bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2026–10–11
thirty-one papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Can pancreatic cancer be stopped in its tracks? Radical tactic raises hopes.
  2. Concurrent AXL Inhibition Enhances RAS and ERK Inhibitor Efficacy in KRAS -mutant Pancreatic and Lung Cancer.
  3. Decline of chaperone-mediated autophagy in aging impairs macrophage clearance of senescent cells.
  4. Does Complexation of Plasma Membrane Cholesterol with Phospholipids Determine its Transbilayer Distribution?
  5. Cell jamming transition is regulated by mitochondrial pyruvate transport and endocytosis.
  6. Chaperone-mediated autophagy in physiological homeostasis, disease and ageing.
  7. Pancreatic Cancer KRAS Breakthrough: Drug Graveyard No More.
  8. Cancer competition for vitamin B2 creates metabolic checkpoint for T cell ferroptosis.
  9. Targeting RAS in pancreatic cancer.
  10. Comprehensive lineage tracing maps the landscape of cell fate decisions in mouse embryogenesis.
  11. SPARCS enables scalable recovery of complex image-based phenotypes for genetic screening.
  12. 5-oxoETE links redox control of epithelial damage detection and resilience.
  13. A non-canonical function of glutathione to suppress ferroptosis via FSP1.
  14. Lipid composition-driven sorting of ABHD5 between monolayer and bilayer surfaces.
  15. Selective elimination of quiescent cancer cells by dequalinium chloride via ROS-mediated ferroptosis.
  16. Lipid remodeling enables adaptation to chronic hyperosmotic stress.
  17. Methods to investigate the erythrocyte membrane biophysical properties relevant to blood circulation.
  18. Emerging mechanisms of ATG8-independent non-canonical autophagy.
  19. INCREASED PREVALENCE OF PANCREATIC CYSTS IN NONSECRETOR (FUT2 NULL) INDIVIDUALS UNDER PANCREATIC SURVEILLANCE.
  20. KDM6 Histone Demethylases Tune Pancreatic Cancer Plasticity.
  21. Global and specific mechanisms stimulate mistranslation in cancer.
  22. Lysosomal Expansion Compartments Mediate Zinc and Copper Homeostasis in Caenorhabditis elegans.
  23. Cuproptosis and the bioinorganic basis of copper-induced cell death.
  24. Circulating tumor cell-immune cell clusters: dynamic engines of metastasis.
  25. A phosphoinositide and RAB switch controls early macropinocytosis.
  26. Active Field Theory Approach to Explain Size Control of Transcriptional Condensates.
  27. Multicellular cooperation and the hallmarks of cancer: A new foundation.
  28. Modeling human tumor evolution in mice.
  29. FRET imaging of ERK activity in an orthotopic xenograft model of patient-derived pancreatic ductal adenocarcinoma using imaging window.
  30. An aggregation-induced emission fluorescent probe for selective lipid droplet imaging and real-time visualization of stress-related lipid metabolism.
  31. Mapping the functional dark proteome in cancer.
  1. Nature. 2026 Oct 01.
    Can pancreatic cancer be stopped in its tracks? Radical tactic raises hopes.
    Heidi Ledford.
      
    Keywords:  Cancer; Medical research
    DOI:  https://doi.org/10.1038/d41586-026-03119-7
  2. bioRxiv. 2026 Aug 11. pii: 2026.08.10.743026. [Epub ahead of print]
    Concurrent AXL Inhibition Enhances RAS and ERK Inhibitor Efficacy in KRAS -mutant Pancreatic and Lung Cancer.
    Yan Ming Ching, Shruthi Narayanan, Jeffrey A Klomp, Tamara Isermann, Sina Loewe, Wen-Hsuan Chang, Andrew M Waters, Sheila R Nicewarner Peña, Elisa Baldelli, A Cole Edwards, Teresa Börding, Runying Yang, Craig M Goodwin, Prson Gautam, Mariano Ponz-Sarvisé, David Horst, Kyle Seamon, Yongxian Zhuang, Linh Tran, Jingjing Jiang, Mallika Singh, Krister Wennerberg, Emanuel F Petricoin, Kirsten L Bryant, Clint A Stalnecker, H Shelton Earp, Adrienne D Cox, Christine Sers, Silvestre Vicent, Channing J Der, Bjoern Papke.
      Resistance limits the clinical efficacy of RAS inhibitors. We applied chemical and genetic screens and identified the AXL receptor tyrosine kinase as a driver of resistance to RAS-ERK inhibition. We determined that combination treatment with the AXL inhibitor bemcentinib (AXLi) together with the RAS(ON) multi-selective tri-complex inhibitor RMC-7977 (RASi) or the ERK-selective inhibitor SCH772984 (ERKi) significantly enhanced growth suppression in human KRAS -mutant pancreatic and lung cancer models. Combined AXLi and RASi treatment of human KRAS -mutant pancreatic cell line-derived xenograft tumors synergistically suppressed ERK activation and MYC expression, and caused tumor regression. Analyses of immunocompetent mouse allograft pancreatic tumor models revealed a largely tumor cell-intrinsic response to inhibitor treatment. We identified an unexpected mechanism whereby KRAS inhibition upregulated the AXL ligand GAS6, activating AXL but inducing an AXL-dependent adaptive resistance mechanism wherein AXL antagonizes RASi efficacy. Our observations support concurrent AXL inhibition as a strategy to enhance RAS inhibitor clinical efficacy.
    STATEMENT OF SIGNIFICANCE: Our findings identify AXL as a driver of resistance to RAS inhibitors, establishing a combination strategy to overcome resistance and enhance RAS inhibitor therapeutic efficacy in KRAS -mutant cancer by maximally inhibiting oncogenic RAS signaling.
    DOI:  https://doi.org/10.64898/2026.08.10.743026
  3. Nat Aging. 2026 Oct 05.
    Decline of chaperone-mediated autophagy in aging impairs macrophage clearance of senescent cells.
    Rebecca Sereda, Kristen Lindenau, Antonio Diaz, Zhaohui Liu, Olaya Santiago-Fernández, Rabia R Khawaja, Ronald Cutler, Jazmin Calyeca, Mericka McCabe, Sylvére Durand, Fanny Aprahamian, Natalia Del Pilar Vanegas, Hu Chen, Felipe Vilicich, Bhakti Chavda, Yair Botbol, Guido Kroemer, Toren Finkel, Evripidis Gavathiotis, Simone Sidoli, Ana L Mora, Mauricio Rojas, Susmita Kaushik, Ana Maria Cuervo.
