bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2026–08–23
37 papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Mechanisms underlying propagation of ferroptotic cell death.
  2. Invasion status stratifies the composition of the human pancreatic cancer perineural niche.
  3. ESMO Clinical Practice Guideline Express Update on daraxonrasib in the treatment of metastatic pancreatic cancer.
  4. Lipid Bilayer-Confined J-Aggregation Transduces Cell Membrane Mechanics into Photoacoustic Signals.
  5. Antisense oligonucleotides against Il6ra ameliorate cancer cachexia in mice.
  6. Single-Molecule Force Spectroscopy Reveals a High-Force Requirement for Dissociation of Integrin Transmembrane Domains.
  7. Spatial Deconstruction of the Plasma Membrane.
  8. HMOX1 controls a heme-ferritin switch that protects cells from ferroptosis.
  9. Biosynthetic solutions to mechanical stress: why do mechanical stresses drive altered metabolism?
  10. Ferroptosis in pancreatic ductal adenocarcinoma: Mechanisms, tumor biology, and therapeutic opportunities.
  11. Daraxonrasib doubles survival in patients with metastatic pancreatic cancer.
  12. Fluorescence-Gated Flow Cytometry Approach for Measuring Lipid Flippase Activity in Mammalian Cells.
  13. Metastatic Cancers Exploit Vagal Sensory Neurons and Neural Repair Programs to Colonize New Tissues.
  14. Organ-specific colonization and niche remodeling in a human tissue model of metastasis.
  15. Daraxonrasib significantly improves overall and progression-free survival in patients with previously treated metastatic pancreatic cancer.
  16. Intercepting pancreatic cancer with a vaccine.
  17. Repression of ferroptotic cell death mediated antitumor immunity by mitochondrial calcium signaling.
  18. Proliferation as a natural strategy to suppress neoplasia.
  19. A single-cell and multi-platform spatial atlas of the human pancreas resolves a transformation-associated epithelial axis and a recurrent boundary-organized tumour microenvironment.
  20. Astrocytes mobilize a broader repertoire of lysosomal repair mechanisms than neurons.
  21. The hallmarks of skeletal muscle health.
  22. A multiplex tissue resource for high-resolution spatial protein profiling in the Human Protein Atlas.
  23. Energetics of stalk intermediates elucidated from hydrostatic pressure effects on membrane fusion.
  24. Lymphatic vessels invade bone in disease but are absent in health and regeneration.
  25. A chemigenetic endogenous Ras activity biosensor for live-cell pharmacology.
  26. Vitamins tune cell death thresholds.
  27. Mimicking Cellular Membranes With Micropatterned Lipid Bilayers.
  28. Voluntary exercise during weight loss attenuates adipose CD8+ T cell exhaustion that persists after weight regain.
  29. NRF2-mediated ferroptosis suppression defines a cancer-specific vulnerability in tumors.
  30. Modern science outreach: A guide for scientists.
  31. The mammalian glycocalyx.
  32. Protein restriction and the hallmarks of aging: A coordinated physiological adaptive response?
  33. Tumor slice cultures enable rapid ex vivo profiling of patient-specific drug sensitivity in pancreatic ductal adenocarcinoma.
  34. You can't say you didn't get fair warning.
  35. Spatially Resolved Epithelial States Delineate Immunosuppressive Niches of Impaired Myeloid Antigen Presentation in PDAC.
  36. Screening of anti-metastasis drugs by targeting angiopellosis and cancer cluster extravasation.
  37. Physics-Guided Neural Reconstruction of Cellular Membranes for 3D Electron Microscopy.
  1. Nat Cell Biol. 2026 Aug 21.
    Mechanisms underlying propagation of ferroptotic cell death.
    Francesca Maremonti, Alireza Dehdari, Nadja Leinung, Derek A Pratt, Andreas Linkermann.
      Necrotic zones in tissues occur in a wide variety of diseases. Ferroptosis, an iron-promoted necrosis driven by lipid peroxidation, has been identified as a key cell death modality in these conditions. Cells undergoing ferroptosis are unique in that they can induce death in their neighbours. Here we review salient aspects of ferroptosis propagation on the molecular, cellular and tissue levels. Cell death propagation is restricted by several ferroptosis-suppression systems. Glutathione peroxidase 4 (GPX4) and ferroptosis-suppressor protein 1 (FSP1) are now well established as master regulators, but various additional systems dictate ferroptosis sensitivity. We discuss how these mechanisms contribute to the suppression of cell death propagation, and how they cause various tissues to be more or less resistant to ferroptosis propagation. Understanding tissue-specific dynamics is critical to interpret the beneficial effects and limitations of future therapeutic approaches for ferroptosis-driven diseases.
    DOI:  https://doi.org/10.1038/s41556-026-02053-0
  2. bioRxiv. 2026 Aug 06. pii: 2026.08.05.743048. [Epub ahead of print]
    Invasion status stratifies the composition of the human pancreatic cancer perineural niche.
    Zainab Hussain, Dig Vijay Kumar Yarlagadda, Qianzi Li, Nuray Tezcan, Pavel Stupakov, Golabahar Sadatrezaei, Richard J Wong, Joan Massagué, Zeynep Tarcan, Olca Basturk, Sylvie Deborde, Christina S Leslie, Mara H Sherman.
      The peripheral nervous system innervates the pancreatic ductal adenocarcinoma (PDAC) microenvironment, and perineural invasion (PNI), the invasion of cancer cells in and around nerves, correlates with metastatic burden and poor outcomes. Though PDAC innervation is near universal and the majority of PDAC patients harbor PNI, the cellular and molecular composition of the heterocellular perineural niche is largely unknown, obscuring functional significance. Here we provide a deeply phenotyped spatial and single-cell atlas of the human PDAC perineural niche, enabling a high-resolution comparison of invaded versus non-invaded nerve neighborhoods. This atlas leverages a novel vision-centric artificial intelligence model for imaging-based spatial transcriptomics, coupled with pathology-guided single-nucleus RNA-seq. These analyses revealed that invaded nerve neighborhoods harbor cancer cells of the classical subtype, together with myofibroblastic cancer-associated fibroblasts (CAFs) and lipid-associated macrophages. Non-invaded nerve neighborhoods, in contrast, harbor inflammatory CAFs and infiltration of B and T lymphocytes. These findings raise the possibility that PNI and not innervation itself is immune-suppressive in this setting, motivating functional studies.
    Statement of Significance: Human PDAC is innervated and almost invariably harbors PNI, but the composition and functions of perineural niches remain unclear. Here we provide a spatial and single-cell atlas of the human PDAC perineural niche, defining cancer and stromal cell states in the context of PNI and nominating this process as potentially immune-suppressive.
    DOI:  https://doi.org/10.64898/2026.08.05.743048
  3. Ann Oncol. 2027 Dec 31. pii: S0923-7534(26)01457-2. [Epub ahead of print]
    ESMO Clinical Practice Guideline Express Update on daraxonrasib in the treatment of metastatic pancreatic cancer.
    ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org
      
    Keywords:  Chemotherapy; KRAS inhibitors; daraxonrasib; metastatic pancreatic cancer; molecular profiling; systemic treatment
    DOI:  https://doi.org/10.1016/j.annonc.2026.08.003
  4. J Am Chem Soc. 2026 Aug 19. 148(32): 34339-34351
    Lipid Bilayer-Confined J-Aggregation Transduces Cell Membrane Mechanics into Photoacoustic Signals.
