bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2026–11–15
forty-four papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Seipin and perilipin 3 promote distinct early steps of nascent lipid droplet biogenesis.
  2. Depletion of Endogenous IL-18 Suppresses Pancreatic Cancer Progression, Reprograms the Tumor Microenvironment, and Enhances KRAS Inhibitor Efficacy.
  3. The optogenetic tool ASAP acutely inhibits autophagy.
  4. Domains or no domains? That is the question: insights from asymmetric bilayer models into plasma membrane lipid organization.
  5. Immune evasion in cancer dormancy and metastatic reactivation.
  6. CASM regulates lysosomal expansion and cell fate during senescence.
  7. The antioxidant addiction of cancer.
  8. NINJ1 and SIGLEC12: specialized mediators of plasma membrane rupture.
  9. Brown adipose tissue sustains thermogenesis through metabolic flexibility in glucose utilization.
  10. From intracellular force maps to organelle and organism physiology.
  11. Paclitaxel-induced disruption of lysosome motility and function in DRG neurons.
  12. A genetically encoded system to purify senescent cells.
  13. Oncogene-mechanics axis: KRAS G12C confers agility enabling malignant mechano-responses to peristalsis in colorectal cancer.
  14. Dietary DGLA-induced ferroptosis is suppressed by vitamin B12-mediated phosphatidylcholine synthesis.
  15. Fatty acid metabolism controls plasma membrane cholesterol accessibility via ATGL-dependent phospholipid remodeling.
  16. Non-cell-autonomous removal of protein aggregates via trogocytosis.
  17. Suppression of epithelial proliferation and tumorigenesis by IgA.
  18. TMEM192 is a calcineurin-regulated membrane receptor for ubiquitin-independent lysophagy.
  19. p53 activates chaperone-mediated autophagy to remodel metabolism and suppress tumorigenesis.
  20. SNX13 and SNX14 interorganelle tethers suppress lysosome membrane damage and neurodegeneration.
  21. Synchrotron X-ray Data of non-diseased and diabetic Human Pancreas Tissue and Islet Segmentation Model.
  22. daNIS-2: a phase III, randomized, double-blind study of the anti-TGF-β monoclonal antibody NIS793 or placebo in combination with nab-paclitaxel/gemcitabine as first-line treatment in patients with metastatic pancreatic ductal adenocarcinoma.
  23. NEIL2 regulates RNA polymerase II dynamics to suppress transcription-replication conflicts in pancreatic cancer.
  24. Altered protein cysteine reactivity in senescent cells is a vulnerability for senolysis to ameliorate aging.
  25. HIF-1α-mediated metabolic reprogramming in hypoxia-driven tumor metastasis.
  26. Acute priming using elevated fluid viscosity recovers young-like single-cell surveillance behaviors in aged human T cells.
  27. Poking the cell surface: mechanics, remodeling, and what force reveals.
  28. Oncogenic KRAS-MAPK signaling sustains a CD73 dependent therapeutic vulnerability in pancreatic cancer.
  29. LipidMem-BigSMILES (LiMBS): A Standardized Representation Language for Lipid Membrane Systems.
  30. The mitochondrion as a mechanometabolic conductor of cancer metastasis: pharmacological insights from the mitochondria-peroxisome interface.
  31. Mitochondrial protein import defects enhance tumour immunogenicity.
  32. Next-generation KRAS G12C inhibitor improves survival in lung cancer.
  33. ESCRT-III assembly restores membrane tension in micron-scale plasma membrane repair.
  34. The Five Phases of cancer cells.
  35. Computational modelling of macrophage facilitated cancer metastasis using a cellular Potts model.
  36. Blood-based PhenoAge may reflect disease burden rather than biological aging in cancer.
  37. Elucidating cancer cachexia-mediated aberrant cardiac wasting signaling in human iPSC-derived cardiac muscle.
  38. ME1 inhibits ferroptosis by targeting GPX4 in HCC through enzymatic and moonlighting functions.
  39. Ubiquitin-dependent signal amplification in lipid saturation sensing.
  40. Mutant KRAS vaccination for pancreatic cancer interception: the G12D immunogenicity paradox.
  41. A TROP2-targeting aptamer enables selective drug delivery and potent antitumor activity in pancreatic cancer.
  42. Fluorescent probes for mapping tumorigenic parameters, polarity and viscosity: implications for future chemotherapeutics.
  43. Targeting the metabolism-autophagy-ferroptosis interactome in cancer drug resistance: molecular targets, structural pharmacology, and combination strategies.
  44. scGWAS-DB: an integrated database bridging GWAS to tissue-resolved single-cell contexts.
  1. bioRxiv. 2026 Oct 22. pii: 2026.10.21.760741. [Epub ahead of print]
    Seipin and perilipin 3 promote distinct early steps of nascent lipid droplet biogenesis.
    Raunaq Deo, Apoorva Bhapkar, Emma Givan, Chao Li, Ehud Haimov, Derk Binns, Philipp E Scherer, Michael M Kozlov, Alexandre Toulmay, William A Prinz.
      Lipid droplets (LDs) are lipid storage organelles with critical roles in metabolism. Cells form LDs in response to various metabolic stresses 1 . LD biogenesis occurs in the endoplasmic reticulum (ER) membrane and begins when triglyceride (TG) in the membrane phase separates 2-4 . After nucleation, nascent LDs grow by absorbing TG from the membrane 5,6 . How cells determine when TG in the ER membrane is added to existing LDs or is used to form new LDs or is not known. Here, we developed the first LD formation assay that allows the synthesis of TG in membranes, mimicking what occurs in cells. LDs arise stochastically after TG production begins. LD nucleation is affected by TG production rate and membrane phospholipid composition. Membrane-embedded LDs suppress nascent LD formation by sequestering TG and destabilizing nascent LDs by Ostwald ripening. We show that cells overcome this suppression in two ways. The ER membrane protein seipin accelerates LD nucleation where it localizes in a membrane, probably by increasing the kinetics of TG phase separation. The LD coat perilipin 3 inhibits nascent droplet dissipation by ripening. Together, our findings reveal a minimal LD formation machinery, and the mechanisms cells use to control whether TG in the ER drives new LD formation.
    DOI:  https://doi.org/10.64898/2026.10.21.760741
  2. Gastroenterology. 2026 Nov 13. pii: S0016-5085(26)07779-6. [Epub ahead of print]
    Depletion of Endogenous IL-18 Suppresses Pancreatic Cancer Progression, Reprograms the Tumor Microenvironment, and Enhances KRAS Inhibitor Efficacy.
    Xinlei Sun, Yifan Ma, Lingzhi Wang, Jian Gao, Yue Fei, Xiaowei Zhang, Rance B Tino, Yeseul Kim, Hua Wang, Kangyu Lin, Dongwei Zhang, Zhongming Zhao, Chunru Lin, John Paul Shen, Sue-Hwa Lin, Linghua Wang, Vincent Bernard, Eugene J Koay, Dan Zhao, Huamin Wang, Wen Jiang, Betty Y S Kim, Anirban Maitra, Yang Chen.
       BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) exhibits a highly complex tumor microenvironment enriched with both inflammatory and immunosuppressive factors. Interleukin-18 (IL-18), a cytokine of the IL-1 family, is elevated in PDAC and correlates with poor patient outcomes. However, the functional role of IL-18 in PDAC progression and immune regulation remains poorly defined.
    METHODS: We generated genetically engineered mouse models with IL-18 depletion in the context of spontaneous PDAC development. Single-cell RNA-sequencing and functional assays were used to analyze PDAC progression, macrophage phenotypes, and cancer cell-macrophage interactions. Mechanistic studies were performed to determine the effects of IL-18 on STAT1 signaling and CD47 expression. The role of IL-18 in therapeutic response was evaluated using KRAS inhibitor (KRASi) treatment models.
    RESULTS: Elevated IL-18 expression correlated with poor patient survival. Genetic depletion of IL-18 significantly suppressed spontaneous PDAC progression and prolonged survival in mice. Mechanistically, IL-18 promoted cancer cell survival by activating STAT1-dependent CD47 expression, thereby impairing macrophage-mediated phagocytosis of cancer cells. In addition, IL-18 depletion reshaped the tumor immune microenvironment by enriching macrophage populations with enhanced antigen-presenting and phagocytic phenotypes characterized by increased MHCII and CD11c expression. Notably, KRAS inhibitor treatment further increased IL-18 expression in PDAC cells, whereas IL-18 depletion enhanced macrophage-mediated clearance of KRASi-treated cancer cells and improved therapeutic efficacy.
    CONCLUSIONS: IL-18 promotes pancreatic cancer progression by enabling cancer cell survival and immune evasion through macrophage reprogramming. Targeting IL-18 may represent a therapeutic strategy to enhance macrophage-mediated anti-tumor immunity and improve responses to KRAS inhibitor therapies in PDAC.
    Keywords:  Genetically engineered mouse models; Interleukin-18; Pancreatic cancer; Tumor microenvironment
    DOI:  https://doi.org/10.1053/j.gastro.2026.10.383
  3. Nat Cell Biol. 2026 Nov 12.
    The optogenetic tool ASAP acutely inhibits autophagy.
    Payel Mondal, Amanda Cyril, Dana Mamriev, Louis Parham, Igor Wierzbicki, Celina Shen, Ginevra Doglioni, Suzanne Dufrense, Anvita Komarla, David J Gonzalez, Maximiliano A D'Angelo, Christina G Towers.
      Autophagy, a conserved recycling process, manages intracellular quality control to mitigate stress. To determine the rapid effects of autophagy perturbation, we developed an optogenetic tool to rapidly inhibit autophagy, termed ASAP. Our approach leverages light-induced proteolytic cleavage to selectively inhibit autophagy within 5 min of light exposure, providing a precise and dynamic approach to study autophagy regulation. Proteomic profiling with ASAP revealed the most tightly regulated autophagy substrates along with previously unidentified substrates, including nuclear pore complex proteins. Of note, autophagy regulates quality control of cytoplasmic complexes of nucleoporins via specific LC3-interacting regions, sparing nuclear pore complex proteins embedded in the nuclear envelope. Upon rapid autophagy inhibition, incomplete nucleoporin complexes accumulate and instead of undergoing autophagic degradation, cytoplasmic nucleoporin complexes aggregate in processing bodies (P bodies). Using ASAP, we demonstrate rapid and specific inhibition of autophagy, revealing that nuclear pore complex proteins are tightly regulated autophagy substrates.
