased monotonically toward PDAC. In exploratory cross-validated benchmarking of PDAC versus low- and high-grade IPMN, excluding IPMN-associated invasive carcinoma (145 versus 56 samples), CATB+EPIPL achieved an AUC of 0.98, with a sensitivity of 92% at an achieved specificity of 92%, exceeding protein-abundance models of diagnostic IHC-associated markers (S100P+IMP3+maspin+MSLN, 0.79) and refitted published IPMN-progression combinations (≤0.91). Against non-diseased pancreas, candidate and comparator panels performed similarly (AUC 0.99-1.00). These biologically informed tissue protein panels warrant independent validation, including immunohistochemical evaluation of EUS-guided fine-needle biopsy specimens and measurement in blood.
    DOI:  https://doi.org/10.64898/2026.10.02.26364030
  23. bioRxiv. 2026 Sep 02. pii: 2026.08.28.747948. [Epub ahead of print]
    Bacterial Peptidoglycan Extends Lifespan by Activating Lysosomal Activity through V-ATPase Binding.
    Herui Fu, Jia Tie, Yan Zhou, Xin Wang, Zhao Shan, Bin Qi.
      Lysosomal dysfunction is a hallmark of aging, yet whether microbial components actively regulate this organelle to influence longevity remains unknown. Here, we identify bacterial peptidoglycan (PGN), a major cell wall component degraded by host lysozyme, as an evolutionarily conserved activator of lysosomal function that extends lifespan in both C. elegans and mice. We show that aging leads to an intestinal decline in lysozyme expression, which impairs bacterial cell-wall digestion and results in systemic PGN deficiency. Late-life PGN supplementation (starting at 18 months of age) significantly prolongs mouse lifespan and improves healthspan. Mechanistically, PGN localizes to lysosomes and directly binds V-ATPase subunits, enhancing ATP hydrolysis activity and promoting lysosomal acidification. This effect is abolished by V-ATPase inhibition (bafilomycin A1) or genetic disruption of lysosomal components ( cup-5 and vha-12 mutants), confirming that functional V-ATPase is strictly required for lysosomal function and the longevity benefit. Importantly, PGN restores lysosomal acidification in aged cells, alleviates cellular senescence markers, and improves multiple hallmarks of aging including locomotion and muscle integrity. Collectively, these findings reveal an evolutionarily conserved mechanism whereby hosts exploit bacterial cell wall components to maintain cellular homeostasis, establishing a gut microbiome-lysosome-longevity axis with implications for microbiome-based anti-aging interventions.
    Highlights: Aging reduces intestinal lysozyme activity, depleting systemic PGN bioavailabilityPGN binds V-ATPase subunits, enhancing ATP hydrolysis and lysosomal acidificationBacterial PGN supplementation extends lifespan and improves healthspanPGN maintains multi-tissue lysosomal homeostasis and reduces cellular senescence during aging.
    DOI:  https://doi.org/10.64898/2026.08.28.747948
  24. Autophagy. 2026 Oct 26. 1-26
    A guide to autophagy-dependent cell death: concepts, criteria, and mechanisms.
    Lingjun Meng, Mingran Dai, Xinyue Zhang, Rui Kang, Daolin Tang, Ning Liu, Lianyue Guan, Liang Han.
      Macroautophagy (hereafter referred to as autophagy) is generally regarded as a cytoprotective process that maintains cellular homeostasis through intracellular recycling and metabolic adaptation. However, under certain conditions, autophagic machinery can contribute directly to cell death. Defining when autophagy functions as a cause rather than a consequence of cellular demise remains a major challenge and complicates the concept of autophagy-dependent cell death (ADCD). Experimental studies indicate that ADCD can occur through multiple mechanisms, including excessive self-digestion, autophagy-dependent lysosomal injury, selective autophagy-mediated degradation of critical cellular components, and specialized death programs such as autosis. These processes intersect extensively with apoptosis, necroptosis, ferroptosis, and pyroptosis, placing ADCD within a broader network of regulated cell death pathways. Evidence from cancer, neurodegenerative, cardiovascular, and inflammatory diseases further suggests that ADCD contributes to pathogenesis and may provide therapeutic opportunities. In this review, we discuss the criteria for defining ADCD, the molecular mechanisms underlying its execution, its interactions with other cell death pathways, and its relevance to human disease. Together, we propose a practical framework for distinguishing bona fide ADCD from cell death merely accompanied by autophagy and provide guidance for establishing autophagy as a causal component of the death process.Abbreviations: AACD: autophagy-associated cell death; ADCD: autophagy-dependent cell death; ADF: autophagy-dependent ferroptosis; ATP: adenosine triphosphate; ATPase: adenosine triphosphatase; AUTACs: autophagy-targeting chimeras; BH3: BCL2 homology 3; CAR-T: chimeric antigen receptor T; cGMP: cyclic guanosine monophosphate; CMA: chaperone-mediated autophagy; DAMPs: damage-associated molecular patterns; DHA: dihydroartemisinin; ER: endoplasmic reticulum; ER-phagy: endoplasmic reticulum-selective autophagy; H2O2: hydrogen peroxide; HIV-1: human immunodeficiency virus type 1; I/R: ischemia-reperfusion; LMP: lysosomal membrane permeabilization; MTOR: mechanistic target of rapamycin kinase; PUFAs: polyunsaturated fatty acids; RHIM: receptor-interacting protein homotypic interaction motif; ROS: reactive oxygen species; sGC: soluble guanylate cyclase; SGLT2: sodium-glucose cotransporter 2; TCR-T: T-cell receptor-engineered T; UPR: unfolded protein response.
    Keywords:  Apoptosis; autophagy; autosis; disease; ferroptosis; regulated cell death
    DOI:  https://doi.org/10.1080/15548627.2026.2753812
  25. Cell Death Dis. 2026 Oct 27. pii: 916. [Epub ahead of print]17(1):
    Autophagy and intratumoral bacteria abundance influence the prognosis of patients with pancreatic carcinoma.
    Yifan Zhang, Toohina L Gobin, Zhenhua Huang, Bingwen Miao, Roma Kurilov, Haitao Sun, Christine Tjaden, Ulrike Heger, Thilo Hackert, Ulf Hinz, Michael Schaefer, Frank Bergmann, Christoph Springfeld, Sadaf S Mughal, Benedikt Brors, Patrick Schaal, Bachar Cheaib, Danilo Licastro, Valerio Iebba, Franco Fortunato.
      The biological and clinical significance of the intratumoral microbiota in pancreatic ductal adenocarcinoma (PDAC) remains poorly defined. Using oncogenic Kras-driven mouse models of pancreatic tumorigenesis and human pancreatic tissue from patients with non-metastatic PDAC treated with neoadjuvant (n = 62) or adjuvant therapy (n = 101), along with samples from intraductal papillary mucinous neoplasms (IPMN, n = 24), chronic pancreatitis (CP, n = 33), and healthy donors (n = 9), we determined tissue lipopolysaccharide (LPS), 16S rRNA sequencing, high-resolution quantitative multiplex immunofluorescence of autophagy markers (LAMP2, LC3B) and LPS, 16S rRNA fluorescence in situ hybridization (FISH) staining, and TLR4 signaling. In KrasCre mice, we identified significant bacterial accumulation in the pancreas, indicated by elevated LPS, increased FISH signals, enhanced TLR4 signaling, and activation of autophagy. Administration of exogenous LPS further amplified autophagy and TLR4 signaling, supporting a mechanistic link between microbial sensing and autophagy. In human tissue, both adjuvant and neoadjuvant PDAC samples showed significantly increased bacterial alpha- and beta diversity compared with controls, while CP showed a similar enrichment pattern that IPMN lacks; the underlying microbial diversity differs fundamentally across these conditions. Increased LPS levels, along with elevated autophagy markers and abundant FISH-positive bacteria, support the presence of intratumoral bacteria. Across four independent transcriptomic datasets, PDAC samples showed elevated expression of bacteria-associated pathways (including TLR4) and autophagy-related genes. Clinically, higher autophagy-associated LAMP2-LC3B colocalization and increased densities of FISH-positive cells were independently associated with prolonged survival in both adjuvant and neoadjuvant or combined PDAC patients. Collectively, these findings link intratumoral microbial enrichment to increased autophagy-associated signaling and improved patient outcomes, suggesting that microbial signals within the tumor microenvironment were associated with favorable survival.