      Autophagy dysfunction and senescence are established drivers of aging, but their potential interaction remains poorly understood. Here we show that age-related decline of chaperone-mediated autophagy (CMA), a pathway for selective lysosomal protein degradation, changes senescent cell properties and impairs their immune clearance. CMA-deficient cells undergo senescence but acquire proteomic, metabolic and secretory features resembling those in aged senescent cells. Their senescence-associated secretory phenotype exhibits enhanced pro-senescence effects on neighboring cells and inhibits macrophage CMA, which impairs their ability to engulf senescent cells. Accordingly, blockage of CMA specifically in macrophages increases senescent cell accumulation in mice and delays senescence resolution during wound healing. Conversely, pharmacological CMA activation reduces senescent cell burden in aged mice and disease severity in a pulmonary fibrosis mouse model. Our findings identify CMA decline as a driver of senescent cell persistence and highlight CMA upregulation as a promising strategy to promote senescence resolution in aged organisms.
    DOI:  https://doi.org/10.1038/s43587-026-01240-w
  4. J Membr Biol. 2026 Oct 07. pii: 38. [Epub ahead of print]259(1):
    Does Complexation of Plasma Membrane Cholesterol with Phospholipids Determine its Transbilayer Distribution?
    Theodore L Steck, Yvonne Lange.
      The transbilayer distribution of cholesterol in the plasma membrane is unresolved in that diverse analyses have yielded contradictory results. We now propose a model based on a novel mechanism. It assumes that (a) sterols associate stoichiometrically with phospholipids and (b) these complexes are filled to capacity in the plasma membrane. The sterol in each leaflet is then the product of the abundance of the leaflet phospholipids and their sterol stoichiometries. We applied the model to the bilayer of the human erythrocyte utilizing literature values for its cholesterol content, the abundance of phospholipids in the two leaflets and their cholesterol: phospholipid stoichiometries (1:1 mole/mole in the exofacial leaflet and 1:2 mole/mole in the endofacial leaflet). The model predicts that the outer leaflet contains about two thirds of the cholesterol in this membrane; i.e., twice that in the inner leaflet. Molecular dynamics simulations have delivered similar sidedness values for membranes in which the exofacial phospholipids have a higher sterol affinity. However, our mechanism holds that sterol affinity is irrelevant if the phospholipids are replete with sterol. Our results meet the requirement that the areas of the two leaflets be about equal. The model predicts that the sterol abundance in one leaflet of a bilayer will exceed that in the other when its phospholipids are fully complexed and have a higher sterol stoichiometry.
    Keywords:  Asymmetry; Bilayer; Cholesterol; Membrane; Sidedness; Transbilayer
    DOI:  https://doi.org/10.1007/s00232-026-00401-7
  5. Proc Natl Acad Sci U S A. 2026 Oct 13. 123(41): e2617216123
    Cell jamming transition is regulated by mitochondrial pyruvate transport and endocytosis.
    Alexandra Bermudez, Zoe Latham, Johnny Diaz, Weihong Yan, Jerry Chen, Dapeng Bi, Andrew S Goldstein, Jimmy K Hu, Neil Y C Lin.
      Epithelial tissues undergo dynamic transitions between fluid-like collective motion and mechanically jammed states during development, injury repair, and disease progression. However, the cellular programs that drive these transitions and regulate collective behavior remain unclear. Using a controlled crowding model integrated with live-cell imaging and time-resolved multiomics, we demonstrate that epithelial crowding triggers early metabolic changes characterized by increased mitochondrial pyruvate anaplerosis that precedes the jamming transition. Restricting mitochondrial pyruvate import increased collective cell motility and delayed jamming in crowded monolayers. This unjammed state is driven by enhanced cytoskeletal remodeling and requires RhoA-myosin II activity. Mechanistically, we show that elevated cytoskeletal signaling promotes macropinocytic uptake, which serves as a required feedback loop to maintain motility. These findings identify mitochondrial pyruvate utilization as an important regulatory input linking metabolic remodeling to the endocytic control of epithelial fluidity.
    Keywords:  collective cell migration; epithelial jamming transition; mechanobiology
    DOI:  https://doi.org/10.1073/pnas.2617216123
  6. Nat Rev Mol Cell Biol. 2026 Oct 05.
    Chaperone-mediated autophagy in physiological homeostasis, disease and ageing.
    Susmita Kaushik, Ana Maria Cuervo.
      Chaperone-mediated autophagy (CMA), the first-described selective lysosomal degradation pathway, is distinguished from other degradative pathways by the unique mechanism by which substrates reach the lysosomal lumen: CMA relies on a cytosolic targeting chaperone and a lysosomal membrane receptor that doubles as a translocation complex. In this Review, we highlight recent discoveries of additional molecular components involved in CMA and describe how genetic and pharmacological modulation of CMA in vivo, along with the identification of the subproteome degraded by CMA in different organs, has revealed an expanding range of physiological functions regulated by CMA in an organ-specific manner. CMA not only degrades damaged proteins but also targets fully functional proteins to terminate their physiological roles. Consequently, CMA dysfunction, as observed in ageing and age-related diseases, leads to cellular alterations beyond the mere accumulation of damaged proteins. We summarize recent findings linking CMA to common diseases and discuss efforts to therapeutically target CMA in these conditions.
    DOI:  https://doi.org/10.1038/s41580-026-01023-6
  7. Clin Cancer Res. 2026 Oct 06.
    Pancreatic Cancer KRAS Breakthrough: Drug Graveyard No More.
    Peter Y Yu, Paul E Oberstein, Anirban Maitra, Manuel Hidalgo.
      Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy and has long been regarded as a therapeutic "drug graveyard", with modest gains from cytotoxic combination chemotherapy and numerous novel agents failing to show benefit in clinical trials. The quest to directly target RAS has moved from concept to reality with the FDA approval of daraxonrasib (Rasonque) for adults with metastatic PDAC who have received at least one prior systemic therapy or are not candidates for multiagent systemic therapy. Here we discuss a wave of clinical trials that are poised to change this narrative and usher in the era of RAS-targeted therapy. Given the flood of compounds and combinations, we focus on therapies that have advanced to phase 3 clinical trials. Collectively, these studies demonstrate how RAS-targeted therapies are poised to transform the PDAC treatment landscape. The current generation of trials will determine whether these emerging strategies can translate into durable survival gains and turn PDAC from a "drug graveyard" into a drug haven for novel therapies.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-25-4177
  8. Cell. 2026 Oct 06. pii: S0092-8674(26)01122-0. [Epub ahead of print]
    Cancer competition for vitamin B2 creates metabolic checkpoint for T cell ferroptosis.
    Huanpeng Chen, Chao Li, Yujing Ke, Zilong Wu, Ziwei Ou, Nanqi Huang, Zhenyu Lin, Huixin Gao, Xuehu Xu, Lijuan Lu, Zhaofeng Huang, Yingjie Bian.