    Yong Hua, Moumita Halder, Lubna Amer, Suhel Khan, Wei-Ze Wang, Benjamin Lam, Mohammad Souri, Jesse V Jokerst.
      Membrane tension, defined as the in-plane mechanical stress of the lipid bilayer, encodes membrane stretch and lipid packing density. Despite its central role in regulating cellular behavior, measuring membrane tension in a direct and noninvasive way in deeper tissue (beyond microscopy) remains a major challenge. Here, we report a supramolecular strategy that transduces membrane mechanics into a spectrally resolved photoacoustic signal through lipid bilayer-confined J-aggregation. We employ two complementary probes: a fluorescence-active system to report aggregation behavior in the lipid bilayer of LUVs and an optimized analogue to enable cellular photoacoustic readout. We found that amphipathic BODIPY-based probes are inserted into lipid membranes and exist as either monomers or slip-stacked J-aggregates with aggregate populations dictated by lipid packing density, which is in turn influenced by membrane tension or lipid composition. Only ordered J-aggregates formed under membrane-confined conditions enable efficient conversion of absorbed light into PA805 signals. Kinetically driven large aggregates spectrally observable via absorption experiments in protein-rich environments are inactive in photoacoustic mode. This decoupling between optical absorption and photoacoustic output reveals aggregate geometry as a critical determinant of photothermal efficiency. Furthermore, the bilayer-confined PA805 on/off behavior minimizes background signals from uninserted probes, enabling wash-free photoacoustic imaging. In model membranes and live cells, PA805 inversely correlates with lipid packing density, enabling noninvasive readout of membrane tension-associated changes.
    DOI:  https://doi.org/10.1021/jacs.6c07895
  5. Mol Ther. 2026 Aug 19. pii: S1525-0016(26)00709-4. [Epub ahead of print]
    Antisense oligonucleotides against Il6ra ameliorate cancer cachexia in mice.
    Yuanyuan Wang, Qingtao Sun, Wenqiang Zheng, Lijie Han, Qian Zhang, Adrian R Krainer, Bo Li.
      Mounting evidence indicates that interleukin-6 (IL-6) plays an essential role in the development of cancer cachexia. Particularly, recent work showed that IL-6 drives cancer cachexia through neurons in the area postrema of the brainstem. However, there are currently no approved drugs for treating cancer cachexia. Here we developed a splice-switching antisense oligonucleotide (ASO)-based therapy for treating cancer cachexia by reducing IL-6 receptor (IL-6R) expression in the brain. In two mouse models of cancer cachexia, a single dose of ASOs, administered by intracerebroventricular injection after cancer onset, reduces IL-6R levels in the brainstem and ameliorates cachectic symptoms. It also extends survival in one of the models. In parallel, the ASO treatment reduces cancer-associated transcriptomic activation of inflammatory pathways in both the brainstem and skeletal muscle. We also developed ASOs that suppress human IL-6R expression, paving the road for clinical studies. Our study thus provides a new approach for treating cancer cachexia.
    DOI:  https://doi.org/10.1016/j.ymthe.2026.08.028
  6. Biophys J. 2026 Aug 21. pii: S0006-3495(26)00582-5. [Epub ahead of print]
    Single-Molecule Force Spectroscopy Reveals a High-Force Requirement for Dissociation of Integrin Transmembrane Domains.
    Mandana Christine Hadawi, Bin Li, Monja Fink, Daniel Bublitz, Andreas Walbrun, Ulrike Majdic, Reinhard Fässler, Matthias Rief.
      Integrins are bidirectional mechanochemical receptors that transmit signals upon ligand binding to the cytoskeleton (outside-in) and cytoskeletal forces back across the membrane (inside-out) to the integrin-ligand bond. Integrins are activated prior to ligand binding, which involves large conformational rearrangements across the extracellular, transmembrane, and cytoplasmic regions. While the conformational and energetic basis of outside-in activation is increasingly well defined, the mechanical forces required for separating the tightly packed αβ transmembrane (TM) helices during inside-out signaling remain largely unknown. Here, we directly quantify the forces required to dissociate integrin TM domains (TMDs) in a lipid environment. Engineered α5β1 polypeptides consisting of TMDs and cytoplasmic tails were reconstituted into lipid nanodiscs and probed using single-molecule optical tweezers. Mechanical marker domains on each cytoplasmic tail verified correct vectorial force application, and fluorescent lipids confirmed nanodisc integrity. We find that the heterodimeric TM complex is a mechanically robust unit. In wild-type constructs, no TMD separation was observed in repeated pulls up to ∼35 pN. Point mutations in the β1-TMD (G744L, L748R) that weaken TMD interactions revealed discrete splitting events. The high mechanical forces necessary for TMD separation support a "ratchet-like" role for mechanical forces in inside-out signaling: rather than actively opening closed TMDs they prevent re-closing of spontaneously split TMDs thus keeping them open and activated.
    DOI:  https://doi.org/10.1016/j.bpj.2026.08.017
  7. J Am Chem Soc. 2026 Aug 19. 148(32): 34849-34863
    Spatial Deconstruction of the Plasma Membrane.
    Venkata Shiva Mandala, Chen Zhao, Qiuying Chen, Steven Gross, Jacob Geri, Roderick MacKinnon.
      The plasma membrane of cells is known to be heterogeneous with regard to the spatial distribution of proteins and lipids, but the nature and origins of this heterogeneity are unclear. In this study, we perform fluorescence microscopy on plasma membrane sheets and find that most proteins occur in protein-rich domains separated by intervening protein-poor regions. We show that the protein-rich domains and protein-poor regions are at least partially preserved in plasma membrane-derived vesicles that lack cytoskeletal elements, permitting their separation and isolation by density centrifugation. Compositional analysis by nuclear magnetic resonance and mass spectrometry shows that different proteins and lipids exhibit distinct tendencies to partition into the protein-rich domains. This differential partitioning is correlated with the function of the different proteins, suggesting segregation based on cellular processes. Likewise, ordered lipids, including cholesterol and sphingomyelin, differentially segregate, being more abundant in the protein-rich domains. We propose that the collective assembly of certain proteins and lipids creates the heterogeneous distribution of membrane components and the emergence of protein-rich domains. These domains could create distinct environments for the function and segregation of various membrane processes.
    DOI:  https://doi.org/10.1021/jacs.6c10688
  8. Sci Adv. 2026 Aug 21. 12(34): eaeg3424
    HMOX1 controls a heme-ferritin switch that protects cells from ferroptosis.
    Izadora de Souza, Izabela Amélia Marques Andrade, Florencio Porto Freitas, Ana Beatriz da Silva Teixeira, Maria Carolina Clares Ramalho, Karoline Almeida Lima, Ancely Ferreira Dos Santos, Werner Schmitz, Gholamreza Fazeli, Clarissa Ribeiro Reily Rocha, José Pedro Friedmann Angeli.