    DOI:  https://doi.org/10.1038/s41419-026-09256-1
  26. Methods Mol Biol. 2027 ;3085 173-189
    Employing High-Resolution Microscopy to Identify Dormant Disseminated Tumor Cells in the Brain.
    Cristina Megino-Luque, Katarzyna Cialowicz, Jose Javier Bravo-Cordero.
      Metastatic dormancy in the brain remains a major clinical problem and a biological challenge to study, as disseminated tumor cells (DTCs) can persist undetectable in a non-proliferative state for years before metastatic relapse. Here, we described an integrated methodological workflow to identify, isolate, and functionally characterize dormant brain metastatic clones taking advantage of high-resolution microscopy including light-sheet and intravital two-photon microscopy. Here, we present a method to generate dormant brain metastatic clones combined with high-resolution imaging for characterization of their dormant state. Briefly, tumor cells are delivered to the brain via intracarotid injection, and light-sheet microscopy is performed for whole-brain visualization of disseminated tumor cells. Individual clones are isolated and screened ex vivo by employing organotypic brain culture, where dormancy-associated phenotypes are assessed by multiphoton imaging. To validate their dormant behavior in vivo, clones exhibiting delayed outgrowth are then reintroduced via intracarotid injection, and brain tissue is analyzed ex vivo via multiphoton imaging. Finally, intracranial intravital imaging enables real-time visualization of dormant tumor cells and their interactions with the brain microenvironment. This pipeline provides a reproducible approach to isolate dormant clones and study brain metastatic dormancy, highlighting the versatility of multiphoton imaging for dynamic analysis of dormant DTCs in the brain.
    Keywords:  Brain metastasis; Disseminated tumor cells; High-resolution intravital imaging; Light-sheet microscopy; Organotypic brain culture; Tumor cell dormancy; Two-photon microscopy
    DOI:  https://doi.org/10.1007/978-1-0716-5591-7_11
  27. J Biol Chem. 2026 Oct 28. pii: S0021-9258(26)02578-0. [Epub ahead of print] 113706
    Influence of hemin on biophysical properties of membranes.
    Zoi Laspa, Nele Jarnot, Luca Andronico, Taras Sych, Anne-Katrin Rohlfing, Nilu Gone, Tatsiana Castor, Thanigaimalai Pillaiyar, Stefan Laufer, Erdinc Sezgin, Meinrad Paul Gawaz.
      Hemin released from erythrocytes activates platelets through both receptor-dependent and receptor-independent mechanisms. While lower hemin concentrations predominantly activate the immune receptor tyrosine-based activation motif (ITAM) signaling via glycoprotein VI (GPVI) and C-type lectin-like receptor 2 (CLEC-2), higher concentrations induce pronounced receptor-independent cellular alterations, including loss of mitochondrial membrane potential, generation of reactive oxygen species (ROS), lipid peroxidation, and plasma membrane fragmentation. However, the mechanism of receptor-independent effect of hemin is still unclear. To test whether hemin can directly interact with and remodel membranes, we employed giant unilamellar vesicles composed of different lipid compositions as model membrane systems and treated them with unlabeled and fluorescently-labeled hemin. We analyzed how hemin treatment alters membrane biophysical properties using fluorescence microscopy, spectral imaging, fluorescence correlation spectroscopy (FCS), and flow cytometry. We found that fluorophore-labeled hemin can be directly visualized in lipid bilayers. Furthermore, high concentrations of hemin increased membrane order in all lipid compositions tested. The strongest effect was observed in more fluid membranes, whereas highly ordered membranes were less affected. Interestingly, in cholesterol-containing membranes, even the lowest hemin concentration produced changes comparable to those induced by the highest concentration, suggesting that cholesterol enhances the influence of hemin on lipid bilayers. Finally, we observed strong increase in permeability of membranes upon hemin treatment. Overall, our findings demonstrate that hemin can directly accumulate in lipid membranes, increase membrane order, reduce membrane fluidity and alter membrane integrity, resulting in enhanced membrane permeability.
    Keywords:  Fluorescent correlation spectroscopy (FCS); giant unilamellar vesicles; hemin; lipid bilayer; membrane biophysics; membrane order; permeability; plasma membrane; platelet
    DOI:  https://doi.org/10.1016/j.jbc.2026.113706
  28. Dig Liver Dis. 2026 Oct 28. pii: S1590-8658(26)00986-2. [Epub ahead of print]
    Optimizing first-line NALIRIFOX and exploring the role of the microbiota in second-line pancreatic cancer treatment: the PRODIGE 105-GERCOR 116 PANORAMIX trial.
    Matthieu Delaye, Marc Hilmi, Paul Gougis, Christelle d' Engremont, Julie Lavole, Pauline Vaflard, Olivier Bouché, Jean-Baptiste Bachet, Nicolas Williet, Brice Chanez, Gaël Roth, Victoire de Lastours, Victoire Cardot-Ruffino, Marie-Line Garcia Larnicol, Dewi Vernerey, Cindy Neuzillet.
       BACKGROUND: Treatment of metastatic pancreatic ductal adenocarcinoma (mPDAC) relies on chemotherapy. Although NALIRIFOX (Nal-IRI, oxaliplatin, 5-fluorouracil [5-FU], leucovorin) improves survival, cumulative toxicity may limit duration, and maintenance strategies remain unexplored. Intratumoral microbiota, particularly Gammaproteobacteria expressing cytidine deaminase, may inactivate gemcitabine and contribute to resistance, a process potentially reversible with antibiotics. We aim to assess maintenance 5-FU after NALIRIFOX and microbiota modulation with fluoroquinolones to enhance gemcitabine sensitivity.
    METHODS: PANORAMIX is a multicenter, proof-of-concept, non-comparative phase II trial conducted across 18 French centers with two sequential randomizations. After 8 cycles of NALIRIFOX, patients with mPDAC are randomized (2:1) to either maintenance 5-FU or continuation of NALIRIFOX (Step 1). In Step 2, patients are randomized (1:1) to ciprofloxacin or placebo combined with gemcitabine-based chemotherapy (± paclitaxel). A total of 108 and 92 patients will be enrolled in Steps 1 and 2, respectively. Main inclusion criteria include age >18 years, confirmed mPDAC, ECOG performance status 0-1, and adequate organ function. Primary endpoints are 6-month progression-free survival (Step 1) and 6-month overall survival (Step 2). Secondary endpoints include toxicity and quality of life.
    CONCLUSIONS: This two-step trial will address key therapeutic questions in mPDAC and support translational research.
    Keywords:  Antibiotics; Maintenance; Microbiota; NALIRIFOX; Pancreatic cancer
    DOI:  https://doi.org/10.1016/j.dld.2026.10.006
  29. Glycobiology. 2026 Sep 29. pii: cwag100. [Epub ahead of print]36(11):
    scGlycoAI: machine learning analysis of single-cell glycan and RNA sequencing data for cell-type annotation and malignancy-associated glycan discovery.
    Dinh Xuan Tuan Anh, Hiroaki Tateno.