    DOI:  https://doi.org/10.1038/s41556-026-02124-2
  4. Biophys Rev. 2026 Oct;18(5): 927-946
    Domains or no domains? That is the question: insights from asymmetric bilayer models into plasma membrane lipid organization.
    Thais Azevedo Enoki.
      The mammalian plasma membrane is characterized by its pronounced lipid asymmetry, including the exceptional enrichment of sphingomyelin (SM) in the exoplasmic leaflet. How this asymmetry influences cholesterol distribution and membrane organization remains a central and unresolved question in cell biology. The lipid raft hypothesis has long provided the prevailing framework, proposing that cholesterol and SM assemble into dynamic liquid-ordered nanodomains that compartmentalize proteins and regulate membrane trafficking, signaling, and host-pathogen interactions. More recently, a phospholipid (and cholesterol) imbalance model offers an alternative view, proposing that the exoplasmic leaflet contains substantially fewer phospholipids but is correspondingly enriched in cholesterol, potentially shifting its composition toward a uniformly liquid-ordered state. In this review, we examine these two conceptual frameworks in light of recent advances in membrane lipidomics and asymmetric model membranes. We discuss the experimental evidence supporting both models and emphasize that many observations attributed to a large phospholipid imbalance are not unique to that interpretation but can also be explained by membrane lateral lipid heterogeneity. We further highlight methodological considerations in enzymatic lipid digestion and cholesterol quantification, underscoring the need for additional experimental validation of leaflet-specific lipid composition. A central theme of this review is the role of interleaflet interactions. Experimental studies using asymmetric model membranes demonstrate that membrane domains in one leaflet can induce lateral organization in the opposing leaflet, even when the latter lacks the lipid composition required to form liquid-ordered domains independently. We suggest that interleaflet coupling provides a physical mechanism that reconciles lipid domain (lipid raft) formation with the compositional asymmetry of the plasma membrane. Rather than viewing the lipid raft and phospholipid imbalance models as mutually exclusive, we propose that their apparent differences depend critically on the magnitude of phospholipid and cholesterol asymmetry and on the strength of transbilayer coupling. Understanding how these factors collectively govern membrane organization will be essential for developing a unified physical description of the plasma membrane and for elucidating the mechanisms underlying cholesterol homeostasis, membrane protein regulation, and cellular signaling.
    Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s12551-026-01468-1.
    Keywords:  Asymmetric bilayers; Coexistence of liquid disordered and liquid ordered phases; Model membrane; Phase diagrams; Plasma membrane
    DOI:  https://doi.org/10.1007/s12551-026-01468-1
  5. Trends Cancer. 2026 Nov 11. pii: S2405-8033(26)00242-6. [Epub ahead of print]
    Immune evasion in cancer dormancy and metastatic reactivation.
    Ron S Gejman, Hsiang-Hsi Ling, Gizem Efe, Karan Luthria, Parin Shah, Benjamin Izar.
      Metastatic dormancy reflects a dynamic immune-tumor equilibrium in which disseminated tumor cells, either as individual cells or multicellular ecosystems, may persist for years before relapse. Recent studies show that dormant cells evade elimination through spatial and numerical rarity, insufficient immune effectors, suppression of innate immune signaling and inflammasome pathways, and adaptation to local immune niches. Inflammatory stress leading to tissue remodeling dampens immune restraint and promotes metastatic outgrowth. Emerging spatial and single-cell genomic and evolutionary profiling approaches now offer a potential path toward defining dormant disseminated tumor cell states and niches directly in patients. Here, we review mechanisms of tumor-immune interactions in dormant cells or incipient metastases and discuss how these could be leveraged to develop strategies to eradicate minimal residual disease, restore immune surveillance, and prevent inflammatory reawakening. We also provide a perspective on how predominantly murine studies in this field may be extended to studying the dormancy paradigm directly in patients.
    Keywords:  cancer dormancy; disseminated tumor cells; immune surveillance; metastatic reactivation; minimal residual disease; tissue-specific immunity
    DOI:  https://doi.org/10.1016/j.trecan.2026.10.008
  6. JCI Insight. 2026 Nov 09. pii: e207890. [Epub ahead of print]11(21):
    CASM regulates lysosomal expansion and cell fate during senescence.
    Yu-Wei Cheng, Michael Z Gao, Jay Xiaojun Tan, Jie Liu, Toren Finkel.
      Cellular senescence, a hallmark of aging, is accompanied by a striking expansion of the cell's lysosomal compartment, yet the pathway leading to increased lysosomal content remains unresolved. Here, we demonstrate that the master lysosomal transcriptional regulator TFEB is activated during senescence through a pathway that involves conjugation of ATG8 onto single membranes (CASM). Using various senescence inducers, we show that senescence induction triggers robust TFEB nuclear translocation and upregulation of TFEB target genes. In contrast, inhibition of the core CASM machinery by CRISPR-mediated deletion of either ATG16L1, ATG12, or ATG5 markedly reduced senescence-induced TFEB nuclear translocation. In ATG16L1-KO cells, reconstitution with WT ATG16L1 but not the CASM-defective ATG16L1F467A mutant restored both ATG8 lipidation on the lysosomal surface and TFEB activation. Moreover, expression of the Salmonella effector protein SopF, a previously described specific CASM inhibitor, similarly blocked senescence-induced TFEB translocation. Functionally, upon stress, CASM-deficient cells exhibited a pronounced shift away from senescence and toward a cell death fate, a phenotype reversed by expressing a constitutively active form of TFEB. Together, these findings identify CASM-dependent TFEB activation as an essential mechanism enabling senescence-associated lysosomal expansion and suggest that lysosomal capacity modulates cell fate decisions in the aftermath of acute stress.
    Keywords:  Aging; Cell biology; Lysosomes
    DOI:  https://doi.org/10.1172/jci.insight.207890
  7. Nat Rev Cancer. 2026 Nov 13.
    The antioxidant addiction of cancer.
    Navdeep S Chandel.
      Reactive oxygen species (ROS) production in cancer cells is elevated by oncogenic signalling, tumour suppressor loss, metabolic reprogramming, and nutrient stress within the tumour microenvironment. Hydrogen peroxide can promote cellular states that favour cancer initiation and a metastatic phenotype. By contrast, excessive ROS production, particularly the uncontrolled generation of lipid peroxides, can trigger cell death pathways such as ferroptosis, thereby limiting cancer progression and metastasis. Cancer cells, therefore, increase their antioxidant capacity to maintain ROS levels high enough to support signalling, but below toxic levels. Antioxidant systems can suppress early neoplastic transformation in some tissues by limiting ROS during precancerous lesion formation. However, after transformation, these pathways can support tumour maintenance, metastatic dissemination and therapy resistance. For decades, strategies to modulate oxidative stress focused primarily on administering dietary antioxidants. However, the lack of clinical benefit from broad dietary antioxidant supplementation and even evidence of harm in some settings, together with growing evidence that tumours are selectively dependent on specific antioxidant pathways at distinct stages of tumorigenesis and metastasis, has shifted attention towards targeting antioxidant defences in established cancers. The key question is whether these pathways can be targeted with sufficient selectivity to spare normal tissues. In this Perspective, I examine how tumour stage-specific dependencies on antioxidant pathways create therapeutic vulnerabilities that can be exploited to treat tumours, prevent metastasis and overcome therapy resistance.
    DOI:  https://doi.org/10.1038/s41568-026-00997-x
  8. Trends Cell Biol. 2026 Nov 12. pii: S0962-8924(26)00213-8. [Epub ahead of print]
    NINJ1 and SIGLEC12: specialized mediators of plasma membrane rupture.
    Hyunjin Noh, Zeena Hashem, Ayaz Najafov.
      Plasma membrane rupture (PMR) is the terminal step of lytic cell death pathways and is implicated in inflammatory diseases, infections, and cancer. Recent work has identified two proteins-ninjurin-1 (NINJ1) and sialic acid-binding immunoglobulin-like lectin 12 (SIGLEC12)-as mediators of PMR. NINJ1 executes PMR during pyroptosis, ferroptosis, and secondary necrosis following apoptosis, but not necroptosis. SIGLEC12 is an effector of necroptotic PMR downstream of transmembrane serine protease 4-mediated cleavage. This review summarizes the molecular mechanisms underlying NINJ1- and SIGLEC12-dependent PMR, their biological functions, and their roles in physiological and pathological contexts. Understanding how these mechanisms are dysregulated in human diseases and co-opted by pathogens will open avenues for developing therapies that target PMR in lytic cell death.
    Keywords:  NINJ1; SIGLEC12; TMPRSS4; lytic cell death; necroptosis; plasma membrane rupture
    DOI:  https://doi.org/10.1016/j.tcb.2026.10.007
  9. Nat Metab. 2026 Nov 13.
    Brown adipose tissue sustains thermogenesis through metabolic flexibility in glucose utilization.
    Nakul Karandikar, Celina Beyer-Teal, Lishu Yue, Ece Kilic, Zeran Lin, Lucie Yammine, Ksenia Morozova, Colleen K Hadley, Santiago Barber, Timothy E McGraw, Paul Cohen.
      Brown adipose tissue (BAT) is a cold-activated organ that uncouples mitochondrial respiration from ATP synthesis to produce heat. Activated BAT can consume an extreme amount of glucose, per gram of tissue, in both mice and humans. However, the contexts, mechanisms and necessity for BAT glucose utilization remain surprisingly undefined in vivo. Here we show that while BAT thermogenesis is maintained across diverse dietary contexts, its glucose utilization is particularly responsive to diet. Importantly, we find cold-induced BAT glucose uptake and thermogenesis to be independent of the previously proposed critical transporter, GLUT1. Instead, inducible GLUT4 loss eliminates cold-induced glucose uptake and compromises BAT thermogenesis only when dietary lipids are low during cold stress. We furthermore illustrate the unexpected capacity for brown adipocytes to sustain ATP levels without glycolysis, even during substantial mitochondrial uncoupling, when alternative nutrients are abundant. Collectively, our work demonstrates that BAT sustains thermogenesis through marked metabolic flexibility across nutrient contexts.