      Modulating the intracellular labile iron pool (LIP) has emerged as a promising strategy to induce ferroptosis in cancer cells, offering a way to overcome resistance to apoptosis-based therapies. One of the main contributors to LIP is heme catabolism mediated by heme oxygenase-1 (HMOX1), which promotes ferroptosis sensitivity by releasing free iron. Beyond its role as an iron donor, heme can influence diverse proteins and signaling pathways that drive tumor progression, but how heme regulates ferroptosis remains poorly understood. Here, we uncover a paradoxical, protective function of heme in the absence of HMOX1 activity. When HMOX1 is inactive, heme becomes stabilized, leading to ferritin up-regulation, suppression of ferroptosis, and rescue of cell death induced by both pharmacological and genetic inhibition of GPX4. Our findings reveal an unrecognized heme-HMOX1-ferritin axis that controls ferroptosis sensitivity. Targeting this pathway may offer a new therapeutic strategy to modulate ferroptosis in cancer.
    DOI:  https://doi.org/10.1126/sciadv.aeg3424
  9. Semin Cell Dev Biol. 2026 Aug 19. pii: S1084-9521(26)00028-5. [Epub ahead of print]184 103694
    Biosynthetic solutions to mechanical stress: why do mechanical stresses drive altered metabolism?
    Allen Lee, Isabel Sakowicz, Cray Minor, Anton V Block, Kolade Adebowale, Kevin M Tharp.
      Cells reside in mechanically stressful microenvironments where protrusive and traction forces from neighboring cells and cell-intrinsic forces derived from adhesions to the extracellular matrix (ECM) establish a dynamical "Mechanoreciprocity". Mechanoreciprocity is the concept that cells respond to the physical properties of the cellular microenvironment by reciprocally exerting proportional forces [1]. However, if feed-forward mechanical stress responses based on energetically demanding cytoskeletal dynamics are the only ways cells reciprocally respond to physical cues, we would not observe the force-induced thickening of bone [2] or hypertension-associated collagen accumulation in the kidney [3]. These processes are examples of adaptive biosynthetic responses by cells that may serve to buffer mechanical stresses in energetically efficient ways. In this review, we will introduce some of the ways in which cells respond to the physical properties of the microenvironment and suppose why these observed metabolic changes serve to support biosynthetic solutions to buffer mechanical stresses, a response that can preserve tissue structure or, in excess, distort it.
    Keywords:  Collagen; Mechanical stress; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1016/j.semcdb.2026.103694
  10. Cancer Lett. 2026 Aug 17. pii: S0304-3835(26)00552-5. [Epub ahead of print]659 218788
    Ferroptosis in pancreatic ductal adenocarcinoma: Mechanisms, tumor biology, and therapeutic opportunities.
    Yangchun Xie, Luting Chen, Yuhua Feng, Tao Hou, Rui Kang, Daolin Tang.
      Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human malignancies, characterized by persistently poor survival rates and limited effective therapeutic options. Ferroptosis, an iron-dependent form of regulated cell death driven by uncontrolled lipid peroxidation, has recently emerged as a potentially targetable vulnerability in PDAC. In this Review, we synthesize current understanding of the core molecular mechanisms governing ferroptosis, including dysregulated iron metabolism, lipid peroxidation pathways, and failure of antioxidant defense systems. We further discuss the complex regulatory networks that shape ferroptosis sensitivity in PDAC, highlighting the contributions of endoplasmic reticulum stress, mitochondrial dysfunction, autophagy, and DNA damage-associated signaling pathways. Within the broader landscape of PDAC biology, ferroptosis exerts context-dependent and sometimes opposing effects, influencing both tumor initiation and the development of therapeutic resistance. Accordingly, PDAC cells engage diverse epigenetic, metabolic, and microenvironmental adaptations to evade ferroptotic cell death, thereby sustaining resistance to therapy. Finally, we review the rapidly expanding spectrum of ferroptosis-based therapeutic strategies, encompassing small-molecule inducers, natural products, and, in particular, advanced nanomedicine platforms designed to enhance intratumoral drug delivery, overcome stromal barriers, and enable coordinated induction of ferroptosis while remodeling the tumor microenvironment.
    DOI:  https://doi.org/10.1016/j.canlet.2026.218788
  11. Cancer. 2026 Aug 15. 132(16): e70513
    Daraxonrasib doubles survival in patients with metastatic pancreatic cancer.
    Leah Lawrence.
      
    DOI:  https://doi.org/10.1002/cncr.70513
  12. J Membr Biol. 2026 Aug 21. pii: 32. [Epub ahead of print]259(1):
    Fluorescence-Gated Flow Cytometry Approach for Measuring Lipid Flippase Activity in Mammalian Cells.
    Klara T Scholtissek, Chris Van den Haute, Filip K Pamula, Joseph A Lyons.
      P4‑ATPase lipid flippases establish transbilayer lipid asymmetry in eukaryotic membranes, with increasing evidence indicating a role for interacting partners in regulating flippase activity. However, assessing interactor‑dependent effects on flippase activity in mammalian cells is complicated by heterogeneous protein expression and background lipid transport. Here, we introduce an expression‑based gating strategy for in‑cell NBD‑lipid uptake assays that improves sensitivity and interpretability under transient expression conditions. Using this approach, we examined the influence of the putative interactors VAMP3 and TMEM230 on the ability of ATP11C to transport phosphatidylserine (PS). VAMP3 exhibited no detectable effect on NBD‑PS uptake, whereas TMEM230 produced a strong inhibitory phenotype. The expression‑based strategy increased resolution between ATP11C variants and substantially reduced the number of events required for reliable analysis. Together, these advances provide a framework for systematic, cell‑based investigation of regulatory interactions governing mammalian P4‑ATPase function.
    Keywords:  Flippase interactors; Flow cytometry; Fluorescent protein tags; NBD-labeled lipid uptake assay
    DOI:  https://doi.org/10.1007/s00232-026-00392-5
  13. Res Sq. 2026 Jul 27. pii: rs.3.rs-10437078. [Epub ahead of print]
    Metastatic Cancers Exploit Vagal Sensory Neurons and Neural Repair Programs to Colonize New Tissues.
    Felipe Almeida de Pinho Ribeiro, Tiago Zaninelli, Telma Saraiva Santos, Gustavo Davanzo, Alliny Bastos, Rúben Silva, Jose de Lima-Junior, Amanda Dionisio, Soraia Mendes-Pierotti, Keneedy Reed, Yuriy Kirichok, Rubia Casagrande, Waldiceu Verri, Igor Smirnov, Jason Weber, David Chen, Jonathan Kipnis.
      Metastasis remains the leading cause of cancer-related mortality, yet the mechanisms that enable disseminated tumor cells to colonize distant organs remain incompletely understood.1,2 Here, we identify vagal sensory neurons as key facilitators of metastatic outgrowth. Using genetic, pharmacologic, surgical, and tissue-targeted denervation strategies in murine models of metastatic melanoma and breast cancer, we show that depletion of vagal sensory inputs markedly reduces pulmonary colonization. Mechanistically, metastatic cells exploit nerve injury-induced protein 1, NINJ1, to engage vagal afferents and activate a β-catenin-dependent transcriptional program. This interaction increases expression of receptors for growth factors and enables cancer cells to respond to macrophage- and fibroblast-derived trophic signals within the metastatic niche. Unbiased co-immunoprecipitation proteomics revealed that NINJ1 sequesters key components of the β-catenin destruction complex, including DVL1, AXIN1, CK1δ/ε, and CK2. Consequently, the presence of vagal sensory neurons leads to an NINJ1-dependent accumulation of active β-catenin form in cancer cells, while pharmacologic inhibition of β-catenin signaling abolished NINJ1-driven growth factor responsiveness. Together, these findings identify a neuro-metastatic axis in which metastatic cells co-opt a vagal sensory neuron-associated repair program to colonize new tissues. Targeting NINJ1 significantly reduced metastatic outgrowth across multiple cancer models and host backgrounds, indicating a broad therapeutic potential of these findings.