      Single-cell glycan and RNA sequencing (scGR-seq) enables characterization of cellular glycan heterogeneity. Here, we present scGlycoAI, an interpretable machine learning framework that integrates scGR-seq data for glycan-centered biological discovery. Using lectin-binding profiles as input, scGlycoAI employs hierarchical machine learning to accurately classify cell types and subtypes within complex tumor microenvironments. Applied to pancreatic ductal adenocarcinoma (PDAC) datasets, scGlycoAI achieved an overall eight-class classification accuracy of 90.3% under leave-one-patient-out validation using glycan features alone. These results demonstrate that glycan signatures, despite their lower dimensionality compared with transcriptomic profiles, are sufficient for robust cell-type annotation and represent cell-type-specific molecular signatures. Feature importance analysis identified PVL lectin binding, which reflects recognition of sialylated and/or GlcNAc-containing glycans, as a key feature of aggressive cancer states. A neural-network model combined with SHAP-based interpretation further revealed that elevated PVL binding was associated with transcriptional programs linked to epithelial-mesenchymal transition, KRAS signaling, extracellular matrix remodeling, and inflammatory responses. Higher expression of the PVL-associated gene signature was associated with poorer overall survival in the TCGA pancreatic adenocarcinoma cohort. Collectively, these findings suggest that glycan-based machine learning enables accurate cell classification while providing biological insights into malignancy-associated glycan states at single-cell resolution. This framework provides a foundation for glycan-centered biomarker discovery and glycan-targeted therapeutic development.
    Keywords:  cell-type annotation; machine learning; pancreatic ductal adenocarcinoma; scGR-seq; single-cell glycomics
    DOI:  https://doi.org/10.1093/glycob/cwag100
  30. Methods Mol Biol. 2027 ;3089 251-264
    Quantitative Mapping of Organelle Positioning in Cultured Cells Using Semi-Automated Image Analysis Pipeline.
    Katerina Jerabkova-Roda, Vincent Hyenne, Jacky G Goetz.
      Subcellular architecture is tightly controlled and contributes to the maintenance of cell homeostasis. Organelles are regulated in size, shape, number, and position, all of which respond to changes in the extracellular environment. Lysosomes are of particular interest as they integrate various functions in the cells (nutrient sensing, metabolism, cell migration, and adhesion), serving as signaling hubs. Their function is tightly linked to their subcellular position, and deregulation of lysosome homeostasis leads to several diseases, including cancer. Therefore, methods allowing precise analysis of organelle subcellular distribution can aid in fundamental, diagnostic, and therapeutic approaches. Here, we provide a versatile image analysis pipeline using ImageJ and CellProfiler. This workflow allows for the quantification of subcellular lysosome distribution in living and fixed melanoma cells, and it is applicable to other subcellular compartments and to various cell types.
    Keywords:  CellProfiler; ImageJ; Immunofluorescence; Live-cell imaging; Lysosomes; Organelle positioning; Radial distribution; Subcellular architecture
    DOI:  https://doi.org/10.1007/978-1-0716-5619-8_17
  31. bioRxiv. 2026 Oct 06. pii: 2026.09.30.755456. [Epub ahead of print]
    Lipid Defect Analyzer (LipiDeA): A Python Framework for Quantifying Lipid Packing Defects in Curved and Neutral Lipid-Containing Membranes.
    Arvin Nazari, Yu-Ming M Huang.
      Lipid packing defects expose hydrophobic regions of membranes and influence protein-membrane recognition, membrane remodeling, and lipid sensing. Quantitative analysis of these defects remains challenging for heterogeneous membranes with strong curvature, mixed bilayer and monolayer organization, and substantial neutral-lipid content. Here, we present Lipid Defect Analyzer (LipiDeA), an open-source Python framework for quantitative analysis of lipid packing defects in complex membrane systems. LipiDeA reconstructs membrane surfaces using triangulated meshes that adapt to local membrane geometry and identifies packing defects from lipid coverage of the reconstructed surface. The framework further classifies bilayer and monolayer regions, resolves defect properties according to local membrane curvature, and distinguishes defects associated with phospholipid tails and neutral lipids. Validation using planar and buckled DPPC bilayers reproduced previously reported packing defect constants and showed that defects preferentially occur in positively curved membrane regions. Application to lipid-droplet-like membranes revealed composition- and topology-dependent defect formation, with the largest defects occurring during the transition from bilayer-dominated to monolayer-containing membranes and distinct defect properties for DAG- and TAG-containing systems. These results highlight the importance of local membrane geometry and composition in determining lipid packing defects.
    Keywords:  Hydrophobic exposure; Lipid organization; Membrane analysis; Membrane biophysics; Surface reconstruction
    DOI:  https://doi.org/10.64898/2026.09.30.755456
  32. Mol Cancer Ther. 2026 Oct 29.
    Dual targeting of DHODH and SLC29A1 overcomes metabolic resistance and enhances antitumor immune responses in PDAC.
    Rajgopal Govindarajan, Shivam Vij, Arnav Joshi, Sandip M Vibhute, Chengyu Gao, Reena Shakya, Jeffrey Patrick, Chad E Bennett, Christopher C Coss, Meixiao Long, Mitch A Phelps, Shafia Rahman, Fredrik I Thege.
      Pancreatic ductal adenocarcinoma (PDAC) displays profound metabolic plasticity that sustains rapid proliferation through heightened demands for nucleotide biosynthesis. Here, we characterize HOSU-53 (JBZ-001), a dihydroorotate dehydrogenase (DHODH) inhibitor demonstrating potent antitumor activity in preclinical PDAC models and define the metabolic determinants of sensitivity and resistance. In HOSU-53-sensitive PDAC cells, DHODH inhibition induces G₂/M cell cycle arrest and triggers apoptotic and ferroptotic cell death. In contrast, resistant cells evade metabolic stress by activating compensatory nucleoside transport and macropinocytosis pathways. Integrated functional and genetic analyses reveal that nucleoside salvage via the equilibrative nucleoside transporter SLC29A1 constitutes a dominant resistance mechanism, enabling uptake of extracellular nucleosides to bypass de novo pyrimidine synthesis. Unbiased metabolomic profiling demonstrates that combined inhibition of DHODH and SLC29A1 precipitates mitochondrial dysfunction, oxidative stress, lipid remodeling, and amino acid depletion, culminating in metabolic collapse and energetic failure. Consistent with these findings, dual inhibition markedly suppresses tumor growth and metastatic burden in xenograft and syngeneic orthotopic PDAC models while reprogramming the tumor microenvironment toward a pro inflammatory, immune activated state. Furthermore, co targeting DHODH and SLC29A1 synergizes with anti-PD 1 immune checkpoint blockade, enhancing immunotherapeutic efficacy. Together, these results establish dual targeting of de novo and salvage nucleotide metabolism as a compelling strategy to overcome metabolic resistance, remodel tumor-immune interactions and potentiate therapeutic responses in PDAC.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-26-0461
  33. bioRxiv. 2026 Oct 07. pii: 2026.10.06.757127. [Epub ahead of print]
    The Spliceosome Scaffold Component BCAS2 Promotes Pancreatic Cancer Progression through Weak 5' Splice Site-Dependent Splicing Regulation.
    Ledong Wan, Mei Wang, Yuma Ishigami, Alexander J Kral, Kuan-Ting Lin, Joseph R Merrill, Scott K Lyons, Adrian R Krainer.
      Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies. Dysregulated RNA splicing has emerged as a critical mechanism contributing to PDAC progression. However, whether structural components of the spliceosome regulate oncogenic alternative splicing was not known. Here, we identify the nineteen complex (NTC) component BCAS2/SPF27 as a critical regulator of PDAC progression. Elevated expression of BCAS2 in PDAC is associated with poor patient outcomes. Transcriptomic analyses revealed that BCAS2 specifically regulates alternative exons with weak splice sites. In particular, BCAS2 promotes SOS1 exon 21 inclusion and consequently RAC-signaling activation. Furthermore, splice-switching antisense oligonucleotide (ASO)-mediated skipping of SOS1 exon 21 suppressed PDAC proliferation and migration. Our findings uncover a role of BCAS2 in the regulation of weak splice-site usage and identify the BCAS2-SOS1-RAC signaling axis as a potential therapeutic vulnerability in pancreatic cancer.
    DOI:  https://doi.org/10.64898/2026.10.06.757127
  34. Cell Rep. 2026 Oct 26. pii: S2211-1247(26)01280-5. [Epub ahead of print]45(11): 118201
    RAStoERK: A reference interaction atlas for insights into signaling and disease.