    DOI:  https://doi.org/10.1038/s42255-026-01652-3
  10. J Cell Sci. 2026 Nov 01. pii: jcs265263. [Epub ahead of print]139(21):
    From intracellular force maps to organelle and organism physiology.
    Felix Campelo, Verena Ruprecht, Aurélien Roux, Kristian Franze, Warwick Bowen, Michael Krieg.
      The mechanical properties of the cell interior are heterogeneous, varying across components and compartments according to function, location and time. However, many current mechanical models of the cell do not fully reflect this, either treating the cell as a simplified isotropic mechanical continuum or focusing on complex mechanics of isolated cellular structures, leaving the integration of mechanical features at cellular-to-tissue levels unresolved. To link mechanics with biological function, complete, spatially and temporally resolved maps of subcellular to mesoscopic mechanical properties in living systems and organisms are needed. Despite major technical advances in mechanobiology over the past decade, only snapshots of these heterogenous material properties have been obtained. Crucially, the integration of quantitative force measurements with microscopy approaches remains a challenge in connecting cell mechanics with biological structure and function. This limitation underlines the urgent need for novel imaging methods to visualize how different organelles, cells and organisms respond to forces and how their mechanical properties are coupled to function and physiology. In this Review, we outline recent developments in this rapidly advancing field and discuss what lays ahead in order to bring spatially and temporally resolved imaging of subcellular mechanics into a quantitative and broadly accessible framework for cell biology.
    Keywords:  Force transmission; Imaging; Mechanobiology; Membrane tension; Microscopy; Stiffness
    DOI:  https://doi.org/10.1242/jcs.265263
  11. Neurobiol Pain. 2026 Jul-Dec;20:20 100239
    Paclitaxel-induced disruption of lysosome motility and function in DRG neurons.
    Kathleen Cate Domalogdog, Ishwarya Sankaranarayan, Úrzula Franco-Enzástiga, Juliet M Mwirigi, Shani Mai Nguyen, Diana Tavares-Ferreira, Theodore J Price.
      Lysosomal trafficking and homeostasis are biological functions that are pivotal for DRG neurons, given their metabolic demands and extremely long axons. Previous studies indicate that lysosomal signaling is altered in a mouse model of chemotherapy-induced peripheral neuropathy (CIPN) and that blocking mitogen activated protein kinase-associated kinase (MNK1/2) signaling can alleviate pain behaviors in CIPN. Here, we investigated lysosome dynamics and lysosome-associated signaling in a mouse model of CIPN induced by paclitaxel (PTX), a chemotherapeutic agent used for various types of cancer. Using spinning disk super-resolution microscope (SPINSR), we demonstrate that PTX treatment in vivo causes reduced lysosome motility observed in vitro. PTX likewise drives the accumulation of Sequestosome 1 (SQSTM1), also known as P62, in cultured mouse DRG neurons, indicating lysosomal dysfunction in DRG neurons. The transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, was also upregulated in the nucleus of cultured mouse DRG neurons treated with PTX. In line with this, increased lysosomal-associated membrane protein 1 (LAMP1) expression was observed in PTX-treated mice. Given that our previous work demonstrated PTX treatment increases MNK1/2-eIF4E signaling in DRG neurons, we examined whether MNK1/2 inhibition could rescue lysosomal dysfunction. Treatment with Tomivosertib (eFT508), a potent MNK1/2 inhibitor, restored P62 levels in DRG neurons of PTX-treated mice and reduced TFEB in DRG treated in vitro. To establish translation relevance, we further show that PTX elevates phosphorylated eiF4E (p-eIF4E) in human DRG neurons, and concurrent eFT508 administration attenuates this effect. Collectively, these findings indicated that PTX disrupts lysosome trafficking and biogenesis, and that MNK inhibition with eFT508 restores lysosomal signaling and can serve as a neuroprotective strategy for CIPN.
    Keywords:  CIPN; Live cell imaging; Lysosome; Paclitaxel
    DOI:  https://doi.org/10.1016/j.ynpai.2026.100239
  12. Cell Rep Methods. 2026 Nov 11. pii: S2667-2375(26)00366-8. [Epub ahead of print] 101665
    A genetically encoded system to purify senescent cells.
    Hourieh Tousian, Rachael A Protzman, Timothy J Sargeant, Julian M Carosi.
      Cellular senescence is a state of irreversible cell-cycle arrest that prevents cancer but promotes aging and inflammation. Conflicting molecular profiles of senescence may arise from contamination by neighboring proliferating cells. Here, we developed SenLect (senescence selection), a genetically encoded system for purifying senescent cells in culture. SenLect expresses mCherry-2A-PuroR under the senescence-activated miR-146a promoter, providing senescent cells a selective advantage over proliferating cells during puromycin treatment. We validated SenLect in primary and immortal cells undergoing replicative senescence or various modes of stress-induced senescence. Selected cells were enriched for cell-cycle arrest, increased cell size, and lysosomal β-galactosidase activity. Removing proliferating cells revealed proteome rewiring during senescence induced by cyclin-dependent kinase 4/6 inhibition, improving detection of senescence-associated secretory phenotype (SASP) signatures, metabolic shifts, and organelle remodeling. SenLect provides a reliable method for isolating senescent cells for downstream applications.
    Keywords:  CP: cell biology; cell-type purification; miR-146a; senescence
    DOI:  https://doi.org/10.1016/j.crmeth.2026.101665
  13. Sci Rep. 2026 ;16 33639
    Oncogene-mechanics axis: KRAS G12C confers agility enabling malignant mechano-responses to peristalsis in colorectal cancer.
    Astha Lamichhane, Vsevolod Cheburkanov, Mykyta Kizilov, Abhinav Shenoy, Audrey G Head, Vladislav Yakovlev, Shreya A Raghavan.
      Oncogene activity and mechanical forces individually and collectively drive colorectal cancer, yet the integration of these signals is unknown. We used a patented peristalsis bioreactor to determine how oncogenic KRAS G12C mutations alter the cellular response to colonic peristalsis. Although both healthy intestinal cells (HIEC-6) and KRAS G12C cancer cells (SW837) sensed peristalsis via ERK phosphorylation (1.7-4.7X increase), their mechano-responses diverged significantly. Peristalsis triggered a 9-fold enrichment of LGR5+ cancer stem cells in KRAS G12C cancer cells, an effect absent in healthy HIEC-6 controls. Using Brillouin microscopy, we discovered that KRAS G12C possessed a mechanically primed state exhibiting 9% reduction in Brillouin Full Width at Half Maximum, indicative of lower intracellular viscosity. Peristalsis further decreased intracellular viscosity in KRAS G12C cells by 11.9%, accompanied by pronounced cell elongation, whereas HIEC-6 maintained viscoelastic homeostasis. This KRAS-dependent mechanical agility enabled KRAS G12C cancer cells to leverage, rather than resist peristalsis, resulting in LGR5 enrichment and malignant progression. Pharmacologic KRAS G12C inhibition with sotorasib reduced LGR5+ cells by 50% under peristalsis, reversing the malignant mechanotype. Conversely, introducing KRAS G12C into HIEC-6 disrupted their mechanical homeostasis and significantly increased LGR5, recapitulating the KRAS-dependent mechano-phenotype. Our findings identify a novel KRAS oncogene-mechanics axis, suggesting that targeting the cell's mechanical state could be a powerful complement to emerging KRAS-directed therapies.
    Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1038/s41598-026-68015-6.
    Keywords:  Brillouin microscopy; Cancer mechanobiology; Oncogene; Peristalsis; Viscosity
    DOI:  https://doi.org/10.1038/s41598-026-68015-6
  14. Ferroptosis Oxid Stress. 2026 ;2(4): 202626
    Dietary DGLA-induced ferroptosis is suppressed by vitamin B12-mediated phosphatidylcholine synthesis.
    Madison S Mortensen, Paige E Silvia, Carissa Perez Olsen, Jennifer L Watts.
       Aims: Ferroptosis is a form of cell death associated with uncontrolled lipid peroxidation of polyunsaturated fatty acids (PUFAs) leading to membrane destruction. We previously showed that dietary dihomo-gamma-linolenic acid (DGLA) induces ferroptosis in Caenorhabditis elegans germ cells in a dose-dependent manner, and that the sensitivity of germ cells to dietary DGLA is altered by many genetic, dietary, and chemical interventions.
    Methods: The severity of germ cell death was documented after dietary supplementation of DGLA, vitamin B12, methionine, and choline to wild type and mutant Caenorhabditis elegans (C. elegans). The presence of germ cells, gametes, and embryos was visualized in young adult worms with 4',6-diamidino-2-phenylindole (DAPI).
    Results: The addition of vitamin B12 rescued DGLA-induced cell death. For this protection, vitamin B12 functions as a cofactor for methionine synthase (METR-1). In addition, dietary methionine and choline rescued germ cell death in the context of low-B12 diets as well as in ferroptosis-sensitive metr-1 and sams-1 mutant strains. The pcyt-1 mutant worms, with reduced capacity for phosphatidylcholine (PC) synthesis, were not responsive to dietary vitamin B12-mediated rescue of DGLA-induced ferroptosis, providing evidence that PC synthesis and homeostasis play key roles in ferroptosis susceptibility. Oleic acid supplementation rescues DGLA-induced cell death in wild type, but not in pcyt-1 mutant strains.
    Conclusion: These studies reveal the requirement for dietary vitamin B12 and sufficient PC synthesis in protection from dietary DGLA-induced ferroptosis, highlighting the importance of phospholipid metabolism in ferroptosis regulation.
    Keywords:  C. elegans; DGLA; Dihomo-gamma-linolenic acid; ferroptosis; germ cells; lipids; phosphatidylcholine; vitamin B12
    DOI:  https://doi.org/10.70401/fos.2026.0045
  15. Nat Commun. 2026 10 14. pii: 11622. [Epub ahead of print]17(1):
    Fatty acid metabolism controls plasma membrane cholesterol accessibility via ATGL-dependent phospholipid remodeling.