    DOI:  https://doi.org/10.21203/rs.3.rs-10437078/v1
  14. Sci Transl Med. 2026 Aug 19. 18(863): eadv6871
    Organ-specific colonization and niche remodeling in a human tissue model of metastasis.
    Alan G Chramiec, Ilaria Baldassarri, Ece Öztürk, Daniel Naveed Tavakol, Miranda C Wang, Max Summers, Keith Yeager, Richard Z Zhuang, Anushka Srivastava, Somnath Tagore, Diogo Teles, Hanina Hibshoosh, Andrea Califano, Peter A Sims, Gordana Vunjak-Novakovic.
      For metastatic colonization to occur, disseminated tumor cells must survive, adapt to, and remodel distant microenvironments in an organ-specific manner. We established a human multitissue model of cancer spread, with engineered bone and lung linked by vascular flow containing circulating cancer cells. Parental MDA-MB-231 cells extravasated toward both tissues, remodeled their niches, and acquired transcriptional programs reflecting adaptation to the local microenvironment, particularly upon homing to bone. Tissue-specific colonization by the bone- and lung-tropic MDA-MB-231 derivatives was quantified in independently perfused bone or lung platforms. Consistent with in vivo behavior, bone-tropic cells showed stronger bone colonization than lung-tropic cells and induced more pronounced osteolysis. In contrast, lung-tropic cells caused greater epithelial disruption in lung tissue and only modest colonization of bone. Distinct patterns of tissue colonization and secreted factors demonstrate that this device recapitulates key features of organ-specific metastasis observed in vivo for this family of cell lines.
    DOI:  https://doi.org/10.1126/scitranslmed.adv6871
  15. CA Cancer J Clin. 2026 Jul-Aug;76(4):76(4): e70097
    Daraxonrasib significantly improves overall and progression-free survival in patients with previously treated metastatic pancreatic cancer.
    Carrie Printz.
      
    DOI:  https://doi.org/10.3322/caac.70097
  16. Nat Med. 2026 Aug 20.
    Intercepting pancreatic cancer with a vaccine.
    Karen O'Leary.
      
    Keywords:  Cancer prevention; Clinical trials; Pancreatic cancer; Vaccines
    DOI:  https://doi.org/10.1038/d41591-026-00041-3
  17. Proc Natl Acad Sci U S A. 2026 Aug 25. 123(34): e2606216123
    Repression of ferroptotic cell death mediated antitumor immunity by mitochondrial calcium signaling.
    Jianwen Chen, Bao Zhao, Hong Dong, Zhiwei Liao, Shen Wang, Anjun Ma, Yajun Sun, Xiang Cheng, Shengyin Lin, Xinghui Li, Gang Xin, Kai He, Bei Liu, Yu L Lei, Qin Ma, Kymberly M Gowdy, Ruili Xie, Xiaolin Cheng, Zihai Li, Haitao Wen.
      Ferroptosis is a unique type of programmed cell death caused by excessive lipid peroxidation and represents a vulnerability in certain types of cancer. However, the signaling mechanisms that modulate ferroptosis and its functional consequence on the tumor microenvironment are poorly understood. Here, we demonstrate an inhibitory effect of mitochondrial calcium uniporter (MCU) on ferroptosis during embryogenesis and tumor development. MCU-dependent production of metabolite acetyl-coenzyme A (acetyl-CoA) supports the normal function of glutathione peroxidase 4 (GPX4), a critical gatekeeper of ferroptosis. Mechanistically, acetylation of GPX4 on lysine 90 (K90) prevents the formation of a detrimental salt bridge between K90 and aspartate 23, therefore protecting GPX4 enzymatic activity and avoiding ferroptosis. Deletion of MCU in cancer cells caused a robust antitumor T cell response and significantly blunted tumor growth. Thus, our findings indicate MCU-mediated acetyl-CoA metabolism as a critical anti-ferroptosis mechanism, which can be investigated as potential therapeutic candidate for tumor treatment.
    Keywords:  GPX4; MCU; ferroptotic cell death
    DOI:  https://doi.org/10.1073/pnas.2606216123
  18. Proc Natl Acad Sci U S A. 2026 Aug 25. 123(34): e2605763123
    Proliferation as a natural strategy to suppress neoplasia.
    Anish A Sarma, Lea Goentoro, John Doyle.
      Cell proliferation is necessary to maintain tissue homeostasis, but proliferation carries with it a risk of cancer. To understand how some organisms suppress cancer while maintaining homeostasis, we developed a dynamical model of cell populations. The model identifies two regimes. In one regime, as expected, proliferation drives accumulation of neoplastic cells. In another regime, unexpectedly, increasing proliferation suppresses accumulation of neoplastic cells. In this regime, as more cells proliferate, more cells also die as a consequence of homeostatic feedback. As long as neoplastic cells are targeted preferentially, the high flux effectively acts as a proofreader. High-flux proofreading works even when the system lacks a highly specific detector of neoplastic cells. As a first experimental test, we examined the jellyfish. Neoplasms are rarely observed in cnidarians, yet simply inhibiting proliferation promotes neoplasms. The quantitative framework developed here offers experimentally testable predictions to assess high-flux proofreading in other systems.
    Keywords:  cancer resistance; control theory; systems biology
    DOI:  https://doi.org/10.1073/pnas.2605763123
  19. bioRxiv. 2026 Aug 03. pii: 2026.07.31.742073. [Epub ahead of print]
    A single-cell and multi-platform spatial atlas of the human pancreas resolves a transformation-associated epithelial axis and a recurrent boundary-organized tumour microenvironment.
    Kaili Liu, Hua Zhong, Rahhul S Elangovan, Yuanhong Sun, Lin Wang, Abigae P Williams, Trisha I Valerio, Coline Furrer, Jacob P Adams, Ashley R Hoover, Wei R Chen.
      Most pancreatic ductal adenocarcinoma (PDAC) single-cell and spatial studies analyze one cohort or platform, obscuring recurrent biology. We assembled a human pancreas single-cell and single-nucleus reference of 1,186,130 cells from 19 studies and interpreted 176 Visium sections comprising 458,877 spots across non-diseased pancreas, chronic pancreatitis, PanIN, IPMN, primary PDAC and metastasis. Marker-supported labels were used after two RNA-based copy-number callers failed known-diploid controls. BANKSY domains, two reference-mapping methods and sample-level analyses resolved a cross-sectional epithelial axis extending from acinar-rich to malignant tissue. Five trajectory algorithms recovered similar ordering on a shared embedding; their consensus was interpreted as transformation-associated, not temporal or clonal. Malignant regions were globally segregated from fibroblast and myeloid compartments. Signed-distance analysis refined this pattern into a malignant core, a CAF/myeloid surround beginning at the tumour boundary and a more distal lymphoid compartment. Candidate extracellular-matrix communication, led by COLLAGEN, LAMININ and FN1, concentrated at the interface. Changes were reproduced in six patient-matched Normal-tumour pairs using exact patient-level tests. Visium HD resolved the same organization at single-cell resolution and showed that 8-um bins distorted immune-adjacency estimates. Xenium also revealed recurrent neighbourhoods but sample-specific stromal boundaries. We provide a confound-aware framework for identifying recurrent epithelial and microenvironmental organization in PDAC.