    Georg Vucak, Sebastian Didusch, Leandro Cannizzaro, Ana Santiago, Markus Hartl, Jörg Menche, Manuela Baccarini.
      The RAS/RAF/MEK/ERK pathway has been extensively studied for its roles in physiology and disease, yet a systems-level view of its interplay with the broader cellular context is lacking, limiting insight into paralog-specific roles, mutation-driven rewiring, and cross-pathway integration. To address this, we simultaneously mapped the interactomes of all pathway components and their activating and inactivating mutations, identifying 2,500 high-confidence interactors, 88% of which previously unreported, and generating a high-confidence, comprehensive reference map of the pathway in resting and activated states. The pathway behaves like a "molecular organism" that connects to other signaling complexes, operates from distinct subcellular sites, and integrates into networks relevant to physiology and disease. Dataset exploration uncovers paralog- and mutation-specific interaction signatures and pathway-level crosstalk, including previously unknown connections to mRNA metabolism and WNT signaling. The interactomes available at RAStoERK.univie.ac.at provide a foundational community resource for unbiased discovery, targeted mechanistic studies, and potential therapeutic exploration.
    Keywords:  AP-MS; CP: molecular biology; RAS-RAF-MEK-ERK pathway; cancer signaling; interactome; network biology; oncogenic mutations; pathway crosstalk; protein-protein interactions; proteomics; proximity labeling
    DOI:  https://doi.org/10.1016/j.celrep.2026.118201
  35. Am J Physiol Endocrinol Metab. 2026 Nov 01. 331(5): E562-E571
    Adipocyte lipolysis is a determinant of skeletal muscle size during fasting and feeding.
    Daniel M Marko, Rhea V Vemula, Meghan O Conn, Nazli Robin, Angela M Schmidt, Irena A Rebalka, Jonathan D Schertzer.
      Intermittent fasting (IF) can lower fat mass, but also muscle mass. The mechanisms governing tissue partitioning during fasting remain unclear. During fasting, adipose-derived fatty acids from lipolysis and lipolysis-fueled hepatic ketogenesis maintain blood glucose and systemic energy homeostasis. We hypothesized that impaired lipolysis during fasting would shift substrate provision from adipose to muscle, increasing muscle catabolism during IF. We tested male adipocyte-specific adipose triglyceride lipase knockout (aKO) and littermate floxed-control mice during ad libitum feeding on a 10-wk 5:2 IF protocol consisting of two nonconsecutive 24-h fasts and 5 ad libitum feeding days per week. After 10 wk of IF, aKO mice had lower blood lipids and ketones and lost more lean mass and less fat mass than floxed-control mice when mice were fed a standard control diet and also retained more inguinal white adipose tissue and had lower hindlimb muscle mass when IF was compared with ad libitum feeding. In addition, aKO mice had larger adipocytes, smaller muscle fibers, and increased expression of the atrogene, Atrogin1. We then provided exogenous lipids by feeding an obesogenic high-fat diet (HFD). HFD-fed aKO mice had higher whole body fat oxidation and lower blood lipids and ketones than floxed-controls. Obese HFD-fed aKO mice still had smaller skeletal muscle myofibers and increased muscle atrogene expression despite smaller adipocytes during ad libitum feeding or IF. Therefore, adipocyte ATGL-mediated lipolysis is a determinant of skeletal muscle size, and lower lipolysis influences the balance of fat vs. muscle loss during fasting.NEW & NOTEWORTHY This study demonstrates that adipocyte ATGL is a critical regulator of adipose-muscle metabolic crosstalk. Limiting adipocyte lipolysis through adipose ATGL deletion reduced blood lipid and ketone fuel availability, thereby increasing adipose retention, decreasing skeletal muscle mass and fiber size, and increasing muscle atrogene expression, particularly during intermittent fasting. These findings support a model in which impaired adipocyte lipid mobilization shifts whole body energy demands away from adipose and toward skeletal muscle, promoting muscle catabolism during fasting.
    Keywords:  ATGL; intermittent fasting; lipolysis; obesity
    DOI:  https://doi.org/10.1152/ajpendo.00262.2026
  36. bioRxiv. 2026 Sep 03. pii: 2026.03.09.710634. [Epub ahead of print]
    Cellquant: a vibecoder's guide to image analysis.
    Abani Neferkara, Leah Chaney Winner, Asif Ali, David Pincus.
      Quantitative fluorescence microscopy is central to modern cell biology, yet experimentalists lacking computational expertise have limited ability to extract reproducible measurements from the images they collect. Here we present cellquant , a pipeline to analyze multi-channel fluorescence images that performs cell segmentation, subcellular localization and colocalization analyses, morphometric quantification, and spatial proximity calculations in two or three dimensions. By replacing the requirement for computational expertise with iterative assistance from large language models (i.e., "vibecoding"), cellquant enables experimentalists with any level of coding experience to quantify imaging data. We validate cellquant on stress granule formation in human HCT116 cells and nucleolar reorganization across a temperature gradient in budding yeast. Dimensionality reduction of a 45-feature output from 8,309 yeast cells resolved cell state transitions and revealed subpopulations of non-responders. Because the cellquant interface is text based, the exact command used in any analysis can be recorded and re-executed, generating reproducible quantification with visual quality control and statistical rigor. Code, documentation, and datasets are freely available.
    DOI:  https://doi.org/10.64898/2026.03.09.710634
  37. Proc Natl Acad Sci U S A. 2026 Nov 03. 123(44): e2604066123
    Ionic liquid-mediated cellular loading for whole tumor cell vaccines.
    Danika Rodrigues, Malini Mukherji, Kyung Soo Park, Maithili Joshi, Litsa Kapsalis, Suyog Shaha, Michael Griffith Bibbey, Metecan Erdi, Samir Mitragotri.
      Conventional whole tumor cell cancer vaccines have demonstrated limited clinical success due to insufficient immunogenicity and challenges in adjuvant codelivery, despite their rich antigen repertoire and high patient-specific activity. Here, we introduce a simple, single-step approach to load immunostimulatory CpG oligodeoxynucleotides into tumor cells undergoing immunogenic cell death using an ionic liquid-containing cocktail. Results indicate that these adjuvant-loaded tumor cells (referred to as IL-Vax) enhance the uptake of cell-based vaccines by dendritic cells and their subsequent activation, leading to potent antitumor immunity. IL-Vax offered strong protection against tumor growth in a prophylactic B16F10 melanoma mouse model. Furthermore, IL-Vax synergized with PD-1 blockade to slow tumor growth and extend survival in a therapeutic model. The modularity of IL-Vax enables the loading of different cargos or cargo combinations, which may be conducive for additional tailoring of such vaccines and potentially other cell loading applications.
    Keywords:  cancer vaccine; immunotherapy; ionic liquid; membrane
    DOI:  https://doi.org/10.1073/pnas.2604066123
  38. Clin Transl Med. 2026 Nov;pii: e70848. [Epub ahead of print]16(11):
    Selective AUTAC-mediated ATP7B degradation unlocks cuproptosis vulnerability in pancreatic ductal adenocarcinoma.
    Zihan Zhang, Min Li, Jiale Feng, Jian-Ang Li, Lei Zhang.
      Cuproptosis arises from mitochondrial copper overload, yet how tumour cells evade this metabolic vulnerability remains unclear. We identify ATP7B as the central barrier to cuproptosis in pancreatic ductal adenocarcinoma (PDAC). ATP7B is aberrantly upregulated in PDAC and predicts poor prognosis. Its depletion increases intracellular copper, activates FDX1, DLAT/DLST lipoylation, disrupts tricarboxylic acid (TCA) metabolism, and reinstates cuproptosis in vitro and in vivo. Mechanistically, ATP7B undergoes ZBTB10-driven K63-linked ubiquitination, recognized by NBR1 for selective autophagic degradation. Leveraging this, we developed an ATP7B-targeting autophagy-targeting chimera (ATAUTAC) that promotes ATP7B clearance, amplifies copper-driven mitochondrial metabolic perturbations, triggers cuproptosis, and inhibits tumour growth with favourable tolerability. Notably, ATAUTAC sensitizes PDAC to gemcitabine, overcoming resistance by exposing latent metabolic fragility. These findings establish ATP7B as a mechanistic hub of cuproptosis tolerance and demonstrate that autophagy-based ATP7B degradation is a druggable strategy for copper-dependent tumour eradication. ATAUTAC offers a promising avenue for precision therapy in PDAC and other refractory malignancies.