      Metabolic competition between tumors and T cells drives immune evasion, but the transporters and mechanisms remain largely elusive. Here, we establish the CareSLCs platform and identify that SLC52A3-mediated vitamin B2 (VB2) uptake is indispensable for T cell antitumor immunity. Mechanistically, VB2 deficiency impairs mitochondrial respiration and glutathione regeneration, leading to mitophagy, labile iron accumulation, and lipid peroxidation that trigger T cell ferroptosis. Unexpectedly, tumors preferentially employ SLC52A2, not SLC52A3, to scavenge VB2 and outcompete T cells. Tumor SLC52A2 ablation enhances T cell function in immunocompetent hosts without appreciably affecting intrinsic tumor growth. Clinically, high tumoral SLC52A2 correlates with T cell dysfunction and poor survival, whereas dietary VB2 intake is associated with reduced cancer risks. Thus, VB2 supplementation or SLC52A3 overexpression augments CAR-T cell antitumor efficacy. Our results suggest that tumoral VB2 competition establishes a metabolic checkpoint driving T cell ferroptosis and that enhancing VB2 uptake reinvigorates T cells to improve cancer immunotherapy.
    Keywords:  CAR-T cell therapy; SLC52A2; SLC52A3; ferroptosis; metabolic competition; vitamin B2
    DOI:  https://doi.org/10.1016/j.cell.2026.09.020
  9. Cancer. 2026 Oct 15. 132(20): e70640
    Targeting RAS in pancreatic cancer.
    Fausto Petrelli, Lorenzo Dottorini, Alberto Zaniboni.
      Pancreatic ductal adenocarcinoma (PDAC) remains among the most lethal malignancies, and activating KRAS mutations occur in more than 90% of tumors. Direct RAS targeting has moved from proof of concept to randomized clinical benefit: in previously treated metastatic PDAC, daraxonrasib improved median overall survival, progression-free survival, and objective response rate versus chemotherapy. Mutation-selective G12C and G12D inhibitors, targeted degraders, and first-line RAS(ON) combinations further broaden the landscape. Comprehensive germline and somatic profiling remains essential even with the availability of multi-selective KRAS inhibitors. KRAS alleles differ biologically, drug activity against individual alleles is not yet fully characterized, and eligibility for clinical trials often depends on the specific genotype. In addition, KRAS wild-type tumors may harbor actionable alterations, including gene fusions, amplifications, or mismatch-repair deficiency. This review synthesizes RAS biology, molecular-testing implications, clinical efficacy and toxicity data, and ongoing phase 2 and phase 3 trials. Priority questions include optimal sequencing, management of rash and mucositis, resistance, biomarker development, and integration into first-line and curative-intent therapy.
    Keywords:  antineoplastic agents; carcinoma; molecular‐targeted therapy; mutation; pancreatic ductal; precision medicine; proteolysis; proto‐oncogene proteins p21(RAS); signal transduction
    DOI:  https://doi.org/10.1002/cncr.70640
  10. Cell. 2026 Oct 08. pii: S0092-8674(26)01196-7. [Epub ahead of print]
    Comprehensive lineage tracing maps the landscape of cell fate decisions in mouse embryogenesis.
    William N Colgan, Luke W Koblan, JoAnne Villagrana, Tien-Chi Jason Hou, Minming Wang, Gokul Gowri, Whitney Chandler, Leonardo A Sepúlveda, Didar Ciftci, Karina Smolyar, Kathryn E Yost, Alicia Young, Lars Wittler, Styliani Markoulaki, Kyle M Loh, Xiaowei Zhuang, Nir Yosef, Zachary D Smith, Jonathan S Weissman.
      A comprehensive cell fate map of mammalian embryogenesis has remained out of reach given the scale, cellular diversity, and non-deterministic nature of development in utero. Here, we use PEtracer to continuously install heritable genetic marks as development progresses, reconstructing lineage trees that resolve ∼75% of cell divisions across >1.4 million cells from 16 replicate embryos. We pair these trees with deep transcriptional profiling to resolve cell fate biases, restriction timing, progenitor pool sizes, and lineage relationships throughout embryogenesis. Using this quantitative reference, we uncover strikingly reproducible lineage architecture between replicate embryos and chart the lineage dynamics driving fate specification across diverse tissues. Specific biological insights include the progressive restriction of neural crest fate, the relative contributions of distinct mesodermal origins to endothelium, and the dynamics of axial elongation. This work provides a foundation for a quantitative and predictive understanding of mammalian development.
    Keywords:  PEtracer; cell fate specification; lineage tracing; mouse embryogenesis; scRNA-seq; single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.cell.2026.09.050
  11. Cell. 2026 Oct 06. pii: S0092-8674(26)01123-2. [Epub ahead of print]
    SPARCS enables scalable recovery of complex image-based phenotypes for genetic screening.
    Niklas A Schmacke, Sophia C Mädler, Georg Wallmann, Andreas Metousis, Varvara Varlamova, Sophia Steigerwald, Sarah B Christ, Marleen Bérouti, Hartmann Harz, Heinrich Leonhardt, Fabian J Theis, Matthias Mann, Veit Hornung.
      Forward genetic screening links genotype to phenotype by introducing random genetic perturbations and identifying phenotype-altering mutations. Although genome-scale screens are routine for simple phenotypes in cultured cells, extending them to complex image-based phenotypes remains challenging. Here, we present spatially resolved CRISPR screening (SPARCS), a microscopy-based platform for forward genetic screening on single-cell images. SPARCS physically isolates mutants in situ by automated laser microdissection, enabling image-based screening at unprecedented scale with multimodal hit phenotyping. We demonstrate SPARCS in genome-wide CRISPR knockout screens of autophagosome formation and activation of the immune sensor STING across 70 million cells. Via machine learning-based image analysis, SPARCS recovered most macroautophagy genes and identified GPHR as a pH-dependent regulator of STING. Mass spectrometry-based proteomics of isolated hit cells revealed endoplasmic reticulum (ER)/Golgi disruption and nominated additional STING regulators via in silico perturbation modeling. These results establish SPARCS as a scalable platform for genome-wide genetic screening of complex cellular phenotypes with a proteome-level readout.
    Keywords:  CRISPR; SPARCS; STING; autophagy; genetic screening; machine learning; microscopy; perturbation; proteomics
    DOI:  https://doi.org/10.1016/j.cell.2026.09.021
  12. Nature. 2026 Oct 07.
    5-oxoETE links redox control of epithelial damage detection and resilience.
    Yanan Ma, Miklós Lengyel, King Lam Hui, Yohannes A Ambaw, Zaza Gelashvili, Leehyeon Kim, Ritchie Ly, Siyang Peng, Meysoon Quraishi, Tobias C Walther, Robert V Farese, Philipp Niethammer.