    DOI:  https://doi.org/10.64898/2026.07.31.742073
  20. iScience. 2026 Aug 21. 29(8): 116866
    Astrocytes mobilize a broader repertoire of lysosomal repair mechanisms than neurons.
    Erin M Smith, Natali L Chanaday, Sandra Maday.
      Lysosomal damage impairs proteostasis and contributes to neurodegenerative diseases, yet cell-type-specific differences in lysosomal repair remain unclear. Using a neuron-astrocyte coculture system, we compared responses to lysosomal injury induced by a lysosomotropic methyl ester. Both neurons and astrocytes showed lysosomal damage, marked by Galectin-3 recruitment to lumenal lysosomal β-galactosides, disrupted lysosomal pH, and engagement of lysophagy receptors TAX1BP1 and p62. However, astrocytes showed a preferential recruitment of ESCRT (endosomal sorting complex required for transport) repair machinery to damaged lysosomes. Additionally, the lysosomal membrane reformation pathway regulated by the RAB7-GTPase-activating protein (GAP), TBC1D15, was more robustly activated in astrocytes. By contrast, the phosphoinositide-initiated membrane tethering and lipid transport (PITT) pathway, mediating lipid transfer between the endoplasmic reticulum (ER) and damaged lysosomes, was engaged in both cell types. Our data reveal a divergence in how neurons and astrocytes mobilize repair pathways to manage lysosomal damage. These data may reflect differences in lysosomal resilience between astrocytes and neurons and inform therapeutic strategies to correct lysosomal dysfunction in neurodegenerative diseases.
    Keywords:  ESCRT; LLOMe; ORP9; PI4K2A; TBC1D15; astrocyte; lysosomal damage; neuron
    DOI:  https://doi.org/10.1016/j.isci.2026.116866
  21. Nat Metab. 2026 Aug 20.
    The hallmarks of skeletal muscle health.
    Anna Vainshtein, Bert Blaauw, Katrien De Bock, Pura Munoz-Canoves, Eric N Olson, Coen A C Ottenheijm, Erik A Richter, Jorge L Ruas, Laurent Schaffer, Bruce Spiegelman, Marco Sandri.
      Skeletal muscle is a central determinant of organismal health. Preserving muscle quality is therefore critical for preventing disease and sustaining quality of life across the lifespan. Despite its central role, the field lacks a unifying framework that defines the core properties of skeletal muscle health. Here, we propose a conceptual framework for muscle homeostasis built around seven interconnected hallmarks-metabolism and bioenergetics, proteostasis, genomics, excitability, structure, regeneration and cross-talk-that collectively govern muscle integrity, adaptability and resilience. Each hallmark is mechanistically grounded, quantifiable and potentially modifiable. This framework provides a unifying blueprint for the next generation of precision diagnostics and targeted therapies for preserving skeletal muscle health.
    DOI:  https://doi.org/10.1038/s42255-026-01595-9
  22. Protein Sci. 2026 Sep;35(9): e70764
    A multiplex tissue resource for high-resolution spatial protein profiling in the Human Protein Atlas.
    Borbala Katona, Rutger Schutten, Filippa Bertilsson, Feria Hikmet, Per Adelsköld, Mattias Forsberg, Kalle von Feilitzen, Loren Méar, Mathias Uhlén, Cecilia Lindskog.
      Spatially resolved protein expression is essential for understanding tissue organization, cellular specialization, and protein function. The open-access Human Protein Atlas database (www.proteinatlas.org) has generated an extensive antibody-based tissue resource for a majority of the human protein-coding genes using conventional immunohistochemistry, enabling body-wide annotation of protein expression across normal human tissues and major cell types. However, single-marker staining often lacks the cellular and subcellular context required to resolve rare cell populations, closely related cell states, or proteins with limited functional characterization. To address this, we established a multiplex tissue resource within the Human Protein Atlas based on a large-scale multiplex immunohistochemistry workflow. The iterative workflow combines optimized antibody panels targeting established markers of cell identity, tissue organization, cellular state, and subcellular structure with candidate proteins of interest. This allows protein expression to be interpreted directly within intact tissue architecture based on expression overlap between candidate proteins and panel markers. In version 25 of the Human Protein Atlas, 1106 proteins have been analyzed using eight multiplex antibody panels across nine tissue settings, including testis, motile ciliated epithelia, salivary gland, endocrine pancreas, and kidney. These panels resolve biological contexts such as stages of spermatogenesis, Sertoli cell and ciliary subcellular compartments, salivary gland acinar and ductal structures, pancreatic endocrine cell types, and nephron segments. Here, we present the design and implementation of the multiplex tissue resource and demonstrate its utility for refining spatial protein annotation across diverse human tissue systems. By providing high-resolution spatial context for protein expression in human tissues, this publicly available resource strengthens functional protein annotation and offers a framework for generating new hypotheses about protein roles in normal tissue biology.
    Keywords:  Human Protein Atlas; antibody‐based proteomics; cell type‐specific expression; functional protein annotation; human tissues; multiplex immunohistochemistry; protein localization; spatial proteomics; subcellular localization; tissue profiling
    DOI:  https://doi.org/10.1002/pro.70764
  23. bioRxiv. 2026 Aug 02. pii: 2026.07.29.741230. [Epub ahead of print]
    Energetics of stalk intermediates elucidated from hydrostatic pressure effects on membrane fusion.
    Daniel Milshteyn, Jacob R Winnikoff, Joel E Morgan, Gonen Golani, Itay Budin.
      Membrane fusion is an essential process in cells that requires a balance of lipid composition to establish biophysical properties conducive to topology changes. During fusion, lipids of opposing membranes must invert and overcome energy barriers associated with forming highly curved stalk and pore intermediates. While theoretical work has modelled the effect of lipid intrinsic curvature on stalk formation, quantifying the relationship experimentally has proven to be a challenge due to the inability to vary lipid curvature without concomitantly changing other properties that affect fusion. Here we address this hurdle by using hydrostatic pressure to modulate lipid intrinsic curvature independently of chemical composition. Using high-pressure stopped-flow fluorimetry, we measured rates of calcium-mediated lipid mixing between populations of vesicles, a process that is strongly inhibited by pressure. We correlated mean lipid intrinsic curvature across pressure with lipid mixing rates by incorporating complementary small-angle x-ray scattering measurements for each individual lipid component. This analysis showed that lipid mixing rates, a proxy for hemifusion, across compositional and pressure regimes are determined by changes in lipid spontaneous curvature. Consistent with previous theoretical models, we find a linear relation between lipid intrinsic curvature and the hemifusion stalk formation energy, offering direct experimental support for the stalk hypothesis.