    Keywords:  ATP7B; cuproptosis; drug development; pancreatic ductal adenocarcinoma; targeted therapies
    DOI:  https://doi.org/10.1002/ctm2.70848
  39. Nat Rev Drug Discov. 2026 Oct 26.
    Nanotherapy targets senescent cells.
    Sarah Crunkhorn.
      
    DOI:  https://doi.org/10.1038/d41573-026-00167-6
  40. Front Aging. 2026 ;7 1971981
    Impaired autophagy and lysosome function in human fibroblast aging.
    Juan José Unzueta-Mendoza, Ian García-Aguirre, Mina Königsberg, Isabel Arrieta-Cruz, Solangy Lizcano-Meneses, Jonathan J Magaña, Adriana Alarcón-Aguilar, Bulmaro Cisneros.
       Background: Human aging is characterized by a progressive, time-dependent deterioration in physiological and cognitive functioning. Aging is driven by an array of interconnected cellular hallmarks, including genomic instability, mitochondrial dysfunction, telomere attrition, epigenetic alteration and dysfunctional autophagy. Autophagy is a cytoprotective (cellular degradation and recycling) pathway that maintains homeostasis during starvation or stress, and whose activity is associated with extended lifespan. This multi-step process comprises autophagosome formation and maturation, autophagosome-lysosome fusion, and cargo degradation. Thus, analysis of autophagy flux is necessary to precisely design therapeutic interventions aimed at restoring autophagy in aging.
    Methods: The autophagy flux was comprehensively analyzed in human skin fibroblasts from donors of different ages (20-96 years old), a cell system that retains age-associated cellular and molecular signatures. The subcellular localization and activity of the master transcription factor of autophagy and lysosome biogenesis, TFEB, was analyzed by confocal microscopy assays and transcriptional expression of TFEB target genes (RT-qPCR) respectively. The autophagy flux was evaluated by monitoring the autophagy markers LC3 and p62 by Western blotting and confocal microscopy analyses, using inhibitor drugs to block autophagy or lysosomal activity. Autophagosome maturation and autophagosome-lysosome fusion were analyzed by colocalizing LC3 with Sintaxin-17 and LC3 with the lysosomal protein LAMP1 respectively, using inhibitor drugs and confocal microscopy assays. The analysis of lysosomal morphology and function was evaluated by lysobrite dye staining and live-cell confocal microscopy analysis.
    Results: The initial stages of autophagy, including activation of TFEB, and autophagosome formation, remained apparently functional in fibroblast aging. In contrast, the rate of both autophagosome maturation and autophagosome-lysosome fusion, as well as the lysosomal function appears to be altered in aged fibroblasts. Specifically, enlarged dysfunctional lysosomes were identified as a hallmark of the fibroblasts of the 96-year-old donor. This lysosomal dysfunction may lead to a reduced ability to degrade canonical autophagy markers, LC3-II and p62, and the accumulation of lipofuscin.
    Conclusion: Overall, the results provide evidence that autophagy flux is impaired at the late stages in aged fibroblasts, specifically in autophagosome maturation and autophagosome-lysosome fusion steps. Furthermore, it was demonstrated that this failure correlates with the presence of enlarged dysfunctional lysosomes. This study underscores the significance of enhancing lysosomal activity to counteract autophagy decline in aging.
    Keywords:  aging; autophagosomes; autophagy flux; fibroblast aging; lysosomes
    DOI:  https://doi.org/10.3389/fragi.2026.1971981
  41. Cancer Metastasis Rev. 2026 Oct 24. pii: 81. [Epub ahead of print]45(4):
    Histopathological growth patterns represent a dynamic biological and clinically-relevant terminus of the metastatic cascade.
    Matthew Dankner, Sébastien Tabariès, Charlotte Girondel, Yasmine Sillis, Peter B Vermeulen, Peter M Siegel.
      The metastatic cascade describes the series of steps by which cancer cells travel from the tumor of origin to a distant site of metastasis. Successful colonization and formation of macrometastases are generally regarded as the terminus of the metastatic cascade. However, a growing body of literature points to the importance of inter- and intra-tumoral heterogeneity during the growth of established metastases, which manifests as distinct histopathological growth patterns (HGPs). HGPs refer to the dynamic interface between cancer cells, stromal cells and parenchymal cells within the metastasis-bearing organ. In several metastatic niches, such as the liver and brain, unique HGPs have been described that reveal aspects of intrinsic disease biology and have important implications for patient survival and therapy response. With emerging technologies, recent studies have revealed spatial insights pertaining to cancer cell-tumor microenvironment interactions at distinct metastatic sites. Herein, we describe the clinical and biological relevance of the dynamic interplay between cancer cells and the native liver or brain cells in the context of metastases from adult solid tumors. When applicable, we draw comparisons between metastatic sites and identify common themes by which HGP and components of the tumor microenvironment can be exploited for therapeutic intervention.
    Keywords:  Brain metastases; Histopathological growth pattern; Liver metastases; Metastatic cancer; Metastatic cascade
    DOI:  https://doi.org/10.1007/s10555-026-10389-0
  42. Cancer Immunol Res. 2026 Oct 28. OF1-OF2
    Oncogenic KRAS Suppresses IFNγ Signaling in Tumor Cells.
    Stephanie K Dougan.
      In this issue, Chen and colleagues show that MHC class II expression by pancreatic ductal adenocarcinoma (PDAC) malignant cells is a robust biomarker of both local production of IFNγ from lymphocytes and intact IFNγ signaling. RAS pathway inhibition can restore malignant cell IFNγ responsiveness in some patients, and malignant cell MHC class II expression may indicate which patients could further benefit from immunotherapy. See related article by Chen et al., p. XX .
    DOI:  https://doi.org/10.1158/2326-6066.CIR-26-1107
  43. Dev Cell. 2026 Oct 30. pii: S1534-5807(26)00365-5. [Epub ahead of print]
    An ECM-driven mechanotransductive signaling module promotes NKX6.1-enriched human pancreatic progenitor formation.
    Jia Zhao, Shenghui Liang, Haoning Howard Cen, Robert K Baker, Timothy J Kieffer.
      Efficient generation of insulin-producing beta cells from human pluripotent stem cells requires precise specification of PDX1+/NKX6.1+ pancreatic progenitors, a developmental bottleneck that limits lineage fidelity and reproducibility across differentiation platforms. Here, we identify a previously unrecognized extracellular matrix (ECM)-coupled mechanotransductive module that promotes an NKX6.1-enriched pancreatic progenitor state. Transcriptomic profiling and targeted perturbations revealed that isoxazole-9 (ISX-9) engages a collagen-TRPV-Ca2+-Ca2+/calmodulin-dependent protein kinase II (CaMKII) axis, linking ECM sensing to NKX6.1 regulation. Collagen I/IV supplementation and TRPV agonists phenocopied ISX-9, whereas inhibition of integrin α1/α2, TRPV channels, or CaMKII abrogated its effect. Downstream of CaMKII, relief of histone deacetylase 4 (HDAC4)-mediated myocyte enhancer factor 2 (MEF2) repression contributed to NKX6.1 regulation, while increased cycling of NKX6.1+ cells accompanied expansion of the progenitor pool. Temporally restricted activation of this module by ISX-9 increased PDX1+/NKX6.1+ progenitors and yielded stem cell-derived islets (SC-islets) with enhanced glucose responsiveness. These findings provide a basis for optimizing microenvironmental cues to improve the generation of NKX6.1-enriched pancreatic progenitors and functional SC-islets.