      Organisms harness oxidative stress to rapidly attract white blood cells to wound sites and to kill pathogens1-3. To this end, host tissues increase their own oxidative stress resilience and repair capacity via adaptive redox signalling4-6. Here, using live zebrafish and human cells, we identify a metabolic redox signalling mechanism that integrates oxidative immune defence with tissue adaptation. We demonstrate that DHRS7, an orphan short-chain fatty acid dehydrogenase-reductase, generates or consumes the pro-inflammatory lipid 5-oxoETE as a function of cytoplasmic NADP+/NADPH ratio. At wounds, where oxidative stress and NADP+ are high, 5-oxo-eicosatetraenoic acid (5-oxoETE) production by DHRS7 rapidly alerts antimicrobial white blood cells through the G-protein-coupled receptor OXER1. In undamaged tissue, where NADP+ is low, DHRS7 quenches unnecessary inflammation. Notably, we find that 5-oxoETE also supports epithelial redox resilience; OXER1-deficient zebrafish exhibit intestinal apoptosis, barrier disruption and microbial inflammation. Mechanistically, 5-oxoETE induces the expression of NUDIX hydrolases, which protect the cytoplasmic nucleotide pool from oxidation and prevent apoptosis in zebrafish and human intestinal cells. Thus, our data reveal a conserved mode of redox sensing and signalling-beyond classic thiol oxidation-that leverages NADPH metabolism to orchestrate the antimicrobial and pro-resilience functions of oxidative stress.
    DOI:  https://doi.org/10.1038/s41586-026-11121-2
  13. Cell. 2026 Oct 06. pii: S0092-8674(26)01126-8. [Epub ahead of print]
    A non-canonical function of glutathione to suppress ferroptosis via FSP1.
    Jing Han, Yu-Dan Zhang, Shuo Liu, Li Yang, Shuang-Li Sun, Ben Zhang, Ao-Kun Liu, Ling-Fan Zhu, Rong Wang, Dan-Dan Song, Xiao Zhuang, Yi-Jia Gao, Jing-Xin Li, Wen-Fei Li, Rong-Rong He, Heng-Xing Zhou, Lu Yu, Shi-Qing Feng, Ren-Jie Chai, Bo Chu.
      It is well established that glutathione (GSH) is mainly utilized by glutathione peroxidase 4 (GPX4) to diminish peroxidized phospholipids and defend against ferroptosis. However, we found that GSH robustly protects a variety of GPX4 knockout (KO) cells from ferroptosis, thus indicating that there is an alternative pathway for GSH to suppress ferroptosis. By carrying out genome-wide CRISPR-Cas9 screening, we identified that ferroptosis suppressor protein 1 (FSP1) is the key factor mediating the GPX4-independent protective effect of GSH. Mechanistically, FSP1 uses GSH to generate reduced ubiquinone, which scavenges oxidized lipids and suppresses ferroptosis. Inhibition of FSP1 abolishes this GSH-dependent ferroptosis protection both in vitro and in vivo. Distinct from NAD(P)H-mediated ubiquinone reduction, GSH-stimulated generation of reduced ubiquinone via FSP1 is independent of flavin adenine dinucleotide (FAD). Together, our work clarifies a new mechanism of GSH-mediated ferroptosis suppression, thus highlighting the potential that targeting GSH metabolism should be beneficial for ferroptosis-related diseases whether or not it is related to GPX4.
    Keywords:  FSP1; ferroptosis; glutathione metabolism; ubiquinone reduction
    DOI:  https://doi.org/10.1016/j.cell.2026.09.024
  14. J Lipid Res. 2026 Oct 07. pii: S0022-2275(26)00196-3. [Epub ahead of print] 101166
    Lipid composition-driven sorting of ABHD5 between monolayer and bilayer surfaces.
    Shahnaz Parveen, Arvin Nazari, James Stebelton, Kahlid Ali, Matthew Sanders, Amit Kumar, Katherine Truex, Yu-Ming M Huang, James G Granneman, Christopher V Kelly.
      Lipid droplets (LDs) are ubiquitous organelles that store neutral lipids and serve as central regulators of lipid homeostasis. Their structure includes a hydrophobic core of triacylglycerols and sterol esters surrounded by a phospholipid monolayer. This organization creates biophysical properties that guide selective protein recruitment. Among LD-associated proteins, α/β-hydrolase domain-containing protein 5 (ABHD5, also known as CGI-58) is a key regulator of lipolysis and broader lipid metabolism, yet the mechanisms guiding its distribution between endoplasmic reticulum (ER) bilayers and LD monolayers remain poorly understood. Because proper membrane association of ABHD5 is essential for activating PNPLA family lipases, identifying the determinants of its membrane selectivity is critical for understanding LD function in health and disease. In this study, we examined ABHD5 binding and sorting behavior using model membrane systems composed of giant unilamellar vesicles (GUVs) and droplet-embedded vesicles (DEVs) incorporating defined phospholipid and neutral lipid compositions. By integrating experimental assays with computational modeling, we quantified how ABHD5 partitions between bilayer membranes mimicking the ER and monolayer surfaces mimicking LDs. Systematic variation of membrane composition and physical properties allowed us to assess how packing defects and neutral lipid content shape ABHD5 localization. Our findings reveal the biophysical features that favor ABHD5 association with LD-like monolayers and provide new mechanistic insight into how cells target regulatory proteins to distinct membrane environments to control lipid metabolism.
    Keywords:  Large unilamellar vesicles (LUVs); Packing defects; Triacylglycerol; and molecular dynamics (MD) simulations; diacylglycerol; droplet-embedded vesicles (DEVs); fluorescence lifetime imaging microscopy (FLIM); giant unilamellar vesicles (GUVs); lipid droplets (LDs); phospholipids; sorting partition coefficient
    DOI:  https://doi.org/10.1016/j.jlr.2026.101166
  15. FEBS Open Bio. 2026 Oct 05.
    Selective elimination of quiescent cancer cells by dequalinium chloride via ROS-mediated ferroptosis.
    Kotaro Miyamoto, Shiori Sakai, Minori Endo, Terigele, Mizuho Niibori, Taiki Morita, Yu Goto, Arisa Yoshida, Tomohiro Tanaka, Ning Lin, Takahiro Kuchimaru, Hiroyuki Nakamura, Masahiro Inoue, Shinae Kizaka-Kondoh, Tetsuya Kadonosono.
      Quiescent cancer cells (QCCs) drive tumor dormancy and recurrence through their resistance to conventional therapies. Furthermore, because QCCs rely on oxidative phosphorylation and maintain a fragile redox balance, we hypothesized that they harbor a targetable redox vulnerability. Here, we show that the mitochondria-targeted agent dequalinium chloride (DQ) selectively kills QCCs in hypoxia- and nutrient limitation-induced quiescent models, including H2228 cells, multicellular spheroids, and colorectal cancer organoids, while sparing proliferating cells and normal fibroblasts. DQ induces ROS accumulation beyond the survival threshold of QCCs, leading to lipid peroxidation and ferroptotic cell death, whereas proliferating cells undergo limited caspase-independent apoptosis. These findings highlight redox imbalance as an actionable vulnerability of QCCs and position DQ as a potential repurposed agent for eliminating QCCs.