    Kalani M Wijesinghe, Chai-Wan Kim, Summer Chen, Emily O Schad, Erin Takeshima, Shuo Li, Chandni B Khandwala, Dylan Calhoon, Megan Danielewicz, Ryan D Leib, Javier Garcia-Bermudez, Desiree Tillo, Andres M Lebensohn, James A Olzmann, Rajat Rohatgi, Maia Kinnebrew.
      Accessible cholesterol, the pool of membrane cholesterol with high chemical activity, regulates vital processes including vertebrate development and pathogen evasion. The mechanisms that govern plasma membrane (PM) cholesterol accessibility are incompletely understood. Using a genome-wide screen we find that acetyl-CoA carboxylase alpha (ACC1) loss causes a ~10-fold increase in PM accessible cholesterol in cells and a male mouse model. We demonstrate that reduced fatty acyl-CoA levels, achieved by targeting metabolic enzymes including ACC1, fatty acid synthase (FASN) or acyl-CoA synthetases long chain (ACSL1, 3 and 4), results in the activation of adipose triacylglycerol lipase (ATGL). ATGL activation elevates polyunsaturated diacylglycerols even in triacylglycerol-deficient backgrounds, suggesting that ATGL acts independently of triacylglycerol hydrolysis. These diacylglycerol species are utilized to generate polyunsaturated phosphatidylcholine and phosphatidylethanolamine, which raises PM fluidity and cholesterol accessibility. Conversely, ATGL inhibition rigidifies the PM, reducing PM accessible cholesterol. Increased PM fluidity impairs cholesterol transport, triggering SREBP2 activation. This study reveals a surprising link between fatty acid metabolism and cholesterol homeostasis, demonstrating how ATGL-dependent lipid remodeling tunes membrane fluidity to regulate intracellular cholesterol signaling.
    DOI:  https://doi.org/10.1038/s41467-026-78470-4
  16. bioRxiv. 2026 Oct 19. pii: 2026.10.13.758691. [Epub ahead of print]
    Non-cell-autonomous removal of protein aggregates via trogocytosis.
    Yoshitaka Kimura, Kazuki Sato, Arun R Chavan, William Kasberg, Malan Silva, Wei Qiu, Nirmala Iyer, Michael Innerberger, Igor Siwanowicz, Scott D Pope, Athreya Rangavajhula, Gang-Qing Yao, Karl Insogna, Eric T Trautman, Christopher K E Bleck, Xiaolei Su, Jennifer Lippincott-Schwartz, Ruslan Medzhitov.
      Protein aggregate formation can cause cell damage and contribute to tissue pathologies including neurodegeneration. Protein aggregates are normally eliminated by cell-intrinsic mechanisms of lysosomal (autophagic) degradation. However, degradative capacity varies between cell types, raising the possibility that high-capacity cell types, such as macrophages, may contribute to aggregate disposal from the low-capacity cells. Here, we show that cellular protein aggregates are removed by macrophages via trogocytosis - a partial engulfment of the target cells. Lysosomal stress upon protein aggregate accumulation promotes cell surface expression of the transmembrane isoform of the macrophage growth factor CSF1 (tmCSF1), which is detected by macrophages through the CSF1 receptor to drive trogocytosis. Insufficient or impaired degradation of protein aggregates in lysosomes results in their transport along microtubules to the plasma membrane where they physically associate with tmCSF1. This enables macrophages to specifically trogocytose protein aggregates. These findings reveal a protein homeostasis system that eliminates protein aggregates in a non-cell-autonomous manner.
    DOI:  https://doi.org/10.64898/2026.10.13.758691
  17. Nature. 2026 Nov 11.
    Suppression of epithelial proliferation and tumorigenesis by IgA.
    Gregory P Donaldson, Gabriella Lima Dos Reis, Marwa Saad, Christopher Wichmann, Izabela Mamede, Guo Chen, Caroline E Harrer, Nicole L DelGaudio, Dayu Zhang, Begüm Aydin, Tiago B R Castro, Sergei I Grivennikov, Bernardo S Reis, Elise G Liu, Stephanie C Eisenbarth, Kivanç Birsoy, Sohail F Tavazoie, Beth M Stadtmueller, Gabriel D Victora, Daniel Mucida.
      Immunoglobulin A (IgA) is the most abundant antibody isotype produced by mammals, and has a specialized role in mucosal homeostasis1. IgA is constantly secreted into the intestinal lumen and binds to commensal microorganisms to regulate their colonization and function2,3, with unclear implications for health. IgA deficiency is common in humans, but difficult to study, because of its complex aetiology and comorbidities4-8. Here we use genetically and environmentally controlled mice to show that various models of IgA deficiency result in increased susceptibility to several models of endogenous colorectal cancer. Cellular and molecular analyses revealed that, in the absence of IgA, colonic epithelial cells induce antibacterial factors and accelerate cell cycling in response to the microbiota. Oral treatment with IgA was sufficient to reduce steady-state proliferation and protect mice from tumours; however, this function was due to the structure of the antibody rather than to binding specificity. In a reductionist culture system, IgA directly suppressed epithelial growth. Co-immunoprecipitation mass spectrometry and targeted CRISPR screening identified DMBT1 as an IgA-binding epithelial surface protein that is required for IgA-mediated suppression of proliferation. Together, IgA and DMBT1 tune the normal cycling of absorptive colonocyte progenitors. In IgA-knockout mice, deleting the transmembrane and cytoplasmic signalling portions of DMBT1 was sufficient to reverse both the increased epithelial cell proliferation and the increased tumour susceptibility seen in these mice. These experiments establish a homeostatic function for IgA in tempering physiological epithelial responses to the microbiota to maintain mucosal health.
    DOI:  https://doi.org/10.1038/s41586-026-11264-2
  18. Nat Cell Biol. 2026 Nov 12.
    TMEM192 is a calcineurin-regulated membrane receptor for ubiquitin-independent lysophagy.
    Xinchang Liu, Yangjun Yang, Wenchan Li, Kesong Peng, Xiangmin Qiu, Ye Xu, Sai Zeng, Dante Neculai, Qiming Sun, Tianhua Zhou, Han-Ming Shen, Wei Liu.
      Lysophagy is a selective form of autophagy responsible for clearing damaged lysosomes. Although existing models predominantly highlight ubiquitin-dependent mechanisms, here we identify the lysosomal membrane protein TMEM192 as a key ubiquitin-independent receptor for lysophagy. We demonstrate that lysophagy persists in cells even when protein ubiquitination is inhibited or autophagy adaptors are deleted. Following lysosomal damage, the efflux of calcium from lysosomes activates calcineurin, leading to the dephosphorylation of TMEM192 at Ser229. This exposes a latent LC3-interacting region and enables direct recruitment of autophagosomes. Depletion of TMEM192 or blockade of its dephosphorylation severely impairs lysophagy, resulting in the accumulation of damaged lysosomes. In a mouse model of acute hyperuricemic nephropathy, deficiency in TMEM192 exacerbates renal tubular injury. Our findings establish a ubiquitin-independent lysophagy pathway, which holds important implications for understanding and intervening lysosomal-related diseases.
    DOI:  https://doi.org/10.1038/s41556-026-02135-z
  19. Dev Cell. 2026 Nov 11. pii: S1534-5807(26)00395-3. [Epub ahead of print]61(11): 2193-2212.e8
    p53 activates chaperone-mediated autophagy to remodel metabolism and suppress tumorigenesis.
    Yi Xu, Qimin Zhou, Yanjun Wu, Sixiang Yu, Yang Zhang, Zheng Wang, Yuting Wang, Junting Xie, Chen Fan, Xiaolu Yang.
      p53 protects against the initiation and progression of cancers, but the mechanisms underlying this function remain incompletely understood. Chaperone-mediated autophagy (CMA) is a form of autophagy unique in vertebrates, yet its regulation and function are unclear. Here, we demonstrate that p53 functions as a central activator of CMA, integrating stress signals to regulate this selective autophagic pathway. Mechanistically, the energy sensor AMP-activated protein kinase (AMPK) inhibits CMA by preventing oligomerization of its receptor LAMP2A. Cytoplasmic p53 interacts with AMPK and relieves this inhibition. By activating CMA, p53 promotes lysosomal degradation of isocitrate dehydrogenases IDH1 and IDH2, thereby reducing intracellular α-ketoglutarate levels, inhibiting reductive glutamine metabolism, and suppressing growth of lung and liver cancers. Tumor-associated p53 mutants fail to promote CMA, whereas oncogenic IDH1/2 mutants evade CMA-mediated degradation. These results suggest that CMA activation may be a fundamental component of p53 function, through which it modulates metabolism and inhibits oncogenic growth.
    Keywords:  AMPK; CMA; IDH1; IDH2; LAMP2A; autophagy; chaperone-mediated autophagy; p53; reductive carboxylation; α-ketoglutarate
    DOI:  https://doi.org/10.1016/j.devcel.2026.10.009
  20. medRxiv. 2026 Oct 23. pii: 2026.10.22.26365257. [Epub ahead of print]
    SNX13 and SNX14 interorganelle tethers suppress lysosome membrane damage and neurodegeneration.
    Kaitlynn Gov, Vanessa B Sanchez, Emma Reynolds, Caroline Bickerton, Teresa Jimenez, Sanghee Yun, Ipsita Chakraborty, Raunaq Deo, Daniel Smith, Thomas Roule, Blessy Paul, Sonakshi Srivastava, Amelia J Eisch, Ophir Shalem, Xilma Ortiz-Gonzalez, Clementina Mesaros, Joseph G Gleeson, Uner Tan, Antoine Pouzet, Caroline Nava, Brett M Collins, William A Prinz, Jeffrey McDonald, Jonathan Levy, Boris Keren, Alexandra Afenjar, Joan Font-Burgada, W Mike Henne, Naiara Akizu.