    Significance statement: Membrane fusion proceeds through a hemifusion stalk intermediate whose formation energy depends on lipid intrinsic curvature, a central prediction of the stalk hypothesis that has lacked direct experimental support. Previous tests relied on changes in lipid composition that affect multiple membrane properties, confounding the contribution of curvature alone. Here we use hydrostatic pressure to tune lipid curvature independently of chemical composition and calibrate its effects with high-pressure SAXS. Hemifusion rates across three lipid compositions and four pressures collapse into a single exponential dependence on mean spontaneous curvature, yielding a linear relation between curvature and energy consistent with continuum elastic theory. This work quantifies how lipid composition tunes fusion kinetics, suggesting that small changes in lipid curvature may strongly affect fusogenicity.
    DOI:  https://doi.org/10.64898/2026.07.29.741230
  24. Cell. 2026 Aug 20. pii: S0092-8674(26)00639-2. [Epub ahead of print]189(17): 5449-5465.e5
    Lymphatic vessels invade bone in disease but are absent in health and regeneration.
    Xinfeng Meng, Kuo Liu, Muxue Tang, Wendong Weng, Zhenqian Zhang, Xiuzhen Huang, Zhen He, Ximeng Han, Ruilin Sun, Ruling Shen, Xin Ma, Tatiana V Petrova, Taija Mäkinen, Michael T Dellinger, Kai Kruse, Ralf H Adams, Bin Zhou.
      A recent study reported the existence of lymphatic vessels in normal bone and suggested their involvement in bone regeneration after injury. However, this conclusion was based on approaches that do not allow unequivocal identification of the spatial localization of lymphatic endothelial cells (LECs). Here, we employed a Prox1-based genetic tool and a dual-recombinase-mediated LEC-specific labeling system to trace lymphatic vessels with high specificity. We found that LECs are present in the connective tissues, including the periosteum surrounding the bone. However, they do not reside within the bone itself, nor do they penetrate the periosteum to facilitate bone regeneration after injury. By contrast, hyperplastic LECs on the bone surface breach the periosteum and invade bone tissue in mouse models of generalized lymphatic anomaly and Gorham-Stout disease. These data demonstrate that lymphatic vessels are absent from bone during homeostasis and regeneration after injury but invade bone during disease. This Matters Arising paper is in response to Biswas et al. (2023), published in Cell. See also the response by Yang et al. (2026), published in this issue.
    Keywords:  bone; disease; dual recombinase; lineage tracing; lymphatic endothelial cells; lymphatic vessels; repair
    DOI:  https://doi.org/10.1016/j.cell.2026.05.039
  25. Nat Chem Biol. 2026 Aug 19.
    A chemigenetic endogenous Ras activity biosensor for live-cell pharmacology.
    Ryan Weeks, Daojia R Zhou, Michelle S Frei, Jin Zhang.
      Ras is a small GTPase that regulates cell growth and proliferation. Hyperactive Ras is prevalent in cancer and has been a therapeutic target for decades. Many lines of evidence have demonstrated that Ras signals from the plasma membrane as well as noncanonical compartments such as the Golgi, making live-cell biosensors for tracking the spatiotemporal dynamics of Ras activity a valuable approach for Ras studies. However, current biosensors are limited in their quantitative capacity for measuring endogenous Ras activity. Here we introduce a chemigenetic biosensor design, making use of circularly permuted HaloTag labeled with the fluorophore JF635, for detecting endogenous Ras activity. This HaloTag-based Ras Activity Reporter (HaloRasAR) revealed the spatiotemporal dynamics of Ras activity downstream of either growth factor signaling or protein kinase C activation. In addition, live-cell characterization of a Ras(G12C) inhibitor and a Ras GEF inhibitor revealed subcellular-specific inhibition profiles. HaloRasAR represents a major advance in spatiotemporal interrogation of Ras signaling and live-cell pharmacology.
    DOI:  https://doi.org/10.1038/s41589-026-02276-0
  26. Trends Cell Biol. 2026 Aug 21. pii: S0962-8924(26)00158-3. [Epub ahead of print]
    Vitamins tune cell death thresholds.
    Rui Kang, Guido Kroemer, Daolin Tang.
      Vitamins are essential micronutrients traditionally viewed as passive cofactors that sustain cellular homeostasis. Emerging evidence challenges this notion, identifying vitamins as active regulators of cell fate that tune the threshold for regulated cell death. Through coordinated control of redox balance, metabolic pathways, and signaling networks, vitamins shape cellular susceptibility to diverse death programs. Their effects are highly context-dependent, enabling both prosurvival and prodeath outcomes depending on dose, cell type, and metabolic state. Recent studies further uncover noncanonical mechanisms linking vitamins to lipid remodeling, membrane trafficking, and organelle integrity. Collectively, these advances establish vitamins as dynamic modulators of cellular vulnerability and highlight their potential as therapeutic targets for selectively manipulating cell death in disease.
    Keywords:  cell death; metabolism; redox; signaling; vitamins
    DOI:  https://doi.org/10.1016/j.tcb.2026.08.002
  27. Chemphyschem. 2026 Aug 27. 27(16): e70534
    Mimicking Cellular Membranes With Micropatterned Lipid Bilayers.
    Thuy An Nguyen, Zexi Xu, Petra Schwille.
      Studying the role of membranes in cell biophysics requires experimental models which faithfully capture the compositional and topological complexity of cellular structures. This is particularly important for membrane structures that are just at the limit of, or even below optical resolution, such as bacterial cells. Micropatterning is one of the key enabling technologies for the precise manipulation of compositional heterogeneity, morphology, and topography in artificial membranes, bringing in vitro models closer to cellular reality. This perspective highlights recent works which implement micropatterning to mimic cellular membranes and discuss how cellular mechanisms, specifically bacterial ones, may be addressed through the replication of membrane heterogeneity, confinement, and nano- and microscale topographical features. It spotlights micropatterning as an invaluable tool for quantitative studies to dissect the topological determinants of cellular function. A thorough understanding of these will lay the foundation for increasingly complex systems to be reconstructed in vitro.
    Keywords:  cellular membrane; microfabrication; micropatterning; supported lipid bilayer; synthetic biology
    DOI:  https://doi.org/10.1002/cphc.70534
  28. bioRxiv. 2026 Jul 28. pii: 2026.07.25.740730. [Epub ahead of print]
    Voluntary exercise during weight loss attenuates adipose CD8+ T cell exhaustion that persists after weight regain.
    Okechukwu Kingsley Oforka, Emily C LaVoy, Matthew A Cottam, Munira Kapadia, Emily Nguyen, Caroline Hegemann, Alyssa H Hasty, Nathan C Winn, Heather L Caslin.
       Background: Weight gain and loss induce adipose CD8+ T cell exhaustion, which persists and may worsen glucose tolerance following weight regain. Because exercise can reduce T cell exhaustion in the blood, we hypothesized that exercise during weight loss would attenuate adipose CD8+ T cell exhaustion and glucose tolerance following weight regain.
    Methods: Male C57Bl/6J mice were fed low-fat or high-fat diets over 8 to 9-week cycles to generate lean, obese, weight loss, or weight cycled groups. Additional weight loss and weight cycled groups were provided exercise wheels during the weight loss phase.