    Keywords:  dequalinium chloride; ferroptosis; mitochondria; quiescent cancer cells; reactive oxygen species
    DOI:  https://doi.org/10.1002/2211-5463.70344
  16. J Cell Biol. 2026 Nov 02. pii: e202603154. [Epub ahead of print]225(11):
    Lipid remodeling enables adaptation to chronic hyperosmotic stress.
    Thomas D Williams, Christian Klose, Robert Ernst, Pedro Carvalho.
      Lipid droplets (LDs) accumulate in response to diverse cellular stresses. However, their regulation and physiological roles remain poorly understood in most contexts. Here, we show that in budding yeast, chronic hyperosmotic stress induces sustained LD accumulation. Unlike the transient LD response observed during acute osmotic shock, chronic stress triggers prolonged, Dga1-dependent triacylglycerol synthesis. In the absence of triacylglycerol synthesis, cellular fitness is impaired. Lipidomic profiling reveals extensive membrane remodeling during chronic hyperosmotic stress, most notably an increase in phosphatidylcholine (PC) resulting in changes to membrane properties. In LD-deficient cells, the hyperosmotic stress-induced PC increase is blunted, while enhancing PC synthesis improves the fitness of triacylglycerol-deficient cells. Thus, LD accumulation and phospholipid remodeling underlie an adaptive response to chronic hyperosmotic stress.
    DOI:  https://doi.org/10.1083/jcb.202603154
  17. Methods. 2026 Oct 06. pii: S1046-2023(26)00206-9. [Epub ahead of print]
    Methods to investigate the erythrocyte membrane biophysical properties relevant to blood circulation.
    Yanisleidys Pantoja-Estrada, Peter G Petrov, Corinne M Spickett.
      Erythrocytes (red blood cells) are critical for the transport of oxygen and carbon dioxide around the body, reaching all tissues ultimately through narrow capillaries which requires significant deformations of the cells. As a result, they must withstand continuous mechanical stress and are specifically adapted with a lipid bilayer enriched in cholesterol and an underlying spectrin-based cytoskeleton for stability and flexibility. Thus, erythrocyte membranes have unique mechanical, biophysical and electrostatic properties suited to their function, which have long been of physiological and biomedical interest. These include membrane elasticity and deformability (bending rigidity or elasticity) as well as membrane fluidity and tension, which depend on the lipid and protein composition of the membrane. This review details the methods available to measure these properties. Measurement of lipid bilayer fluidity or polarity commonly uses solvatochromic dyes (e.g. laurdan), while dyes responsive to membrane tension include Flipper-TR, a fluorescence lifetime imaging (FLIM) reporter. Transmembrane potential and membrane dipole potential can be measured by partitioning of lipophilic dyes and ratiometric fluorescence imaging, respectively. Analysis of spatial fluctuations, driven by thermal energy, can be monitored non-invasively by advanced imaging techniques and provide information on membrane elasatic parameters. A variety of mechanical approaches that cause perturbation of the membrane and measure its resistance have also been used, including micropipette aspiration, optical tweezers, atomic force microscopy (AFM). The principles, advantages and challenges of these methods for understanding erythrocyte membrane are discussed, as well as cell stresses and diseases that affect them.
    Keywords:  Bending modulus; Membrane elasticity; Membrane fluidity; Membrane tension; Membrane viscosity; Red blood cells; Shear modulus
    DOI:  https://doi.org/10.1016/j.ymeth.2026.09.007
  18. J Physiol Biochem. 2026 Oct 07. pii: 102. [Epub ahead of print]82(1):
    Emerging mechanisms of ATG8-independent non-canonical autophagy.
    Suvam Saha, Debasish Kumar Ghosh.
      ATG8-independent autophagy represents an emerging field of cellular degradation that challenges the long-held view that LC3/GABARAP lipidation is universally required for autophagosome formation and autophagic flux. Over the past decade, studies across mammals, plants, and protozoa have revealed that cells can execute degradative mechanisms through alternative macroautophagy, microautophagy-like pathways, and autophagy-like systems that operate with reduced or absent reliance on ATG8 proteins. These discoveries have reshaped the conceptual framework of autophagy by separating membrane biogenesis, cargo sequestration, and lysosomal delivery into potentially ATG8-uncoupled modules. ATG8-independent pathways are now recognized as important for stress adaptation, organelle quality control, developmental remodeling, and selective cargo degradation. This review summarizes the historical development, mechanistic diversity, and biological relevance of ATG8-independent autophagy, and discusses its implications for disease biology and therapeutic targeting. Understanding these unconventional pathways will be essential for a complete view of autophagic regulation in health and disease.
    Keywords:  ATG8-independent autophagy; Autophagy machinery diversity; Autophagy regulation; Non-canonical autophagy; Organelle quality control; Stress-induced cellular degradation
    DOI:  https://doi.org/10.1007/s13105-026-01243-6
  19. Cancer Epidemiol Biomarkers Prev. 2026 Oct 08.
    INCREASED PREVALENCE OF PANCREATIC CYSTS IN NONSECRETOR (FUT2 NULL) INDIVIDUALS UNDER PANCREATIC SURVEILLANCE.
    Yuto Hozaka, Masataka Hayashi, Emy Abou Sleiman, Bryson W Katona, Randall E Brand, Sapna Syngal, Matthew B Yurgelun, James J Farrell, Amitabh Chak, Elena M Stoffel, Tamas A Gonda, Mohamad Dbouk, Elham Afghani, Jin He, Ralph H Hruban, James R Eshleman, Marcia Irene Canto, Michael G Goggins.
       BACKGROUND: Pancreatic surveillance commonly detects pancreatic cysts, most of which are presumed intraductal papillary mucinous neoplasms (IPMN). FUT2, the gene responsible for secretor status, has been implicated in IPMN development, although not with pancreatic cancer risk.
    METHODS: We evaluated the association between inactivating variants in FUT2, FUT3 and ABO and pancreatic cysts in 1,865 patients in the multicenter Cancer of the Pancreas Screening (CAPS) cohort. Multivariable logistic regression was performed to estimate adjusted odds for presumed IPMN prevalence. A Johns Hopkins surgical cohort of 1582 patients with IPMN, pancreatic ductal adenocarcinoma (PDAC), or carcinoma arising from IPMN was analyzed to examine trend in variant proportion by malignant progression.