      Lysosome membrane permeabilization (LMP) is an emerging signature of neurodegenerative diseases, yet the mechanisms that enable an effective repair are largely undefined, particularly in neurons. Here, we reveal sorting nexin (SNX) proteins SNX13 and SNX14 maintain lysosome membrane lipid composition to support efficient LMP repair and neuronal survival. We identify loss of function mutations in SNX13 in children manifesting a previously unrecognized cerebellar neurodegenerative disorder. Consistently, Snx13 ablation in mice causes cerebellar Purkinje cell death and signatures of ataxia-like motor deficits. We show loss of SNX13 or its ataxia-linked paralog SNX14 perturbs lysosome morphology, positioning, and acidity and causes increased susceptibility to lysosome damage. Using lysosome immunoprecipitation and proteomics, we comprehensively map lysosome proteome remodeling during membrane damage and repair, finding that SNX13 or SNX14 deficiency blunts recruitment of repair machinery, including ESCRTs and PITT pathway proteins, to damaged lysosomes. Mechanistically, we determine SNX13 and SNX14 support lysosome integrity through interorganelle lipid crosstalk. We define SNX13 and SNX14 as lipid binding proteins that localize to ER-lysosome junctions, where they support lysosomal phosphoinositide levels in response to membrane damage. In line with this, loss of SNX13 or SNX14 impairs lysosome PtdIns4P signaling. Altogether, our work reveals a conserved mechanism of interorganelle lipid crosstalk by SNX13/14 family proteins that safeguards lysosome membranes, maintaining them competent for repair, and is defective in cerebellar neurodegeneration.
    DOI:  https://doi.org/10.64898/2026.10.22.26365257
  21. Sci Data. 2026 Nov 06. pii: 1542. [Epub ahead of print]13(1):
    Synchrotron X-ray Data of non-diseased and diabetic Human Pancreas Tissue and Islet Segmentation Model.
    Lukas Hessel, Jonas Albers, Matthias M Gaida, Christoph Eckert, Caroline V Schimmel, Klara Schulze, Verena Wagner, Philipp Mayer, Alexander Rathenborg, Thomas Hank, Christoph W Michalski, Elizabeth Duke, Martin Loos, Gabriel A Salg.
      Three-dimensional virtual histology using synchrotron radiation micro-computed tomography enables non-destructive visualization of biological tissue microarchitecture with isotropic resolution. To support quantitative studies of human pancreatic morphology, we provide high-resolution 3D X-ray imaging datasets of 55 pancreatic tissue cores from 32 individuals. The collection comprises histologically non-diseased pancreatic tissue from organ donors and non-neoplastic regions of surgical resection specimens from patients with pancreatic cancer, including subgroups with insulin-dependent diabetes or following neoadjuvant chemotherapy. Formalin-fixed, paraffin-embedded tissue cores with a diameter of 1 mm were imaged at 650 nm isotropic voxel size, yielding a mean effective spatial resolution of 1.66 µm. The cohort includes reconstructed volumes, corresponding immunohistochemistry, clinical metadata, expert-validated annotations, and dataset-specific example 2.5D U-Net models for automated segmentation of islets of Langerhans. A representative co-registered section yielded a Dice similarity coefficient of 0.81 and intersection-over-union of 0.67. This openly accessible, FAIR-compliant resource supports quantitative analysis of endocrine, exocrine, ductal, and stromal architecture and provides a reproducible reference framework for three-dimensional virtual histology of human pancreatic tissue and computational benchmarking.
    DOI:  https://doi.org/10.1038/s41597-026-08613-1
  22. ESMO Open. 2026 Nov 09. pii: S2059-7029(26)02566-4. [Epub ahead of print]11(11): 108621
    daNIS-2: a phase III, randomized, double-blind study of the anti-TGF-β monoclonal antibody NIS793 or placebo in combination with nab-paclitaxel/gemcitabine as first-line treatment in patients with metastatic pancreatic ductal adenocarcinoma.
    S Paulson, M Ikeda, L Shen, A Stein, T Macarulla, M Milella, T Golan, Z Wainberg, J Taieb, L Wang, F Polydoros, C Abecunas, E López, E M O'Reilly.
       BACKGROUND: This phase III, randomized, double-blind study (daNIS-2) evaluated the efficacy and safety of NIS793, an anti-transforming growth factor-beta (TGF-β) monoclonal antibody, in combination with gemcitabine and nab-paclitaxel [standard of care (SOC)] versus placebo and SOC as first-line treatment in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC).
    PATIENTS AND METHODS: The study included a safety run-in (n = 21 patients enrolled) followed by a randomized part (n = 490 patients randomly assigned). Patients were assigned 1 : 1 to receive NIS793 or placebo with SOC. The primary endpoint was overall survival (OS), secondary endpoints included progression-free survival (PFS), overall response rate (ORR), safety, pharmacokinetics, and exploratory biomarker analyses.
    RESULTS: The study was terminated early following an interim analysis due to an unfavorable benefit-risk profile. Median OS was 9.2 months in the NIS793 arm versus 11.2 months in the placebo arm (hazard ratio 1.26, 95% confidence interval 1.01-1.59). The estimates of ORR and median PFS indicate a less favorable treatment effect with NIS793. Safety profiles were comparable between arms, although higher rates of anemia, epistaxis, and rash were observed with NIS793; serious adverse events were more frequent in the NIS793 arm, with most being grade ≥3. Pharmacodynamic markers such as Pro-C3 supported target engagement. However, such target engagement did not translate into clinical benefit and early circulating tumor DNA dynamics were associated with less favorable outcomes. Biomarker analyses suggested that unfavorable benefit-risk profile of NIS793 was most pronounced in patients with a low epithelial-to-mesenchymal transition signature and a classical molecular subtype.
    CONCLUSIONS: NIS793 in combination with SOC did not improve survival outcomes in first-line mPDAC and was associated with an unfavorable benefit-risk profile. Exploratory biomarker findings highlight the complexity of TGF-β signaling and underscore the need for refined patient selection strategies in future trials.
    DOI:  https://doi.org/10.1016/j.esmoop.2026.108621
  23. bioRxiv. 2026 Oct 20. pii: 2026.10.19.760262. [Epub ahead of print]
    NEIL2 regulates RNA polymerase II dynamics to suppress transcription-replication conflicts in pancreatic cancer.
    Fan Meng, Anthony Fernandez, Changfei Luan, Marc A Attiyeh, Qianhua Feng, Alexander Lee, Haihua Feng, Tiane Li, Tingting Zhou, Yun R Li, Russell Rockne, Terence Williams, David Dawson, Binghui Shen, Jen Jen Yeh, Yilun Liu, Maria Ninova, Mustafa Raoof.
      Transcription-replication conflicts (TRCs) arise from spatiotemporal interference between replication and transcription machinery and contribute to genome instability in cancer cells. In pancreatic ductal adenocarcinoma (PDAC) cells, oncogenic KRAS drives TRC formation, and base excision repair (BER) contributes to TRC resolution as an adaptive response. Here, we show that TRCs are enriched in pancreatic tumor sections from patients and are associated with malignant progression. We identify NEIL2, a bifunctional DNA glycosylase in the BER pathway, as a critical regulator of TRCs in PDAC cells. Mechanistically, NEIL2 loss causes aberrant RNA polymerase II (RNAPII) occupancy at transcription start sites and downstream of transcription end sites. Dysregulated RNAPII dynamics promote R-loop-dependent and -independent TRCs contributing to replication stress, DNA damage, and impaired cancer cell proliferation. Notably, the DNA-binding motif of NEIL2 necessary for canonical BER function is dispensable for TRC regulation. Together, these findings reveal an unrecognized role for NEIL2 in regulating RNAPII dynamics and mitigating TRCs in pancreatic cancer cells.
    DOI:  https://doi.org/10.64898/2026.10.19.760262
  24. Nat Aging. 2026 Nov;6(11): 2469-2492
    Altered protein cysteine reactivity in senescent cells is a vulnerability for senolysis to ameliorate aging.
    Rong Wu, Fan Yang, Jiacheng Li, Tong Wu, Ruitu Lyu, Junhong Xiang, Xue Gao, Rukang Zhang, Hao Fan, Chunzhao Yin, Jiayi Tu, Zhicheng Xie, Chufan Cai, Freya Q Zhang, Kelly Xue, Jeronimo Najarro, Lei Dong, Rui Su, Angelo Y Meliton, Em Lundberg, Jonah K Chen, Janane Rahbani, Nickolai O Dulin, Nicole Arellano, Jun-Wei B Hughes, Shannon E Elf, Yu-Ying He, Bruce M Bissonnette, Robert B Hamanaka, Gökhan M Mutlu, Judith Campisi, Chuan He, Jing Chen.
      How diet shapes aging and age-related diseases marked by senescent cell accumulation remains unclear. Here we report vanadyl sulfate (VS), a mineral dietary supplement, as a senolytic agent. Oral VS ameliorates phenotypes of aging and diverse age-related disorders and extends lifespan in male mice. Integrated functional omics analyses show that senescent cells exhibit globally reduced proteome cysteine reactivity but increased expression and apparent cysteine reactivity of proteins essential for endoplasmic reticulum proteostasis. This redox-proteostasis state is linked to glutathione disulfide (GSSG) accumulation and can be recapitulated by GSSG delivery in nonsenescent cells. Mechanistically, VS inactivates reactive cysteines and promotes disulfide bond formation in senescent cells, leading to protein misfolding, aggregation and ultimately cell death. Glutathione reductase downregulation promotes GSSG accumulation, distinguishing senescent from nonsenescent cells and conferring selective susceptibility to VS. Our findings reveal an exploitable redox-proteostasis vulnerability of senescent cells with therapeutic potential to ameliorate aging.
    DOI:  https://doi.org/10.1038/s43587-026-01253-5
  25. Front Cell Dev Biol. 2026 ;14 1997123
    HIF-1α-mediated metabolic reprogramming in hypoxia-driven tumor metastasis.
    Shulun Shao, Mengxin Wang, Renjian Xie, Shenglan Liu, Wei Dai, Tai Zeng, Lei Lai, Kunpeng Zhang, Yumei Li.