    Results: As expected, weight loss increased total and exhausted CD8+ T cells by flow cytometry. Mice that ran the most during weight loss had the lowest proportion of exhausted CD8+ T cells. Notably, exercise reduced the proportion of exhausted CD8+ T cells even after the cessation of exercise and weight regain in all mice. However, exercise did not improve glucose tolerance or macrophage inflammation following weight regain. Moreover, exercise did not affect the induction of innate immune memory in adipose macrophages following weight loss.
    Conclusion: The addition of exercise to a weight loss intervention remarkably reduced exhausted CD8+ T cells in the adipose tissue even after the cessation of exercise and weight regain. While exercise did not affect macrophage inflammation or glucose tolerance following weight regain, these results illuminate new questions about the persistence and mechanisms by which exercise reduces tissue CD8+T cell exhaustion and the direct role of macrophages in modulating glucose tolerance with weight cycling.
    DOI:  https://doi.org/10.64898/2026.07.25.740730
  29. Redox Biol. 2026 Aug 19. pii: S2213-2317(26)00351-4. [Epub ahead of print]96 104352
    NRF2-mediated ferroptosis suppression defines a cancer-specific vulnerability in tumors.
    Dichun Huang, Mae Zhang, Ben N Stansfield, Mona Ahmed, Tianbao Xu, Lewis Alexander, Annadurai Anandhan, Mengjiao Ma, Pengfei Liu, Yang Yang-Hartwich, Deyu Fang, Eli Chapman, Joe G N Garcia, Pak Kin Wong, Aikseng Ooi, Donna D Zhang.
      NRF2 is a master regulator of redox and metabolic homeostasis that protects normal tissues from stress but is frequently hijacked by cancers to sustain survival and therapy resistance. Although NRF2 is dispensable for normal tissue function, its role in maintaining cancer cells within the native tumor microenvironment has remained undefined. Here, we uncover an essential and previously unrecognized tumor-specific dependency on NRF2. Using an inducible KrasFSF.G12D/+;Nrf2Fl/Fl;Rosa26CreERT2/CreERT2 (KNR) mouse lung cancer model, we demonstrate that NRF2 deletion alone, without pharmacologic intervention, eradicates cancer cells, reduces tumor burden, and prolongs survival. Single-cell RNA sequencing coupled with artificial intelligence-based genotype classification revealed that NRF2-deleted cancer cells are selectively eliminated, whereas non-cancerous cells tolerate NRF2 loss. Mechanistically, NRF2 deletion induces ferroptosis, a regulated iron-dependent cell death pathway, evidenced by induction of canonical ferroptotic genes (Ptgs2, Acsl4, Tfrc) and protein markers (SO2/3-PRDX3, COX2, TfR1). Importantly, these data support that NRF2 loss induces ferroptotic cell death in vivo within established tumors, in the absence of exogenous ferroptosis inducers or external stress. These findings establish that cancer cells depend on NRF2 to suppress intrinsic ferroptotic stress for survival, a dependency not shared by normal tissues. This discovery fundamentally redefines the pathological role of NRF2 and positions NRF2 inhibition as a standalone, tumor-selective therapeutic strategy to eliminate Kras-driven malignancies by unleashing ferroptosis.
    DOI:  https://doi.org/10.1016/j.redox.2026.104352
  30. Cell. 2026 Aug 20. pii: S0092-8674(26)00812-3. [Epub ahead of print]189(17): 5174-5181
    Modern science outreach: A guide for scientists.
    Ashley Moses, Annie Zhang, Michael Todorovic, Rohan Ramakrishna, Matthew Facciani, David M Eagleman, Richard Sever, Harris A Eyre, Saad Bhamla, John P Moore, Sandra Bond Chapman, Khara M Ramos, Erika C Hayden, Robert C Malenka, Ben Rein.
      Science communication offers immense value for fostering public trust and enhancing the quality of our modern information ecosystem. However, it remains under-prioritized and is rarely taught in the scientific enterprise. Addressing this gap thus represents an enormous opportunity for the field of science, and it starts with upskilling researchers in public engagement efforts. To that end, this paper outlines six actionable practices to help scientists effectively reach and engage broad audiences, with a focus on leveraging modern media and emerging dissemination channels. Notably, these practices bridge theory and practice: they are both theoretically backed and have been successfully implemented already by the authors. We encourage scientists at all levels and across disciplines to implement these strategies to engage broad audiences and contribute positively to public discourse.
    Keywords:  accessibility; messaging; open science; podcasts; public understanding; science communication; social media
    DOI:  https://doi.org/10.1016/j.cell.2026.07.014
  31. Curr Biol. 2026 Aug 17. pii: S0960-9822(26)00871-7. [Epub ahead of print]36(16): R889-R895
    The mammalian glycocalyx.
    Ling-Ting Huang, Matthew J Paszek.
      For generations of biology students, the fundamental model of the cell membrane was defined by the fluid mosaic model: a fluid and dynamic phospholipid bilayer studded with various integral and peripheral proteins. While elegant, this well-known picture of the cell membrane omits a crucial component: a dense, carbohydrate-rich coating that covers most eukaryotic cells. This structure, known as the glycocalyx, forms the true outer interface between cells and their environment. The glycocalyx is not simply a decorative sugar coating. It participates in cell signaling, mechanical protection, immune recognition, host-pathogen interactions, and the regulation of vascular function. The glycocalyx is present on all cells in our body, but its thickness and composition vary enormously amongst cell types. On many cells, the glycocalyx is only tens of nanometers deep, whereas on specialized surfaces, it can be much more substantial. For instance, the glycocalyx of the vascular endothelium can reach hundreds of nanometers to several micrometers in thickness, forming a dynamic molecular forest that projects outward from the membrane.
    DOI:  https://doi.org/10.1016/j.cub.2026.07.006
  32. Cell Metab. 2026 Aug 17. pii: S1550-4131(26)00330-X. [Epub ahead of print]
    Protein restriction and the hallmarks of aging: A coordinated physiological adaptive response?
    Sora Q Kim, Sangho Yu, Christopher D Morrison.
      Protein restriction extends lifespan across species and engages many hallmarks of aging. We propose that these diverse responses can be understood as components of a single coordinated physiological state. This response involves both cellular nutrient sensing and endocrine and neural coordination, with enhanced longevity emerging from this adaptive response.
    DOI:  https://doi.org/10.1016/j.cmet.2026.08.005
  33. NPJ Precis Oncol. 2026 Aug 20. pii: 325. [Epub ahead of print]10(1):
    Tumor slice cultures enable rapid ex vivo profiling of patient-specific drug sensitivity in pancreatic ductal adenocarcinoma.
    Benjamin Heckelmann, Daniel Fetzner, Olga Lapshyna, Ashinikumar Singh Hidam, Annika Brauer, Anna Maxi Wandmacher, Benedikt Färber, Jannis Duhn, Meike Ten Winkel, Louisa Bolm, Kim Honselmann, Steffen Deichmann, Christoph Röcken, Darko Carstven, Jens Marquardt, Corinna Keber, Timo Gemoll, Susanne Sebens, Tobias Keck, Ulrich Wellner, Rüdiger Braun.