    RESULTS: In the CAPS cohort, older age (OR per year; 1.06 [1.05-1.07]; p < 0.001), FUT2-null (non-secretors) (OR: 1.66 [1.30-2.12]; p<0.001), non-O blood group (OR: 1.31 [1.06-1.62]; p=0.012), having familial-only vs. genetic/familial risk (OR: 1.49 [1.20-1.85] p<0.001), and participating site (OR; 2.20 [1.78-2.73], p<0.001) were associated with having pancreatic cysts. There were no significant FUT2/ABO presumed IPMN prevalence interactions. In the combined cohort, the proportion of FUT2-null patients with IPMN without carcinoma (by imaging or pathology) was 319 (27.4%) of 1162; 57 (24.3% of 234) with IPMN and carcinoma, and 225 (22.5%) of 998 with PDAC alone (p=0.009 for trend).
    CONCLUSIONS: IPMN is more prevalent in FUT2-null patients under pancreas surveillance, but the increased FUT2-null prevalence is not observed in patients with IPMN with carcinoma.
    IMPACT: Pancreatic cancer risk conferred by having IPMN may be lower in FUT2-null compared to FUT2-intact individuals.
    DOI:  https://doi.org/10.1158/1055-9965.EPI-26-0807
  20. Cancer Res. 2026 Oct 06.
    KDM6 Histone Demethylases Tune Pancreatic Cancer Plasticity.
    Laura Leonhardt, Jia Mei, Audrey M Hendley, Suhail A Ansari, Sudipta Ashe, David I Berrios, Lars-Henrik Joost, Lina Fadel, Merve Yigin, Johannes Wirth, Nadja Lewandowski-Hoppe, Hasna Maachi, Felix Schicktanz, Marianne Remke, Richard Lindner, Lucia Y Li, Oghenekevwe M Gbenedio, Yuehan Hui, Elie Ghabi, Claudio Luchini, Giuseppe Malleo, Jin He, Rondell P Graham, Jeroen P Roose, David W Dawson, N Henriette Uhlenhaut, Annette Feuchtinger, Katja Steiger, Grace E Kim, Matthias Hebrok.
      Aberrant epigenetic regulation is a central driver of tumorigenesis, and the reversibility of epigenetic modifications underscores their potential as therapeutic targets. Epigenetic factors often function in a highly context-dependent manner, necessitating rigorous study of their dynamic and complex roles. Here, we uncovered an intricate regulation of tumor development and plasticity by the KDM6 family of H3K27me3 histone demethylases in pancreatic ductal adenocarcinoma (PDAC), a disease with sustained high mortality and limited treatment options. Temporally resolving KRAS-driven tumor development revealed a switch from tumor suppressive to oncogenic functions for KDM6B, with implications for tumor aggressiveness in rodents and patients. These oncogenic functions were mediated by regulation of NOTCH signaling, a pathway known to promote PDAC tumorigenesis. Concurrent elimination of KDM6A and KDM6B led to profound phenotypic changes resembling sarcomatoid carcinomas, a rare, poorly characterized subtype of human PDAC. These tumors exhibited altered oncogenic networks, including NOTCH and JNK signaling, that may support development of therapies tailored to molecular subtypes. Given the critical and distinct activities of KDM6 histone demethylases during PDAC development, targeting KDM6 activities may be beneficial in the right cellular and temporal context.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-3126
  21. Nat Cell Biol. 2026 Oct 05.
    Global and specific mechanisms stimulate mistranslation in cancer.
    Demi Wernaart, Amos Fumagalli, Mrittika Adhikary, Xiaodong Feng, Olaf Geintzer, Edwin S Kyei-Baffour, Onno B Bleijerveld, Liesbeth Hoekman, Ceri Zwart, Alexander Fish, Lisanne Giebel, Artur Burylo, Natalie Proost, Pierre-René Körner, Ferhat Alkan, Chao Yang, Janne Brouwer, Cecilia Anna Henriksen, Eric Westhof, Julien Champagne, Olaf van Tellingen, Marina Rodnina, Reuven Agami.
      Tryptophan codon-specific mistranslation, in the form of ribosomal frameshifting and tryptophan-to-phenylalanine (W > F) codon reassignments (substitutants), is induced in cancer cells by the limiting level of tryptophan imposed by anti-tumour immunity. While the oncogenic mitogen-activated protein kinase pathway drives frameshifting, whether substitutants are genetically regulated remains unknown. Here we screened for genes that control W > F substitutants following interferon-γ-mediated tryptophan shortage. This screen identified ADAR1, an enzyme that converts adenosine to inosine in double-stranded RNA molecules, and FTSJ1, an enzyme that 2'-O-methylates the anticodon region of several tRNAs. We demonstrate that ADAR1 sustains expression of key players in the ribosome quality control pathway, which in turn is essential for mistranslation events. FTSJ1, in contrast, specifically drives W > F mistranslation by methylation of tRNATrp to promote its binding to WARS1 loaded with phenylalanine instead of tryptophan. As ADAR1 and FTSJ1 levels are elevated in many cancer types, we propose that cancer cells deploy global and specific mechanisms to promote mistranslation in response to anti-tumour immunity.
    DOI:  https://doi.org/10.1038/s41556-026-02088-3
  22. Metallomics. 2026 Oct 07. pii: mfag030. [Epub ahead of print]
    Lysosomal Expansion Compartments Mediate Zinc and Copper Homeostasis in Caenorhabditis elegans.
    Joy R Armendariz, Sean Teng, Camdyn Rakow, Raquel Herrera, Samuel Herrera, Moshe T Gordon, Si Chen, Stefan Vogt, Hanwenheng Liu, Makena Jarvis, Katryna Reese, Aidan T Pezacki, Christopher J Chang, Byung-Eun Kim, Daniel L Schneider, Adelita D Mendoza, Kerry Kornfeld.
      Zinc is an essential transition metal that participates in many biological processes. In C. elegans, excess zinc is stored in lysosomes in intestinal cells; this process involves increasing the expression of the zinc transporter CDF-2 and remodeling of lysosomes characterized by an increase in the volume of the expansion compartment. To determine if this is a more general property, we investigated other metals. Here we report that lysosomes are remodeled in response to excess copper, manganese, and cadmium, with each metal causing an increase in the volume of the expansion compartment. Mutants with a reduced number of lysosomes were hypersensitive to growth retardation caused by excess copper and manganese, suggesting metal toxicity is prevented by metal sequestration in lysosomes. We developed a method to analyze isolated lysosomes by X-ray Fluorescence Microscopy; zinc, copper, and manganese are detectable in the lumen of lysosomes, and the concentration of zinc in the lysosomes increased substantially in worms exposed to excess dietary zinc. To further analyze copper, we examined localization of CUA-1.1, a copper transporter that moves copper into the lumen of lysosomes. Like the zinc transporter CDF-2, CUA-1.1 localizes to both the acidified and expansion compartments in excess copper. These results indicate that the same intestinal lysosomes store both zinc and copper. Furthermore, lysosome remodeling characterized by an increase in volume of the expansion compartment is not specific to excess zinc but is a more general phenomenon during metal storage in lysosomes.