      Tumor metastasis is a multistep process that requires profound metabolic plasticity to support cancer cell invasion, survival in circulation, colonization of distant organs, and metastatic outgrowth. Hypoxia is a hallmark of solid tumors and a major driver of metastatic progression. As a central transcriptional regulator of the hypoxic response, hypoxia-inducible factor-1α is stabilized under oxygen deprivation and orchestrates broad metabolic reprogramming by regulating glycolysis, lactate production and export, mitochondrial respiration, lipid metabolism, amino acid utilization, redox homeostasis, and interactions with the tumor microenvironment. These metabolic adaptations not only provide bioenergetic and biosynthetic support for disseminating cancer cells but also promote epithelial-mesenchymal transition, extracellular matrix remodeling, angiogenesis, immune evasion, and premetastatic niche formation. In this review, we summarize current knowledge regarding the mechanisms by which hypoxia-inducible factor-1α-mediated metabolic reprogramming contributes to different stages of the metastatic cascade. We also discuss the therapeutic potential and limitations of targeting hypoxia-inducible factor-1α-associated metabolic vulnerabilities in metastatic cancer. A better understanding of the context-dependent functions of hypoxia-inducible factor-1α may facilitate the development of more effective anti-metastatic strategies.
    Keywords:  hypoxia; hypoxia-inducible factor-1α; metabolic reprogramming; tumor metastasis; tumor microenvironment
    DOI:  https://doi.org/10.3389/fcell.2026.1997123
  26. Nat Commun. 2026 10 15. pii: 11649. [Epub ahead of print]17(1):
    Acute priming using elevated fluid viscosity recovers young-like single-cell surveillance behaviors in aged human T cells.
    Yoseph W Dance, Alice Amitrano, Nicolas C Macaluso, Chanhong Min, Ladaisha T Thompson, Annaka M Saffron, Zhuoxu Ge, Ian M Smith, Charles Ezenwanne, Nicholas Milcik, Abigail Fennell, Kendall A Pyndell, Crystal Szczesny, Jacqueline Langdon, Jeanine A Ursitti, Christopher W Ward, Kimberly M Stroka, Jeremy D Walston, Sean X Sun, Konstantinos Konstantopoulos, Jude M Phillip.
      Aging is a complex biological process often characterized by increased vulnerability to disease, infection, and death. This increased vulnerability is mechanistically linked to a progressive and functional decline of the immune system. In humans, aged T cells lose their ability to effectively surveil complex microenvironments, thereby decreasing their capacity to clear infections, eradicate diseases, and maintain physiological homeostasis. However, specific mechanisms by which aged T cells lose this capacity to surveil remain unclear. Here, we profile three core characteristics of T cell surveillance at single-cell resolution, specifically migration, deformability, and sensing. While aged human T cells retain their capacity to migrate ex vivo, they exhibit impaired cellular deformability and deficiencies in sensing local biological signals. To modulate this surveillance defect, we perform mechanical reprogramming using elevated fluid viscosity. Results indicate that acute priming of aged T cells with elevated fluid viscosity recovers a transient young-like surveillance phenotype, particularly within CD4+ memory T cell populations. This recovered young-like phenotype is mechanistically linked to elevated SDF-1α receptor expression together with increased membrane tension, cortical F-actin, and Arp3 expression. Altogether, these findings identify a key source of surveillance defects among aged T cells and offer an effective mechano-inducible strategy for modulating single-cell behaviors.
    DOI:  https://doi.org/10.1038/s41467-026-78411-1
  27. Biophys Rev. 2026 Oct;18(5): 975-1001
    Poking the cell surface: mechanics, remodeling, and what force reveals.
    Bruno Pontes.
      What happens when you poke a living cell, applying a localized external force to its surface? The answer depends, in part, on how long you keep poking. The plasma membrane and the actomyosin cortex beneath it form a mechanically active interface that changes in disease and can itself be reshaped by force. This review explores how the cell surface responds to such force in two overlapping experimental regimes. Poke briefly, over seconds, and force becomes a readout, revealing biophysical parameters that report on cell state and serve as candidate single-cell markers of disease. Keep poking, over minutes, and force can remodel the surface, suggesting that it may act not only as a perturbation but also as an instructive signal. What emerges is a mechanical fingerprint whose potential for diagnosis, disease monitoring, and, eventually, controlled manipulation of cell surfaces is only beginning to be understood.
    Keywords:  Cell surface mechanics; Force-driven remodeling; Mechanobiology; Mechanomics; Membrane tension; Membrane-cortex adhesion; Rheology; Viscoelasticity
    DOI:  https://doi.org/10.1007/s12551-026-01473-4
  28. bioRxiv. 2026 Oct 25. pii: 2026.10.20.760559. [Epub ahead of print]
    Oncogenic KRAS-MAPK signaling sustains a CD73 dependent therapeutic vulnerability in pancreatic cancer.
    Khadija Turabi, Urvinder Kaur Sardarni, Katherine E Ankenbauer, Sabrina M Torbit, Christopher P Taranto, Shwetapadma Dash, Audrey Meade, Amelia T Cephas, Kelsey A Klute, Marina Pasca di Magliano, Thomas McFall, Kathleen E DelGiorno, Jennifer M Bailey-Lundberg.
      Pancreatic ductal adenocarcinoma (PDAC) is predominantly driven by oncogenic KRAS signaling and sustained by a desmoplastic, immunosuppressive microenvironment limiting therapeutic response. CD73-mediated adenosine signaling supports this immune-excluded, tumor-supportive microenvironment. Whether dual targeting of KRAS-MAPK and CD73 signaling creates a therapeutic opportunity to improve tumor control remains unexplored. Analysis of KRAS-mutant cancer cell lines revealed increased expression of NT5E and adenosine receptor ADORA2B. Pharmacologic and genetic suppression of oncogenic KRAS inhibited CD73 expression through a MAPK-dependent program. In syngeneic KPC tumors, conversely, CD73 inhibition with quemliclustat increased ERK phosphorylation in vivo, suggesting adaptive MAPK activation following CD73 blockade. Combined CD73 and RAS(ON) inhibition in vivo produced the strongest antitumor response, reducing endpoint tumor volume beyond either monotherapy. This combination significantly suppressed tumor proliferation and αSMA-positive stroma and resulted in a substantial reduction in CD163-positive macrophage infiltration. RAS-MAPK targeted therapy was also associated with increased CD8α-positive T cell infiltration and granzyme B-positive staining. As therapeutic responses in PDAC have been linked to the gut microbiome, we further examined treatment-associated changes in the microbiome. RAS-MAPK inhibition produced the most pronounced microbial alterations, which correlated with tumor volume and immune markers. Together, these findings identify KRAS-MAPK driven CD73 signaling as a therapeutic vulnerability in PDAC and support combined CD73 and RAS(ON) inhibition as a strategy to suppress tumor growth, remodel stroma, and alleviate tumor-associated immune suppression.
    Keywords:  CD73; Combination therapy; Desmoplasia; KRAS; MAPK signaling; Pancreatic ductal adenocarcinoma; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.64898/2026.10.20.760559
  29. J Chem Theory Comput. 2026 Nov 10. 22(21): 11634-11646
    LipidMem-BigSMILES (LiMBS): A Standardized Representation Language for Lipid Membrane Systems.
    Pratima Khadka, Shikha Nangia.
      Molecular dynamics simulations of lipid membranes lack a standardized, machine-readable representation, creating significant barriers to reproducibility, data sharing, and AI-driven analyses. Current membrane descriptions are fragmented across software-specific input files, making it difficult to reconstruct published systems or compare results among studies. Here, we introduce LipidMem-BigSMILES (LiMBS), a line notation not a simulation tool or membrane-building program, for lipid membrane simulations that extend SMILES, BigSMILES, and CG-BigSMILES to membrane systems. LiMBS version 1.0 uses a dual-block architecture that separates a system-level descriptor block from a chemical structure block, enabling the independent specification of membrane geometry, composition, environmental conditions, and molecular identity. The framework supports planar bilayers, vesicles, and bacterial outer membranes in atomistic, coarse-grained, and supercoarse-grained resolutions within a unified syntax. We provide a reference tool that reads, checks, and standardizes LiMBS strings, and we show that its output can be handed off to existing membrane-building software for system construction. LiMBS1.0 is human-readable, machine-readable, tool-independent, and compatible with FAIR data principles, providing a standardized description layer for membrane simulations that supports reproducible reporting, interoperable databases, and AI-enabled membrane biophysics.
    DOI:  https://doi.org/10.1021/acs.jctc.6c01274
  30. Front Pharmacol. 2026 ;17 1983363
    The mitochondrion as a mechanometabolic conductor of cancer metastasis: pharmacological insights from the mitochondria-peroxisome interface.
    Subhajit Dutta, Namrata Maity.
      Metastasis demands more than sustained ATP production: cancer cells must move organelles, remodel membranes, manage oxidative stress, and reprogram metabolism as they pass from invasion to distant colonisation. Mitochondria sit at the centre of this adaptation. This Review organises their contribution around four linked axes: deployment to the cell cortex and invadopodia; reactive oxygen species and metabolite signalling; VDAC1-dependent metabolite, calcium, apoptotic and mtDNA gating; and HIF-1α-BNIP3-dependent remodelling of the mitochondrial pool. We then ask how this mitochondrial programme is altered by peroxisomes. The two organelles share components of the fission machinery, coordinate lipid-derived substrate use and cellular redox balance, and divide tasks in hydrogen-peroxide control, ether-lipid synthesis, organelle quality control and MAVS signalling. These connections matter pharmacologically. A DRP1- or redox-directed intervention may affect both organelles, whereas VDAC1 provides a more mitochondria-restricted target logic. Peroxisomal pathways are also context dependent: fatty-acid shortening and ether-lipid synthesis can increase metabolic flexibility and membrane remodelling, yet the same pathways may raise oxidative stress or create ferroptotic susceptibility. By separating established molecular links from mechanisms that remain untested in metastatic models, we propose a hierarchical view in which mitochondria remain the principal mechanometabolic conductor, while peroxisomes set important boundary conditions for substrate use, redox signalling, immune responses and therapeutic selectivity. We also state the limitation this framing carries. The mitochondrial arm of the framework rests on direct experimental evidence, whereas a causal contribution of mitochondria-peroxisome contacts to invasion, transit or colonisation has not been demonstrated: it is inferred here from contact biology characterised without testing metastatic endpoints, from division machinery shared between the two organelles, and from biochemical coupling. The interface is therefore advanced as a testable framework for target selection and pharmacological attribution, not as an established driver of metastasis.