      Pancreatic ductal adenocarcinoma (PDAC) is characterized by chemotherapy resistance, partly driven by its dense and heterogeneous tumor microenvironment (TME). Since most preclinical PDAC models inadequately capture the tissue architecture, their translational value for therapeutic testing remains limited. This study investigated organotypic tissue slice cultures (OTSCs), which preserve the multicellular tissue architecture, as a rapid platform for personalized ex vivo drug response profiling. OTSCs were generated from 27 resected PDAC specimens. Following workflow establishment and quality control, ex vivo drug profiling was performed in 15 patients using gemcitabine, gemcitabine plus paclitaxel, and FOLFIRINOX. Treatment response was assessed by quantitative digital pathology, and an ex vivo sensitivity score (EVSS) was defined. Clinical correlations with longitudinal follow-up were assessed in ten patients. OTSCs preserved tissue architecture and revealed interpatient heterogeneity. In exploratory analyses of clinically matched patients, ex vivo sensitivity was associated with prolonged PFS (median 445 vs. 141 days, log-rank p = 0.0027; HR per 10 EVSS points 0.625; 95% CI 0.484-0.807, p = 0.00032), while lower preoperative CA 19-9 levels and higher GATA6 expression were associated with higher EVSS and longer overall survival. OTSC-based profiling enables rapid, patient-specific drug response assessment in PDAC and supports evaluation as a functional stratification tool.
    DOI:  https://doi.org/10.1038/s41698-026-01663-z
  34. Autophagy. 2026 Sep;22(9): 2057-2058
    You can't say you didn't get fair warning.
    Daniel J Klionsky, Nicholas Ktistakis.
      The journal Autophagy is now in its twenty-second year. Unlike many, perhaps most, other journals we have instituted various requirements to help ensure scientific clarity and reproducibility. Two of the most important requirements are the use of standardized nomenclature and the inclusion of specific ordering information for reagents. These are not arbitrary formatting issues - there are specific reasons they are required, which we will remind you of below. The point of this editor's corner is to explain that these requirements are now going to be enforced upon manuscript submission.
    DOI:  https://doi.org/10.1080/15548627.2026.2692832
  35. bioRxiv. 2026 Jul 29. pii: 2026.07.28.741300. [Epub ahead of print]
    Spatially Resolved Epithelial States Delineate Immunosuppressive Niches of Impaired Myeloid Antigen Presentation in PDAC.
    Cameron Walker, Ruohan Wang, Hadeesha Piyadasa, Brooks Benard, Carl Pelz, Jenny Eng, Kevin Hawthorne, Rosalie Sears, Andrew J Gentles, Tyler Risom, Michael Angelo.
      Bulk transcriptomic classifiers stratify pancreatic ductal adenocarcinoma (PDAC) into classical and basal-like subtypes with prognostic and therapeutic relevance, yet increasing evidence indicates that these epithelial programs frequently coexist within individual tumors. How these intermediate states affect the local tumor microenvironment remains poorly defined. Here, we integrate multiplexed ion beam imaging (MIBI) with bulk RNA sequencing to resolve epithelial subtype identity at the level of spatially contiguous cancer nests and quantify their associated microenvironments. Across 47 primary tumor samples from 34 patients, we identified classical, intermediate, and basal cancer cell states at single-cell resolution and delineated discrete cancer nests with mixed or dominant subtype compositions. Distance-resolved spatial analysis reveals that basal-rich cancer nests are surrounded by locally immunosuppressive microenvironments characterized by reduced expression of MHC class II and co-stimulatory molecules in proximal myeloid cells, independent of myeloid abundance. These regions are enriched in fibroblast-dominated neighborhoods and distinct cell-cell interaction architectures. Using EcoTyper analysis of two independent bulk RNA-seq cohorts, including an OHSU discovery cohort (N = 277 patients) and TCGA as a validation cohort (N = 147 patients), we identified poor-prognosis tumor ecotypes enriched for basal epithelial states that similarly exhibited depleted myeloid antigen presentation signatures, linking spatial niche phenotypes to transcriptional ecotypes and patient outcomes. Together, these findings demonstrate that epithelial subtype programs in PDAC are organized at the level of spatially defined cancer nests and that basal cancer programs reside within localized niches of myeloid antigen presentation dysfunction, linking intratumoral architecture to immune suppression and clinical prognosis.
    DOI:  https://doi.org/10.64898/2026.07.28.741300
  36. Sci Adv. 2026 Aug 21. 12(34): eaed4204
    Screening of anti-metastasis drugs by targeting angiopellosis and cancer cluster extravasation.
    Xiao Cheng, Mengrui Liu, Shiqi Hu, Kaiyue Zhang, Zhang Yue, Shuo Liu, Dashuai Zhu, Zhenzhen Wang, Chao Lu, Na Yan, Brian S Henick, Ke Cheng.
      Metastasis accounts for 90% of cancer-related deaths. Extravasation is a necessary step for cancer metastasis. Currently, there are no drugs that specially target extravasation. Most cancer therapies target either proliferation or angiogenesis. We previously identified "angiopellosis" as the dominant mechanism by which vascular endothelial cells undergo conformational changes and actively "push" circulating cancer cells out of blood vessels. In this study, we developed an image-based high-throughput drug screening assay by coculturing cancer membrane-coated spheres with endothelial monolayers. Through this platform, we identified Bay 61-3606 as a lead angiopellosis inhibitor. Bay 61-3606 substantially reduced cancer cluster extravasation, an activity solely supported by angiopellosis and associated with higher metastatic potential, in both zebrafish and mouse models. Furthermore, Bay 61-3606 decreased distant metastases in murine models of lung carcinoma and triple-negative breast cancer. Mechanistically, Bay 61-3606 targeted the c-Jun amino-terminal kinase signaling pathway, down-regulating COL8A1 expression in endothelial cells and impairing the angiopellosis process.
    DOI:  https://doi.org/10.1126/sciadv.aed4204
  37. bioRxiv. 2026 Aug 04. pii: 2026.08.01.742159. [Epub ahead of print]
    Physics-Guided Neural Reconstruction of Cellular Membranes for 3D Electron Microscopy.
    Atsushi Matsuda, Se Min Kim, Matthew Akamatsu, Christopher T Lee.
      AWith advances in three-dimensional electron microscopy modalities, quantitative characterization of membrane ultrastructure has emerged as an approach to interrogate how organization of proteins and other components around the membrane drive structure and function. Hindering these efforts, the confident reconstruction of geometric features such as membrane curvature is challenging since it requires the calculation of higher-order derivatives from discrete membrane representations. Modern advances in using neural networks to learn continuous implicit representations of complex shapes present a promising solution to this problem. This work presents a physics-informed neural network framework for reconstructing membrane geometries to curvature-order accuracy from images using an implicit neural representation. Benchmarking using synthetic data illustrates that physics-based regularization during training improves accuracy of recovered curvatures, improving robustness to image noise. Application to experimental datasets demonstrate that the framework generalizes to complex cellular structure, such as the Golgi apparatus and mitochondria. We further perform three-dimensional curvature analysis of endocytic pits in cells to reveal anisotropic curvatures at the pit neck, previously predicted to be a lower-energy pathway for neck constriction. This work provides a unified framework for reconstructing three-dimensional membrane shape, including curvature, from volumetric imaging data. By capturing membrane geometry more accurately, our approach yields mechanical insights that can be linked to molecular-scale interactions.
    DOI:  https://doi.org/10.64898/2026.08.01.742159
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