    DOI:  https://doi.org/10.1093/mtomcs/mfag030
  23. J Biol Inorg Chem. 2026 Oct 05.
    Cuproptosis and the bioinorganic basis of copper-induced cell death.
    Yijian Qiu, Michael J Lukey.
      Copper is an essential yet potentially toxic biological trace element, whose functions in cells arise from its unique redox and coordination chemistry. The same chemical properties that make copper indispensable for a variety of fundamental biological processes, including respiration and antioxidant defense, also render it highly toxic when intracellular concentrations exceed homeostatic levels. Recently, a copper-dependent form of regulated cell death (RCD) termed cuproptosis has been identified, in which excess copper triggers cytotoxicity by directly binding the metabolic machinery of mitochondria to induce proteotoxic stress. Hallmark features of cuproptosis include the high-affinity coordination of copper with lipoylated proteins and the destabilization of iron-sulfur (Fe-S) cluster enzymes within the mitochondrial matrix, which together trigger metabolic dysfunction and protein aggregation that ultimately lead to cell death. Cuproptosis thus represents the first RCD pathway whose execution depends directly on metal-protein coordination chemistry. Emerging evidence indicates that cuproptosis may contribute to the pathogenesis of a variety of human diseases including cancer, neurodegeneration, and genetic disorders of copper metabolism. A precise mechanistic understanding of this form of RCD therefore has the potential to reveal new opportunities for therapeutic intervention. Here, we examine the bioinorganic basis of cuproptosis, its intersections with cellular copper handling systems, its role in disease processes, and the potential therapeutic strategies that aim to exploit this pathway for clinical benefit.
    DOI:  https://doi.org/10.1007/s00775-026-02175-8
  24. Trends Cancer. 2026 Sep 22. pii: S2405-8033(26)00214-1. [Epub ahead of print]
    Circulating tumor cell-immune cell clusters: dynamic engines of metastasis.
    Fangjia Tong, Xin Liu, Deyu Fang, Patricia A Robinson, William J Gradishar, Rongfu Wang, Huiping Liu.
      Circulating tumor cell (CTC) clusters are potent drivers of metastasis, exhibiting markedly greater metastatic capacity than single CTCs. Beyond homotypic CTC clusters, CTCs dynamically engage immune cells to form heterotypic clusters with enhanced metastatic fitness. Rather than passive assemblies, these clusters function as coordinated metastatic ecosystems, integrating adhesion, immune modulation, and metabolic adaptation to promote survival, plasticity, and immune evasion. Recent advances in CTC isolation, single-cell and spatial multiomics, and artificial intelligence-driven analyses have enabled unprecedented resolution of these dynamic interactions. Together, these findings support a conceptual shift from isolated single-cell dissemination to multicellular cooperation as an important principle of metastasis and identify CTC-immune cell clusters as actionable targets for next-generation therapies to boost immunity and prevent metastasis.
    Keywords:  circulating tumor cells; heterotypic CTC–immune cell clusters; immunotherapy; metastasis
    DOI:  https://doi.org/10.1016/j.trecan.2026.09.003
  25. J Cell Sci. 2026 Oct 09. pii: jcs.265349. [Epub ahead of print]
    A phosphoinositide and RAB switch controls early macropinocytosis.
    Hélène Spangenberg, Emilie Løgith Moe, Øyvind Ødegård Fougner, Marte Sneeggen, Meng Pan, Kia Wee Tan, Maria Mateo Tortola, Camila Valenzuela, Yuen-Yan Chang, Harald Stenmark, Camilla Raiborg, Kay Oliver Schink.
      Macropinocytosis is a non-selective endocytic process by which cells take up large amounts of extracellular fluid into giant vesicles known as macropinosomes. This mechanism is used by immune cells to sample the surroundings for antigens and can be exploited by cancer cells for nutrient uptake. What determines macropinosome fate after internalization is largely unknown. Here we investigate the role of the phosphatidylinositol 3-kinase VPS34/PIK3C3 and its product phosphatidylinositol 3-phosphate (PtdIns3P) in macropinosome fate determination. VPS34 inhibition reduced successful macropinosome maturation and fluid-phase uptake and prevented recruitment of early endosomal factors, including the small GTPase RAB5A and its effectors, to forming macropinosomes. Instead, forming macropinosomes under VPS34 inhibition accumulated regulators of endocytic recycling, including RAB8A, RAB10, RAB11A, and PtdIns4P, which led to fusion of macropinosomes with the plasma membrane. Whereas RAB5A was critical for establishment of endosomal identity, macropinosome fusion with the plasma membrane depended on RAB8A. Thus, macropinosome maturation is regulated by a VPS34-dependent phosphoinositide and RAB transition that determines whether newly formed macropinosomes acquire endosomal identity or recycle to the plasma membrane.
    Keywords:  Endocytosis; Macropinocytosis; Membrane transport; Phosphoinositides; Rab GTPases
    DOI:  https://doi.org/10.1242/jcs.265349
  26. Macromol Biosci. 2026 Oct;26(10): e70268
    Active Field Theory Approach to Explain Size Control of Transcriptional Condensates.
    Kathrin Hertäg, Samuel Shoup, Leonhard T Thews, Radhika Khatter, Eugenio Ferrario, Joshua F Robinson, Sina Wittmann, Sandra Schick, Thomas Speck.
      Transcription factors organize into liquid-like condensates to facilitate gene expression, yet the physical mechanisms governing their formation and properties remain poorly understood. We study the size statistics of transcriptional condensates in human HAP1 cells using widefield and super-resolution microscopy tagging the epigenetic reader BRD4. We find that hubs that appear monolithic in widefield resolve into clusters of smaller droplets that resist coarsening. We link this size control to Active Model B+, a non-equilibrium field theory that captures a regime of reverse Ostwald ripening out of thermal equilibrium. In this regime, chemically driven currents cause larger droplets to transfer mass back to smaller ones, stabilizing a state of microphase segregation. The observed exponential size distribution of BRD4 foci quantitatively matches our numerical simulations, suggesting a universal physical picture for the non-equilibrium self-limitation of cellular condensates.
    Keywords:  Ostwald ripening; chemical physics; effective field theory; nanotechnology; physics; resist; thermal equilibrium; transcription factor
    DOI:  https://doi.org/10.1002/mabi.70268
  27. Evol Med Public Health. 2025 ;13(1): 374-380
    Multicellular cooperation and the hallmarks of cancer: A new foundation.
    Carlo C Maley, Amy M Boddy, Aurora M Nedelcu, Athena Aktipis.