    Keywords:  cancer metastasis; ferroptosis; mechanometabolism; mitochondria; organelle dynamics; peroxisomes; pharmacological selectivity; redox signalling
    DOI:  https://doi.org/10.3389/fphar.2026.1983363
  31. Nature. 2026 Nov 11.
    Mitochondrial protein import defects enhance tumour immunogenicity.
    Thomas D Jackson, Jonathan M Palozzi, Christopher D McGann, Tevis Vitale, Ruth Choa, Hieu H M Nguyen, Joao A Paulo, Pedro Latorre-Muro, Jonathan G Van Vranken, Matthew Ravichandran, Bingsen Zhang, Manisha Yadav, Steven P Gygi, Pere Puigserver.
      Tumour cells evade detection and elimination by the immune system through a suite of adaptations1, including the repression of antigen presentation, which is required for the recognition of tumour cells by CD8+ T cells. Mitochondria have emerged as targets for enhancing antitumour immunity; however, the extensive mitochondrial proteome has remained largely unstudied for its ability to modulate immune responses. Here we show that defects in the mitochondrial protein import machinery promote tumour immunogenicity and synergize with immune checkpoint blockade treatment in melanoma models. Mitochondrial protein import perturbation, specifically through depletion of the TIM23 import complex subunit TIMM50, enhances tumour immunogenicity through a pathway involving mitochondrial DNA escape, cGAS-STING pathway activation and interferon-β (IFNβ) secretion. Secreted IFNβ signals through the type I IFN receptor to activate the JAK-STAT pathway, resulting in increased antigen presentation on MHC class I complexes. Mitochondrial DNA escape in Timm50-depleted cells is linked to the formation of mitochondrial-derived vesicles. Depletion of SNX9 and RAB9, involved in mitochondrial-derived vesicle formation2, suppresses mitochondrial DNA-dependent type I IFN production and signalling. By disrupting mitochondrial proteostasis and membrane architecture, defective protein import in Timm50-depleted cells drives the immune phenotype. This study shows that mitochondrial protein import inhibition causes tumour immunogenicity, including sensitization to immune checkpoint blockade, by promoting mitochondrial DNA escape and IFNβ-driven MHC class I antigen presentation.
    DOI:  https://doi.org/10.1038/s41586-026-11249-1
  32. Nat Med. 2026 Nov 10.
    Next-generation KRAS G12C inhibitor improves survival in lung cancer.
    Ulrike Harjes.
      
    Keywords:  Clinical trials; Lung cancer; Targeted therapies
    DOI:  https://doi.org/10.1038/d41591-026-00057-9
  33. J Cell Biol. 2027 Feb 01. pii: e202601076. [Epub ahead of print]226(2):
    ESCRT-III assembly restores membrane tension in micron-scale plasma membrane repair.
    Xinan Meng, Yuanyuan Wang, Erqing Gao, Liwei Guan, Yiyuan Ge, Jingyi Kang, Jingxiu Xu, Jingyang Yuan, Shujun Cai, Eric Miska, Wei Yang, Suhong Xu.
      Plasma membrane integrity is essential for cellular survival, yet how cells repair micron-scale plasma membrane ruptures remains poorly understood. Here, using the genetically tractable Caenorhabditis elegans epidermis, we combine live imaging, genetics, super-resolution microscopy, and biophysical approaches to define a size-dependent role for endosomal sorting complexes required for transport (ESCRT)-III in large-scale membrane repair. Small wounds induce transient, focal VPS-32 accumulation, whereas large wounds trigger the formation of a persistent but dynamic, circumferential ESCRT-III assembly that remains associated with the wound during repair. Formation of this assembly requires conserved ESCRT regulators, including ALX-1, TSG-101, and VPS-4, together with VPS-32 polymerization. The wound-associated ESCRT-III assembly is required for membrane tension restoration and efficient membrane repair, while disrupting VPS-32 polymerization impairs tension recovery, reduces vesicle recruitment and wound closure, and consequently compromises axon regeneration and organismal survival following injury. Together, our findings suggest that large plasma membrane wounds induce a persistent, dynamic ESCRT-III assembly that restores membrane tension and facilitates vesicle-mediated membrane addition to promote wound repair.
    DOI:  https://doi.org/10.1083/jcb.202601076
  34. Trends Cell Biol. 2026 Nov 07. pii: S0962-8924(26)00212-6. [Epub ahead of print]
    The Five Phases of cancer cells.
    Xinyu Liu, Min Yan, Bin He, Keith W Kelley, Quentin Liu.
      Beyond identifying individual malignant hallmarks, the central challenge in cancer biology is to uncover the fundamental organizing principles that underlie the interactive nature of cancer cell behavior. Here, we transform the ancient Wuxing theory into a mechanistically grounded, hypothesis-generating biological framework that conceptualizes cancer cell biology around five mutually interacting processes: Pliability, Hybridity, Aggressivity, Sociability, and Evolutivity (PHASE). By engaging in the circuit of mutual promotion and restriction, these phases form an integrated regulatory system that provides a rationale for organizing diverse malignant properties. Within this framework, cancer traits emerge as context-dependent manifestations of the proposed core interactions. Collectively, PHASE offers a complementary perspective for understanding disease progression that could advance interaction-guided therapeutic strategies to target human cancers.
    Keywords:  PHASE; biological processes; cancer hallmarks; cancer therapy; mutual interaction
    DOI:  https://doi.org/10.1016/j.tcb.2026.10.006
  35. Soft Matter. 2026 Nov 09.
    Computational modelling of macrophage facilitated cancer metastasis using a cellular Potts model.
    Siddhant Sharma.
      Breast cancer mortality primarily results from metastatic dissemination. Macrophages are known to actively facilitate cancer cell invasion through the CSF-1/EGF paracrine signalling loop. This signalling loop involves tumour cells secreting colony-stimulating factor 1 (CSF-1) to recruit macrophages, which in turn release the epidermal growth factor (EGF) that promotes tumour cell migration and invasion. However, it remains incompletely understood how CSF-1/EGF chemical signalling cues and other related processes like chemotaxis, cell adhesion, and contact inhibition collectively give rise to the coordinated and persistent migration of tumour-macrophage aggregates required for invasion towards the endothelium. Here, a 2D cellular Potts model (CPM) is developed to investigate the spatiotemporal dynamics of how these coupled processes together govern tumour-macrophage aggregate formation and co-migration. Simulations show that metastasis depends on the combined influence of chemoattractant signalling, chemotactic responsiveness, physical cell-cell interactions, and directional migration rather than on any single process alone. In particular, changes in these processes can alter the collective mobility of tumour-macrophage aggregates, resulting in differences in cell displacement and migratory behaviour. Spatial variations in the CSF-1 and EGF fields generate cues for macrophage and cancer cell chemotaxis, with changes in their secretion and degradation rates influencing how these cues develop and persist across the simulation domain. Contact inhibition can attenuate chemotactic migration in dense cellular environments, while directional TAM migration contributes to tumour-macrophage movement towards the endothelium, with metastatic burden maximized at an intermediate directed-motion strength value. Overall, findings herein highlight the non-intuitive effects of changes in individual parameters and provide insight into the conditions that favour coordinated tumour-macrophage migration and invasion towards the endothelium. The framework herein can also help identify additional regulatory mechanisms that can be targeted through chemotherapy or immunotherapy strategies to limit metastasis.
    DOI:  https://doi.org/10.1039/d6sm00489j
  36. medRxiv. 2026 Oct 19. pii: 2026.10.15.26365671. [Epub ahead of print]
    Blood-based PhenoAge may reflect disease burden rather than biological aging in cancer.
    Anish K Simhal, Jasme Lee, Kay See Tan, Patrick J McCormick, Gregory W Fischer, Joseph R Scarpa, Guillermo Sapiro, Joshua S Mincer.
      PhenoAge, a blood-based biological aging clock, is associated with cancer outcomes, a finding taken as evidence that biological aging shapes prognosis. In 3,067 patients undergoing primary tumor resection, PhenoAge acceleration rose with tumor stage. One or two of its eight blood components, differing by cancer type, carried the prognostic signal, and replacing its general-population weights with equal weights did not weaken it. In cancer, PhenoAge may reflect disease burden rather than biological aging.
    DOI:  https://doi.org/10.64898/2026.10.15.26365671
  37. JCI Insight. 2026 Nov 09. pii: e203276. [Epub ahead of print]11(21):
    Elucidating cancer cachexia-mediated aberrant cardiac wasting signaling in human iPSC-derived cardiac muscle.
    Nora Hosny, Houda Cohen, Mohamed Waleed Elafany, Jeff Schreifels, John Bauer, Rishi Gulati, Brian R Thompson, Julia C Liu, Joseph M Metzger.
      Cancer cachexia is a debilitating syndrome of involuntary body mass loss featuring profound skeletal muscle wasting and high mortality. Cardiac muscle wasting is prominent in cancer patients and cancer survivors. We developed a human induced pluripotent stem cell-derived cardiac myocyte (hiPSC-CM) platform modeling cancer cachexia using conditioned media and Transwell coculture with C26 or HCT116 tumor cells. Cachectic hiPSC-CMs exhibited atrophy, reduced contraction amplitude, prolonged relaxation time, and elevated oxygen consumption rate, reflecting wasting, contractile dysfunction, and metabolic dysregulation. Mechanistically, suppression of the AKT/mTORC1/S6 signaling axis notably reduced total and p-AKT, decreased the p-S6/S6 ratio, and downregulated RPTOR, which coincided with FOXO1/3 activation and FOXO1 nuclear translocation, promoting downstream atrophic remodeling. Concurrently, Atrogin-1 upregulation reduced calcineurin A, impairing NFAT nuclear translocation, thereby suppressing downstream growth signaling. Increased autophagic flux with an elevated LC3BII/LC3BI ratio accompanied these changes. Following withdrawal of cachexia-inducing stimuli, Atrogin-1 and autophagy markers normalized within 1 week; however, contractile and metabolic impairments persisted, indicating delayed functional recovery. These findings establish the FOXO/Atrogin-1/calcineurin A/NFAT axis, operating within the broader context of AKT/mTORC1 suppression, as a central regulatory mechanism of cachexia-induced cardiac wasting, unveiling a tractable therapeutic target.