    Keywords:  ECM; SC-islets; human pluripotent stem cells; mechanotransduction; pancreatic progenitors
    DOI:  https://doi.org/10.1016/j.devcel.2026.10.003
  44. Sci Adv. 2026 Oct 30. 12(44): eaeg5364
    Augmenting intercellular mitochondrial transfer for tissue repair and rejuvenation.
    John Soukar, Kayli Jones, Natalie M Garza, Valeria Duran Salas, Shounak Roy, Vishal M Gohil, Akhilesh K Gaharwar.
      Cells exhibit innate reparative communication, enabling the exchange of bioactive molecules and, in some cases, entire organelles. Harnessing this endogenous process of intercellular organelle transfer represents an emerging therapeutic paradigm for restoring cellular function in diseases driven by organelle dysfunction. Mitochondrial transfer has gained prominence for its ability to restore bioenergetic capacity, mitigate oxidative stress, and rescue metabolic function in cells with impaired mitochondrial activity. Given that genetic or acquired defects in mitochondrial function are associated with diverse pathologies, including neurodegeneration, cardiovascular diseases, metabolic disorders, skeletal muscle defects, immune dysregulation, and age-associated decline, mitochondrial transfer offers broad therapeutic potential. Mitochondrial transfer seeks to deliver functional mitochondria to injured cells to reestablish metabolic competence. However, insufficient organelle trafficking and limited control over transfer dynamics remain critical barriers to clinical translation. Recent biotechnological developments aimed at enhancing donor-recipient connectivity, increasing mitochondrial availability, and modulating transfer machinery have begun to address some of these key challenges. This review highlights recent advances in mitochondrial transfer bioengineering, emerging therapeutic applications, and key challenges that must be resolved to enable clinical deployment.
    DOI:  https://doi.org/10.1126/sciadv.aeg5364
  45. Biochem Biophys Rep. 2026 Dec;48 102845
    Addressing complex autofluorescence signatures in solid tissue samples to enhance full spectrum flow cytometry of non-immune cells.
    Christina Gkantsinikoudi, Manuela Terranova-Barberio, Neil Dufton.
      FSFC is an emerging technology that can greatly enhance our understanding of the single-cell proteomic landscape. We demonstrate that this application is applicable to cells derived from solid tissues which have traditionally been hampered by their complex autofluorescence signatures and lack of optimized tools for non-immune cells. We present a protocol and discuss key controls that minimize the impact of unmixing errors, enabling us to resolve multiple EC subpopulations isolated from different tissues in models of chronic tissue injury.
    Research topics: vascular biology, cell heterogeneity, full spectrum flow cytometry.
    Keywords:  Autofluorescence; Endothelial cell phenotyping; Endothelial heterogeneity; Fibrosis; Full spectrum flow cytometry; High-dimensional single-cell analysis; Inflammation
    DOI:  https://doi.org/10.1016/j.bbrep.2026.102845
  46. Cancer Cell. 2026 Oct 29. pii: S1535-6108(26)00436-8. [Epub ahead of print]
    Intrinsic resistance to KRAS inhibition: Interfering with interferon.
    Borja Miguel-López, Matthias Drosten.
      In this issue of Cancer Cell, Zhang et al. perform multi-omics profiling on a large collection of patient-derived pancreatic ductal adenocarcinoma organoids to elucidate the mechanisms underlying intrinsic resistance to KRAS inhibition. This work identifies suppression of innate immune signaling through sustained MYC activity as the principal driver of intrinsic resistance.
    DOI:  https://doi.org/10.1016/j.ccell.2026.10.001
  47. Mol Aspects Med. 2026 Oct 29. pii: S0098-2997(26)00079-8. [Epub ahead of print] 101523
    Nobel 2026: Optogenetics - how we can control the nerve cells of others!
    Mihnea P Dragomir, George A Calin.
      
    DOI:  https://doi.org/10.1016/j.mam.2026.101523
  48. Bio Protoc. 2026 Oct 20. 16(20): e5832
    Quantitative Colocalization Analysis in Fluorescence Microscopy.
    Charles James Myers, Beiyan Nan.
      Spatial organization of macromolecules is fundamental to cellular function, with colocalization providing key insights into molecular interactions and biological processes. However, quantification remains challenging due to diverse localization patterns and irregular sample geometries. Here, we present a protocol for analyzing colocalization between two fluorescent probes using coAnalyzer, a MATLAB-based software package. coAnalyzer features a user-friendly graphical interface and supports region of interest (ROI) selection, image merging, line scanning, signal isolation, scatterplot generation, and quantitative analysis. coAnalyzer enables colocalization analysis of any two fluorophores, regardless of the proteins or dyes involved. Its broad applicability across a wide range of organisms and sample types demonstrates the robustness, flexibility, and versatility of the platform. Key features • Provides both quantitative and semi-quantitative colocalization analysis using multiple coefficients. • Features a user-friendly graphical user interface (GUI) that provides step-by-step visualization of the analysis process. • Supports 1D (line scan) and 2D analysis. • Analyzes large datasets and generates histograms for effective data presentation.
    Keywords:  Colocalization; Fluorescence microscopy; Manders’ correlation; Pearson’s correlation; Quantification
    DOI:  https://doi.org/10.21769/BioProtoc.5832
  49. Am J Physiol Cell Physiol. 2026 Oct 16.
    A fluorescence-based assay to measure chaperone-mediated autophagy in cell and tissue lysates.
    Sunny Sharma, Anila Jonnavithula, Logan Cameron Sorrels, N A Wajidunnisa, Eric Michael Netzel, Megan Tandar, Scott N Orton, MacKenzie Woodrum, Sohom Mookherjee, Sihem Boudina, Djamel Lebeche, J David Symons, Rajeshwary Ghosh.
      Intracellular proteolytic mechanisms are important in clearing aberrant proteins causal for different pathologies including cardiovascular diseases, cancer, and neurological disorders. Chaperone-mediated autophagy (CMA) is a protein degradation pathway that employs chaperones to bind proteins bearing a unique KFERQ (Lys-Phe-Asp-Arg-Gln)-like motif and delivers them to lysosomes for degradation via a CMA-specific receptor, namely, Lysosome Associated Membrane Protein 2A (LAMP2A). Several assays are available to monitor CMA function. However, most of these methods are laborious, expensive and cannot be performed on frozen samples. We have developed a straightforward and inexpensive fluorogenic assay to assess CMA activity in both fresh and frozen samples. The CMA substrate, KFERQ-AMC (7-amino-4-methylcoumarin), was synthesized by Solid-Phase Peptide Synthesis. Mechanistically, AMC fluorescence remains quenched when the fluorophore is conjugated to KFERQ. Upon lysosomal hydrolysis of KFERQ-AMC, free AMC is released, and its fluorescence levels serve as an indicator for CMA activity. Lysate from fresh or frozen mouse tissue and cells when incubated with the KFERQ-AMC peptide displayed a time-dependent increase in CMA activity (0-15 hours for tissues and 0-6 hours for cells). KFERQ-AMC fluorescence was markedly reduced in cultured cells following transfection with Lamp2a siRNA, indicating suppression of CMA activity. In contrast, overexpression of Lamp2a via adenoviral delivery enhanced CMA and promoted KFERQ-AMC degradation. Notably, inhibition of proteasomal or macroautophagic pathways had no effect on KFERQ-AMC degradation, underscoring the assay's specificity for CMA. This novel fluorescence-based approach provides a valuable tool for elucidating the role of CMA across diverse experimental systems.
    Keywords:  Chaperone-Mediated Autophagy; E64D; Fluorescence; KFERQ-AMC; LAMP2A; Lysosome; Macroautophagy; Peptides; Proteasome
    DOI:  https://doi.org/10.1152/ajpcell.90174.2026
  50. Trends Cancer. 2026 Oct 29. pii: S2405-8033(26)00237-2. [Epub ahead of print]
    Exercise against cancer: recent advances and open questions.