      Multicellularity evolved independently several times across the tree of life. In all cases, these events were dependent on various types of cellular cooperation. We previously identified five universal foundations of cellular cooperation that are required in all complex multicellular lineages to allow the collection of cells to function and reproduce as a whole (i.e. a multicellular individual). These include: proliferation inhibition, controlled cell death, resource allocation, division of labor, and maintenance of the extracellular environment. We propose that there is a sixth universal foundation of multicellularity that breaks down in cancer: proximity maintenance. By staying in close proximity, cells can more easily provide benefits for one another, communicate, coordinate their behavior, and evolve increased size and complexity. Here, we revisit and further develop the five original foundations of multicellular cooperation in the context of the evolution of multicellularity from unicellular ancestors and their implications for cancer progression. In our previous work, we suggested that the breakdown of all these cooperative behaviors is reflected in the universal hallmarks of cancer. Similarly, the breakdown of proximity maintenance maps to another hallmark of cancer-activating invasion and metastasis.
    Keywords:  cancer; cooperation; evolution; hallmarks; mulitcellularity
    DOI:  https://doi.org/10.1093/emph/eoaf026
  28. STAR Protoc. 2026 Oct 03. pii: S2666-1667(26)00525-3. [Epub ahead of print]7(4): 104872
    Modeling human tumor evolution in mice.
    Dale M Watt, Louise E Mitchell, S Leah Etheridge, Philip D Dunne, Daniel J Murphy, Karen Blyth.
      Cancer develops through an evolutionary process driven by mutation and selective pressures imposed by the microenvironment. To be translationally relevant, experimental models must recapitulate these clinical complexities. In this Primer, we consider how different mouse-modeling strategies can be aligned with human tumor evolution, focusing on mutation order, the emergence and competition of initially rare mutant clones within genetically mosaic tissues, and microenvironmental context. By comparing conventional genetically engineered mouse models (GEMMs), transplant-based models, and emerging tools such as somatic editing and the tandem arrayed regulator (TAR) allele system, we offer a guide for selecting the most appropriate mouse model to address specific evolutionary questions.
    Keywords:  Cancer; Model Organisms; NMGN Focused Collection
    DOI:  https://doi.org/10.1016/j.xpro.2026.104872
  29. J Cell Sci. 2026 Oct 09. pii: jcs.265075. [Epub ahead of print]
    FRET imaging of ERK activity in an orthotopic xenograft model of patient-derived pancreatic ductal adenocarcinoma using imaging window.
    Houssam Al-Koussa, Daisuke Taniguchi, Masafumi Kuroda, Yukino Inomata, Ye Huaze, Akihito Machinaga, Nobuyuki Kakiuchi, Seishi Ogawa, Hiroshi Seno, Shigeki Higashiyama, Michiyuki Matsuda, Toru Hiratsuka.
      Intravital imaging of cancer xenograft models enables the observation of cells in their tissue microenvironment. Application of molecular activity probes to intravital imaging, however, often poses technical difficulties. Here we sought to visualize Extracellular signal-regulated kinase (ERK) activity in an orthotopic xenograft model of pancreatic cancer. Our custom-made pancreatic imaging window (PIW) enabled long-term tracking (> 2 weeks) of cancer xenografts showing heterogeneous growth potential. Our validation approach of Förster resonance energy transfer (FRET) imaging by a kinase-dead mutant ERK biosensor suggested the local pH may affect the ratiometric interpretation of FRET efficiency. Nevertheless, our FRET analysis allowed to detect pharmacological inhibition of ERK activity, which supports the validity of the experimental model to dissect heterogeneous drug responses of cancer cells in their microenvironment. Of note, we found that collagen signal was negatively correlated with local ERK activity heterogeneity, highlighting the benefit of our imaging system to observe the intricate pharmacodynamics modified by fibrosis. Our intravital live imaging platform paves the way for a novel pre-clinical model that links the molecular dynamics to the living tissue environment of pancreatic cancer.
    Keywords:  ERK; FRET; Intravital imaging; Pancreatic Cancer; Xenograft
    DOI:  https://doi.org/10.1242/jcs.265075
  30. RSC Adv. 2026 Oct 05.
    An aggregation-induced emission fluorescent probe for selective lipid droplet imaging and real-time visualization of stress-related lipid metabolism.
    Xian Ren, Shaohua Zhu, Yajun Lian, Wenjing Ma, Lingbo Qu, Bing Yu.
      Lipid droplets (LDs) are dynamic organelles essential for cellular energy homeostasis and lipid metabolism. Dysregulation of LDs has been increasingly associated with a range of diseases, including neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, in which abnormal lipid accumulation and oxidative stress are common features. Despite their biological importance, available tools for real-time, high-fidelity visualization of LD dynamics in living systems remain limited. In this study, we developed TPA-LDs, an aggregation-induced emission (AIE) fluorescent probe for LD imaging. The probe adopts a donor-π-acceptor (D-π-A) structure and operates through an intramolecular charge transfer (ICT) mechanism, which contributes to its resistance to photobleaching under the imaging conditions, LD selectivity, and sensitivity to low-polarity environments characteristic of LDs. We show that TPA-LDs can selectively label LDs in live A549 cells and plant tissues, enabling real-time visualization of LD dynamics under physiological and pathological conditions, including nutrient stimulation, oxidative stress, and ferroptosis. Owing to the central role of LDs in stress responses and lipid metabolism, TPA-LDs may provide a useful imaging tool for investigating LD-associated biological processes and their relevance to human diseases, including disorders of the nervous system.
    DOI:  https://doi.org/10.1039/d6ra07468e
  31. Nat Rev Cancer. 2026 Oct 08.
    Mapping the functional dark proteome in cancer.
    John R Prensner, William A Freed-Pastor, Jennifer G Abelin, Catherine J Wu, Yifat Merbl, Yitzhak Pilpel, Ton N Schumacher, Jonathan S Weissman, Sebastiaan van Heesch, Reuven Agami.
      A generation after the genomics revolution, and with the advent of proteomic technologies, the dark proteome now stands as a potential new direction for cancer science and therapeutics. The dark proteome covers a vast terrain of previously undiscovered and uncharacterized protein molecules derived from alternative genomic loci or altered RNA translation. Over the past decade, an unprecedented depth of resolution of the dark proteome has been attained, identifying diverse classes of dark proteins with thousands of members each. Increasingly, individual dark proteins are also being characterized as functional components of cancer cell biology as well as potential therapeutic targets. Therefore, as a whole, the dark proteome offers the possibility to advance cancer science, diagnosis and treatment. Yet, many fundamental questions about the dark proteome remain, including key gaps in knowledge regarding its regulation, contribution to cancer phenotypes and antigenicity, and tractability for clinical-grade therapies. This Perspective outlines the current state of knowledge of the dark proteome in cancer, highlighting critical areas in which further research is needed. Furthermore, it poses guiding questions that illuminate important directions of growth for the field of the cancer dark proteome.
    DOI:  https://doi.org/10.1038/s41568-026-00985-1
This page is being maintained by Thomas Krichel. It was last updated on 2026‒10‒11 at 23:00.