    Keywords:  Cancer; Cardiology; Cardiovascular disease; Oncology; Ubiquitin-proteosome system
    DOI:  https://doi.org/10.1172/jci.insight.203276
  38. Mitochondrion. 2026 Nov 10. pii: S1567-7249(26)00122-4. [Epub ahead of print]92 102232
    ME1 inhibits ferroptosis by targeting GPX4 in HCC through enzymatic and moonlighting functions.
    Zitao Jiao, Kejia Lu, Xinyi Liu, Yahui Zou, Hui Li, Wei Jiang, Xiaowei Zhang.
      Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Malic enzyme 1 (ME1) is upregulated in HCC and linked to poor prognosis. We demonstrate that ME1 promotes HCC malignancy and sorafenib resistance by inhibiting ferroptosis. Mechanistically, ME1 has a dual function: it generates NADPH to mitigate ROS, and independently, it binds glutathione peroxidase 4 (GPX4) to recruit USP8, preventing GPX4 ubiquitination. Pharmacological treatment with HY-124861, a compound that targets ME1, reduced ME1 protein levels and disrupted the ME1-dependent suppression of ferroptosis, restoring ferroptosis sensitivity. Combining HY-124861 with sorafenib suppressed tumor growth. Collectively, our findings establish ME1 as a therapeutic target to overcome sorafenib resistance.
    Keywords:  Ferroptosis; GPX4; HCC; ME1; Sorafenib
    DOI:  https://doi.org/10.1016/j.mito.2026.102232
  39. EMBO Rep. 2026 Nov 11.
    Ubiquitin-dependent signal amplification in lipid saturation sensing.
    Jona Causemann, Barbara Schmidt, Daniel Granz, Thorsten Mosler, Martin Jung, Ivan Dikic, Heiko Rieger, Robert Ernst.
      Cellular membranes are dynamic platforms whose composition and biophysical properties are surveyed by sensor proteins to maintain homeostasis. Failure to preserve membrane homeostasis, however, results in cellular stress and organelle dysfunction. Using the prototypical lipid saturation sensor Mga2, we explored how weak physical cues that modulate rotational movements in the transmembrane region are converted into decisive biochemical outputs that ultimately control the production of unsaturated fatty acids. Using reconstituted systems and purified components, we quantitatively follow the ubiquitylation of Mga2 via the E3 ligase Rsp5. Kinetic modeling reveals that several rounds of ubiquitylation contribute to signal amplification and uncovers the first transfer of ubiquitin onto Mga2 as a kinetic gatekeeper. The minimal system composed of the sensor protein and a canonical E1-E2-E3 ubiquitylation cascade is sufficient to discriminate saturated and unsaturated membrane lipid environments even in the absence of deubiquitylating enzymes such as Ubp2. Our findings provide a mechanistic framework for how membrane property sensors convert weak, fluctuating physical cues into robust biochemical outcomes.
    DOI:  https://doi.org/10.1038/s44319-026-00997-w
  40. Signal Transduct Target Ther. 2026 Nov 09. pii: 486. [Epub ahead of print]11(1):
    Mutant KRAS vaccination for pancreatic cancer interception: the G12D immunogenicity paradox.
    Morten Orebo Holmström, Mie Linder Hübbe, Inna Markovna Chen, Mads Hald Andersen.
      
    DOI:  https://doi.org/10.1038/s41392-026-03088-3
  41. Sci Adv. 2026 Nov 13. 12(46): eaee3585
    A TROP2-targeting aptamer enables selective drug delivery and potent antitumor activity in pancreatic cancer.
    Yuanding Liu, Zhaofeng Luo, Yuan Gao, Tao Pan, Changjie Yang, Zheng Zhang, Die Yu, Yifan He, Daiquan Chen, Sainan Guo, Yingbin Liu, Yang Sun, Weihong Tan.
      Pancreatic ductal adenocarcinoma (PDAC) remains difficult to treat, highlighting the need for strategies that selectively deliver cytotoxic agents to tumor cells. Trophoblast cell-surface antigen 2 (TROP2) has been proposed as a candidate therapeutic target in PDAC, but non-antibody-based delivery formats remain underexplored. Using protein-SELEX, we identified T17, a high-affinity aptamer that specifically binds to TROP2, and conjugated it to monomethyl auristatin E through an MC-Val-Cit-PAB linker to generate the aptamer-drug conjugate T17-M. Preclinical evaluation in cellular and animal models showed that T17-M retained TROP2-dependent binding, underwent clathrin-mediated internalization and lysosomal processing, and suppressed tumor growth in cell-line-derived and patient-derived xenografts. T17-M also reduced liver metastasis and induced calreticulin exposure, ATP release, and HMGB1 secretion, consistent with immunogenic cell death. In immunocompetent models, T17-M promoted dendritic-cell activation and CD8+ T cell infiltration, while its combination with PD-1 blockade further enhanced tumor control and prolonged survival. These findings provide preclinical proof-of-concept for T17-M as an alternative TROP2-targeted drug-delivery strategy for PDAC.
    DOI:  https://doi.org/10.1126/sciadv.aee3585
  42. Chem Commun (Camb). 2026 Nov 10.
    Fluorescent probes for mapping tumorigenic parameters, polarity and viscosity: implications for future chemotherapeutics.
    Shayeri Biswas, Woo Seok Choi, Sankarprasad Bhuniya, Min Hee Lee.
      Cellular polarity and viscosity are key physicochemical parameters that play crucial roles in maintaining cellular homeostasis and regulating metabolic processes. Alterations in these parameters, particularly decreased polarity and elevated intracellular viscosity, are closely associated with cellular dysfunction and contribute to cancer initiation, tumor progression, and metastasis. Such biophysical changes disrupt normal cellular organization, promoting the transformation of healthy tissues into aggressive and invasive tumor phenotypes. In recent years, a variety of solvatochromic fluorescent probes based on intramolecular charge transfer (ICT) and twisted intramolecular charge transfer (TICT) mechanisms have been developed to visualize changes in intracellular polarity and viscosity during different stages of cancer development. Moreover, lipid droplets (LDs), dynamic organelles involved in lipid storage and metabolic regulation, have emerged as potential biomarkers for cancer detection due to significant alterations in their abundance and microenvironment in cancer cells compared with normal cells. Importantly, LD-targeted photodynamic therapy (PDT) strategies have recently shown considerable promise for anticancer treatment. This review summarizes recent advances in fluorescent probes for mapping intracellular polarity, viscosity, and LDs in cancer cells, and highlights the emerging potential of LD-targeted therapeutic approaches for future cancer diagnosis and treatment.
    DOI:  https://doi.org/10.1039/d6cc06147h
  43. Biochem Pharmacol. 2026 Nov 07. pii: S0006-2952(26)00949-4. [Epub ahead of print]254(Pt 4): 118606
    Targeting the metabolism-autophagy-ferroptosis interactome in cancer drug resistance: molecular targets, structural pharmacology, and combination strategies.
    Junjie Liang, Han Lei, Tai Li, Jianchu Huang, GuangHang Zhu, Wenjun Luo, Zhiduan Cai, Guibin Xu.
      Cancer drug resistance can involve both genetic alterations and reversible changes in metabolism, stress responses, and susceptibility to cell death.Metabolic reprogramming, autophagy, and ferroptosis are closely connected in this process: metabolic adaptation sustains energy and antioxidant production and remodels membrane lipids; autophagy buffers therapeutic stress through nutrient recycling and organelle quality control; and ferroptosis-defense systems limit lethal phospholipid peroxidation. Their interactions can stabilize treatment-tolerant states, although the direction and importance of each process vary by tumor lineage, treatment history, and microenvironment. This review evaluates molecular nodes connecting these processes, with emphasis on GPX4, SLC7A11/xCT, the NCOA4-FTH1 ferritinophagy interface, the USP18-hyperoside (HYP; not to be confused with hypericin) axis, WWP1, ENO1, and DHODH. In this review, we compare interventions using explicit evidence criteria: physical target engagement, causal contribution to a defined resistant phenotype, and pathway association when direct engagement or resistance causality has not been established. We also assess how experimentally determined structures, selective autophagic cargo, parallel ferroptosis-defense systems, tumor context, and translational constraints affect the interpretation of resistance-reversal claims. This framework is intended to distinguish mechanistic plausibility from pharmacologically actionable evidence.
    Keywords:  Autophagy; Combination therapy; Drug resistance; Ferritinophagy; Ferroptosis; Metabolic reprogramming
    DOI:  https://doi.org/10.1016/j.bcp.2026.118606
  44. Nucleic Acids Res. 2026 Nov 10. pii: gkag1128. [Epub ahead of print]
    scGWAS-DB: an integrated database bridging GWAS to tissue-resolved single-cell contexts.
    Xiuli Zhu, Ziyang Wang, Yin-Ying Wang, Peilin Jia.
      The integration of genome-wide association studies (GWAS) with single-cell RNA sequencing has enabled the dissection of complex trait architectures across tissue-resolved cellular contexts. However, existing resources lack the ability to identify hub genes underlying trait-cell-type associations, dissect gene-gene interaction topologies, or detect shared genes across multiple traits. Here, we present single-cell-assisted Genome-Wide Association Study DataBase (scGWAS-DB) (https://ngdc.cncb.ac.cn/scgwasdb), an integrated database that bridges population-scale genetics with single-cell biology. scGWAS-DB integrates 3,649 high-quality GWAS datasets with single-cell atlases spanning 74 human tissues and 1,713 cell types. From these data, we identified 213,992 significant triplets, encompassing 821,480 gene-gene interactions. Among them, we further distinguished 584,944 co-occurrent and 7,365 mutual exclusive gene-gene interaction patterns. Systematic integration of these networks revealed recurrent cellular signatures across diverse diseases. Collectively, scGWAS-DB provides a systematic resource for interpreting the cellular basis of complex traits, prioritizing hub genes and cell types that could provide insights in future studies of drug target development and disease-relevant cellular circuit discovery.
    DOI:  https://doi.org/10.1093/nar/gkag1128
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