    Abel Plaza-Florido, Helene Rundqvist, Daniel A Galvão, Tomàs Pinós, Ana Ruiz-Casado, Carmen Fiuza-Luces, Keri Schadler, Kerry S Courneya, Alejandro Lucia.
      More than a century after observations linking muscular activity to reduced cancer risk, exercise oncology has progressed from epidemiological association to interventional evidence. Large cohort studies associate physical activity with reduced cancer incidence and mortality, and a Phase 3 randomized trial now demonstrates cancer-specific survival benefits of structured exercise. In parallel, preclinical and emerging human studies provide mechanistic insight into how exercise may modulate tumor biology, including effects on immune surveillance, vascular function, metabolism, and systemic signaling. Despite these advances, gaps remain-notably, the limited integration of exercise variables into oncology trials and sparse mechanistic data from patients, particularly in pediatric cancers. This opinion article synthesizes recent clinical and mechanistic advances and outlines priorities for biologically informed integration of exercise into cancer research and the standard of care.
    Keywords:  exerkines; metabolism; oncology; physical activity; tumor biology
    DOI:  https://doi.org/10.1016/j.trecan.2026.10.003
  51. Front Immunol. 2026 ;17 1938077
    Tumor-educated macrophages promote ferroptosis inhibition in pancreatic cancer via activating the p62-KEAP1-NRF2 pathway.
    Shouying Li, Dongxue Qi, Hanyang Yi, Lina Yang, Tonglei Xu, Wenkai Zhou, Weidong Xu, Ziheng Xu, Haodong Tang, Fangliang Xie, Chunfang Zhang, Xuyang Liang.
       Background: Pancreatic cancer is one of the most aggressive and lethal gastrointestinal malignancies, and ferroptosis resistance contributes to chemoresistance. Tumor-educated macrophages(TAMs) are key components of the tumor microenvironment, but whether and how they regulate ferroptosis in pancreatic cancer cells remains largely unknown. This study aimed to investigate the regulatory role of tumor-educated macrophages (TEMs) in pancreatic cancer cell ferroptosis and the underlying molecular mechanism.
    Methods: TEMs were generated by coculturing THP-1 cells with the pancreatic cancer cell lines PANC1 and CFPAC, and TEM-conditioned medium (TEM-CM) was collected to treat pancreatic cancer cells. Ferroptosis was induced by erastin, and ferroptotic events were assessed by lipid ROS, MDA, iron accumulation, GSH levels, and transmission electron microscopy. RNA sequencing was performed to identify differentially expressed genes. The expression and activity of VEGFR2, C-Raf, ERK1/2, mTOR, LC3, p62, KEAP1, and NRF2 were investigated by treating cells with pharmacological inhibitors (Ki8751, LY3009120, chloroquine, and ferrostatin-1), performing gene knockdown and overexpression, and conducting Western blot co-immunoprecipitation, ubiquitination, and cycloheximide chase assays. In vivo experiments were conducted using an orthotopic mouse model of pancreatic cancer (n = 5 per group).
    Results: TEM-CM reduced the sensitivity of PANC1 and CFPAC cells to erastin-induced ferroptosis, as evidenced by decreased lipid ROS, MDA, and iron accumulation and increased GSH levels. Neutralization of VEGF, but not IL-10 or TGFβ, significantly reversed the ferroptosis-inhibiting effect of TEM-CM. RNA sequencing identified TM7SF2 as a key mediator. TEM-CM upregulated TM7SF2 mRNA and protein levels, activated mTOR, and suppressed autophagy, leading to p62 accumulation. Accumulated p62 competitively bound KEAP1, disrupted the KEAP1-NRF2 interaction, inhibited NRF2 ubiquitination and degradation, and promoted NRF2 nuclear translocation, thereby upregulating GPX4, HMOX1, and GCLM. Mechanistically, TEM-derived VEGF bound VEGFR2 and activated the C-Raf/ERK1/2 pathway by upregulating TM7SF2, which in turn promoted mTOR phosphorylation. These effects were reversed by TM7SF2 knockdown, VEGF neutralization, VEGFR2 inhibition, or C-Raf inhibition.
    Conclusions: These findings suggest that TEM-derived VEGF promotes ferroptosis resistance in pancreatic cancer cells through the VEGFR2-TM7SF2-C-Raf/ERK1/2-mTOR-autophagy-p62-NRF2 axis. This axis may represent a potential therapeutic target for overcoming ferroptosis resistance in pancreatic cancer. However, our conclusions are mainly based on in vitro cell models, and further validation in additional cell lines, patient-derived organoids, and in vivo models is warranted.
    Keywords:  NRF2; TM7SF2; VEGF; autophagy; ferroptosis; mTOR; pancreatic cancer; tumor-educated macrophages (TEM)
    DOI:  https://doi.org/10.3389/fimmu.2026.1938077
  52. Prog Biophys Mol Biol. 2026 Oct 27. pii: S0079-6107(26)00081-7. [Epub ahead of print] 101964
    Lysosomal biophysics in CLN3 disease: Connecting membrane transport, molecular homeostasis, and tissue dysfunction.
    Najla Khaled Al Abdulsalam, Rabab S Hamad, Elsayed A Elmorsy, Sameh Saber.
      CLN3 disease (CLN3 Batten disease) is a lysosomal neurodegenerative disorder characterized by early retinal degeneration and progressive neurological dysfunction, yet the mechanisms connecting CLN3-dependent membrane physiology to selective cellular and tissue vulnerability remain unresolved. This review integrates current evidence across four experimentally separable scales: membrane biophysics, molecular and organellar homeostasis, cell-specific function, and tissue pathology. Direct electrophysiological studies support a luminal pH-sensitive CLN3-dependent lysosomal chloride conductance associated, in tested systems, with changes in luminal chloride, pH, cathepsin activity, and protein degradation. Independently, CLN3 deficiency disrupts glycerophosphodiester clearance, phospholipid and cholesterol handling, cation-independent mannose 6-phosphate receptor trafficking, hydrolase delivery, and autophagic lysosomal reformation. These organellar abnormalities coexist with distinct phenotypes in retinal pigment epithelium, neurons, microglia, astrocytes, and brain endothelial cells, together with retinal, neural-circuit, and myelin abnormalities at the tissue level. Current evidence does not establish a universal chloride-first or storage-first cascade; instead, it supports interacting CLN3-dependent modules whose causal ordering may vary by cell type, model, and disease stage. We therefore propose a multiscale mechanistic framework that links measurable lysosomal physical variables to molecular homeostasis, cell-specific function, and tissue vulnerability while preserving the distinction between direct evidence and mechanistic inference. This framework defines testable priorities for causal ordering, rescue experiments, and mechanism-matched target engagement in CLN3 disease.
    Keywords:  CLN3 disease; Endolysosomal homeostasis; Glycerophosphodiester metabolism; Lysosomal ion transport; Membrane biophysics; Tissue vulnerability
    DOI:  https://doi.org/10.1016/j.pbiomolbio.2026.101964
  53. bioRxiv. 2026 Oct 08. pii: 2026.10.06.757201. [Epub ahead of print]
    The impact of sex and ancestry on the molecular landscape of pancreatic adenocarcinoma.
    Caroline Y Chen, Jaron Arbet, Chenghao Zhu, Jieun Oh, Paul C Boutros.
       Background: Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related mortality, with an increasing incidence and dismal 10% survival at 5 years despite best available care. PDAC is characterized by low tumour cellularity, recurrent driver mutation alterations, and substantial inter and intra-tumoural heterogeneity. The influence of individual genetic features such as sex and ancestry on tumour heterogeneity remains poorly understood.
    Methods: We assembled a cohort of PDAC across five datasets for a total of 7,527 tumours. Measures of genomic instability were assessed across sex and ancestry on a global level (SNV density and percent genome altered by copy number events), and at a gene level for recurrent events. KRAS variant frequencies, ploidy and mRNA abundance were also evaluated. Ancestry was assigned using ADMIXTURE from germline genotypes where available, and patient reported otherwise.
    Results: We observed ancestry-specific mutation patterns in global point mutation density, with higher SNV burden in African PDAC tumours and lower SNV burden in Asian PDAC tumours as compared to European tumours. We also identified an ancestry bias in the driver gene, GNAS , in which driver SNVs in GNAS was detected more frequently in those of Asian ancestry, and less frequently in those of African ancestry. No sex- or ancestry-associations were found for KRAS , but individual KRAS variants showed a trend towards ancestry-related variation.
    Conclusions: These findings demonstrate that ancestry contributes to the genomic heterogeneity of PDAC, shaping both global and gene-specific mutation patterns. This work underscores the importance of including diverse ancestries in PDAC molecular profiling efforts which may inform the development of tailored molecular diagnostics and targeted therapies.
    DOI:  https://doi.org/10.64898/2026.10.06.757201
  54. Redox Biol. 2026 Oct 21. pii: S2213-2317(26)00444-1. [Epub ahead of print]98 104445
    Isoenzyme-specific determination of glutathione peroxidase activity in cell lysates and GPX1/GPX4-HiBiT cellular target engagement.
    Madeleine S Barrett, Jonathan H Shrimp, Alina Löser, Dorian M Cheff, Qing Cheng, Anna P Kipp, Matthew D Hall, Elias S J Arnér.
      Glutathione peroxidases (GPX) are primarily selenoproteins that maintain cellular redox balance. GPX1, GPX2 and GPX4 are associated with cancer progression and treatment resistance, but the lack of isoenzyme-specific cellular assays has limited evaluation of GPX-targeting compounds. As GPX1 and GPX2 share high sequence homology, as well as substrate and inhibitor profiles, their individual activities are difficult to distinguish. Here, we present a glutathione reductase (GR)-coupled assay using auranofin to quantify combined GPX1/GPX2 activity and total GPX activity in crude cell lysates. The method was validated using multiple cell lines, with or without selenium supplementation, spiked human recombinant enzymes, and knockdown cells. Combined GPX1/GPX2 activity correlated with GPX1 protein levels and accounted for the majority of GPX activity in selenium-supplemented cells. GPX4's low catalytic turnover limits the feasibility of measuring its activity in cell lysates, so we established a high-throughput cellular thermal shift assay (CETSA) using HiBiT-tagging of GPX1 and GPX4 in HT1080 cells to quantify isoenzyme-specific target engagement. Using this new complementary assay platform, we found that ferroptosis inducers RSL3, PACMA-31 and ML-162 destabilized GPX4 in cells, RSL3 and ML-162 destabilized cellular GPX1, but none of these compounds had a strong effect on either total GPX, or GPX1/GPX2 activities in lysates. Additional reported GPX1/GPX2 or GPX4 inhibitors showed minimal GPX4 target engagement, whereas GPX1 was readily targeted in cells. The FDA-approved drugs, ceftibuten and omapatrilat, inhibited GPX1/GPX2 activity more potently than auranofin in cell lysates, suggesting that GPX1/GPX2 suppression may contribute to their cellular effects. Together, these complementary GPX assays presented here provide practical tools for evaluations of specific GPX isoenzyme cellular activities and development of selective GPX-targeted therapies.
    Keywords:  Auranofin; CETSA; Ferroptosis inducers; GPX lysate activity assay; GPX1; GPX2; GPX4; Glutathione peroxidase; HiBiT tagging; Isoenzyme-specific; Target engagement
    DOI:  https://doi.org/10.1016/j.redox.2026.104445
  55. bioRxiv. 2026 Sep 04. pii: 2026.09.02.748765. [Epub ahead of print]
    E-cadherin-mediated neighborhood surveillance dictates pre-malignant outcomes.
    Elizabeth A N Thompson, Clara Schimmer, Tatiana Omelchenko, Michele Paganini, Jesse S S Novak, Sienna T Muller, Alain R Bonny, Marina Schernthanner, Sairaj M Sajjath, Charlotte J Bell, Alp Gorgulu, S Martina Parigi, Katherine S Stewart, Priyam Banerjee, Elaine Fuchs, Stephanie J Ellis.
      Stratified epithelia accumulate oncogenic mutations throughout life, yet overgrowths are rare. How epithelia detect and eliminate aberrant clones remains poorly understood. Using a mouse model of oncogenic clonal mosaicism in the skin, we find that pre-malignant epidermal cells redistribute E-cadherin to interfaces shared with wild-type neighbors, generating local tension heterogeneity that triggers elimination by cell competition. We show that gain or loss of E-cadherin can each drive competitive elimination, and although mechanical routes differ, both establish tension heterogeneity between neighbors, rather than any absolute adhesion state, as the critical determinant of epidermal fitness. This mechanism carries the seeds of its own failure: these tension differentials precipitate clonal sorting, depleting the wild-type contacts that surveillance requires. Pre-malignant cells then become supercompetitors, eliminating wild-type neighbors and expanding hyperplastically. Mechanical heterogeneity therefore endows tissues with an active, yet inherently fragile error-correction system whose collapse initiates a switch in competitive status, increasing tumorigenesis susceptibility.
    DOI:  https://doi.org/10.64898/2026.09.02.748765
  56. Nat Struct Mol Biol. 2026 Oct 28.
    A nanoscale map of the human cell surface proteome reveals spatial and functional organization.
    Brendan M Floyd, Elizabeth L Schmidt, Nicholas A Till, Benjamin S Waldman, Jonathan L Yang, Pinyu Liao, Benson M George, Jan E Carette, Ryan A Flynn, Carolyn R Bertozzi.
      The cell surface proteome governs processes essential for development, immunity and disease, yet its large-scale spatial organization remains uncharted. Here, we systematically map the surface proteome of human T lymphocytes and B lymphoblasts using proximity labeling of 85 antigens. Coupled with data-independent acquisition mass spectrometry, this approach reveals functional modules, including known complexes such as the T cell receptor alongside clusters not previously implicated in cell membrane functions. Notably, we identify mitochondrial proteins at the surface, suggesting that they may bear underappreciated roles at the plasma membrane. A machine learning classifier predicts surface protein associations, revealing the IL-10 receptor beta subunit's regulation of type I interferon signaling. Spatial modeling distinguishes widely dispersed from localized antigens, indicating active mechanisms of surface organization. In summary, this work provides a large-scale map of the human surfaceome and a resource for exploring its spatial and functional organization.
    DOI:  https://doi.org/10.1038/s41594-026-01914-4
  57. EMBO J. 2026 Oct 30.
    ATAD2B governs epigenetic silencing of the epithelial program to fuel cancer metastasis and neuronal migration.
    Arun Mahesh, Mohammed Inayatullah, Mikkel G Terp, Ziyi Zang, Charles Mariasoosai, Martin R Larsen, Carla Maria L Alves, Odd L Gammelgaard, Henrik J Ditzel, Vijay K Tiwari.
      Epithelial-to-mesenchymal transition (EMT) is a pivotal developmental program that is frequently co-opted to drive cancer aggressiveness and metastasis. While the dynamic remodelling of histone H3 lysine 27 acetylation (H3K27ac) landscapes is a hallmark of EMT, the specific chromatin readers decoding these epigenetic signals remain largely unknown. Here, we identify ATAD2B as a novel H3K27ac reader essential for cell migration in both cancer metastasis and brain development. Multi-omics profiling revealed that, at EMT onset, ATAD2B targets H3K27ac at active epithelial identity genes via its bromodomain and recruits HDAC1 to epigenetically silence them, enforcing a mesenchymal state. ATAD2B loss impairs migration and invasion in breast cancer lines and Patient-Derived organoids, whereas its overexpression accelerates in vivo lung metastasis and correlates with poor patient survival. Furthermore, ATAD2B promotes the migration of newborn neurons in the developing brain. Our findings establish ATAD2B as a versatile chromatin reader orchestrating cell motility across development and disease.
    DOI:  https://doi.org/10.1038/s44318-026-00933-7
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