bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2026–07–19
thirty-one papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. CDK8 remodels the tumor microenvironment and promotes resistance to KRASG12D inhibitors and daraxonrasib in PDAC.
  2. Pancreatic cancer cachexia promotes cardiac dysfunction through altered adrenergic signalling in the heart.
  3. Polyamine-mediated inhibition of ferroptosis contributes to geroprotection.
  4. Conditional dependency of oncogenic KRAS in driving ketone body catabolism and pancreatic cancer growth.
  5. ER quality control: how cells detoxify their own membrane from lipid stress.
  6. First-in-human testing of a mutant KRAS vaccine for pancreatic cancer interception in high-risk cohorts.
  7. KRAS on Empty: Lipid Oxidation Blockade Reveals a Metabolic Achilles' Heel in Pancreatic Cancer.
  8. Pre-clinical cancer cachexia causes glucose hypermetabolism prior to overt weight loss.
  9. Ketogenic diet mediates intestinal tumorigenesis through lipids not ketones.
  10. Ferroptosis induction via genetic approaches - CRISPR/Cas9-based disruption on key anti-ferroptotic genes.
  11. Sensitive detection of lysosomal membrane permeabilization using the galectin puncta assay.
  12. Overcoming Daraxonrasib Resistance: Allele-Specific Mechanisms Guide Salvage Therapy in Pancreatic Cancer.
  13. Cell Phenotype Phase Separation in Epithelial-Mesenchymal Transition-Mediated Collective Cell Migration.
  14. Lysosomes and lysosomal dysfunction in ageing biology.
  15. Prognostic Value of Intratumoral Expression of Claudin 18.2 in Resected Pancreatic Cancer.
  16. Metabolic adaptations of the tumor macroenvironment and their role in cancer progression and survivorship.
  17. Reframing cancer cachexia: from malnutrition to treatable disease.
  18. Lysosomes in Ferroptosis: Regulatory Mechanisms and Molecular Targets.
  19. Regulatory T cell immunosuppressive function requires chaperone-mediated autophagy.
  20. Organotropism-specific circulating tumor cells profiles: Morphology and heterotypic clustering predict metastatic sites in liquid biopsy of solid tumors.
  21. An encyclopedia of human enhancer-gene regulatory interactions.
  22. Sex-divergent skeletal muscle remodeling emerges early in cancer cachexia.
  23. Iron overload suppresses LKB1 and induces IL36G anti-tumor immunity in PDAC metastasis.
  24. Metabolite glues as a means of purine sensing and chemotherapeutic response.
  25. ELDR-Glo, a biosensor for cell age and quiescence depth.
  26. Multiscale in vivo imaging of tumor evolution using a germline conditional triple-reporter mouse.
  27. Ridge-assisted micro positioning of cells in a channel.
  28. Benefit of adjuvant chemotherapy for resected pancreatic cancer following neoadjuvant FOLFIRINOX or Gemcitabine-Nab-paclitaxel: a multinational analysis.
  29. Autophagy maintains high endothelial venule identity and function during inflammation.
  30. Lysosome as a central hub in ferroptosis-driven pathologies.
  31. Myelin basic protein binding is modulated by leaflet asymmetry and lipid composition.
  1. EMBO J. 2026 Jul 11.
    CDK8 remodels the tumor microenvironment and promotes resistance to KRASG12D inhibitors and daraxonrasib in PDAC.
    Kathleen M McAndrews, Krishnan K Mahadevan, Bingrui Li, Anaïs M Comptdaer, Amari M Sockwell, Sami J Morse, Patience J Kelly, Sarah I Patel, Michelle L Kirtley, Barbara A Moreno Diaz, Hengyu Lyu, David H Peng, Sima Khazaei, Aislyn Schalck, Xunian Zhou, Hikaru Sugimoto, Aaron A Bickert, Lakshmi Kavitha Sthanam, Meagan R Taylor, Shreyasee V Kumbhar, Kent A Arian, Yasaman Barekatain, Francesca Paradiso, Paola A Guerrero, Vincent Bernard, Navid Sobhani, Alondra N Camacho-Acevedo, Kiara E Bornes, Phuong Thao Tran, Anirban Maitra, Timothy P Heffernan, Raghu Kalluri.
      Mutations in KRAS are a dominant driver of pancreatic ductal adenocarcinoma (PDAC), with about 50% of patients presenting with KRASG12D mutations. Small molecule inhibitors targeting KRASG12D suppress PDAC; however, the contribution of the tumor microenvironment (TME) to the sustained efficacy of KRASG12D inhibition and mechanisms of resistance to KRASG12D suppression remain to be elucidated. Here, integrated spatial transcriptomics, single-cell RNA sequencing, and CODEX-based spatial proteomics analyses of PDAC mouse models uncover that while KRASG12D inhibition by MRTX1133 initially increases CD11c+ cells and T cell infiltration proximal to cancer cells, long-term treatment results in reversal of the immune responses leading to resistance promoted by multiprotein mediator complex associated kinase CDK8. CDK8 imparts this resistance via induction of CXCL2 chemokine secretion, inhibition of FAS expression, and remodeling of the TME to promote immune evasion. Targeting CDK8 by itself or in combination with αCTLA-4 immunotherapy overcomes resistance to KRASG12D inhibition. We also provide evidence of CDK8 upregulation in PDX tumors resistant to inhibitors selective for RAS(ON) and RASG12D(ON): daraxonrasib and zoldonrasib, respectively, highlighting a common KRAS vulnerability node for TME resistance.
    DOI:  https://doi.org/10.1038/s44318-026-00854-5
  2. J Physiol. 2026 Jul 17.
    Pancreatic cancer cachexia promotes cardiac dysfunction through altered adrenergic signalling in the heart.
    Parham Diba, Peter R Levasseur, Samuel D Newton, Khia Min Sabrina Koh, Paige C Arneson-Wissink, Xinxia Zhu, Peter Pham, Heike Mendez, Luke Whitcomb, Ariana Sattler, William R Woodward, Beth A Habecker, Daniel L Marks, Aaron J Grossberg.
      Cancer cachexia is a metabolic syndrome commonly observed in patients with pancreatic ductal adenocarcinoma (PDAC), characterized by wasting of skeletal and cardiac muscle. This condition is associated with the neurohormonal stress response and activation of the sympathetic nervous system. However the impact of cachexia on cardiac adrenergic signalling remains poorly understood. Here we used a preclinical model of PDAC cachexia to investigate how sympathetic input to the heart is altered. We found desensitization of β1-adrenergic receptor (β1-AR) in the heart, along with evidence of increased adrenergic tone. Pharmacological blockade with the β1-selective antagonist metoprolol partially restored adrenergic responsiveness in PDAC mice, suggesting that elevated adrenergic drive contributes to β1-AR desensitization. The impaired β1-AR sensitivity blunted the chronotropic response to dobutamine and reduced inotropic reserve under adrenergic stress. Together these findings uncover disruption of cardiac adrenergic signalling in PDAC cachexia. KEY POINTS: Pancreatic cancer-associated cachexia promotes β1-adrenergic receptor desensitization in the heart. Pancreatic cancer-induced β1-adrenergic receptor desensitization is partly mediated by increased adrenergic transmission to the heart. β1-adrenergic receptor desensitization in mice with pancreatic cancer reduces contractile reserve under adrenergic stress.
    Keywords:  adrenergic signalling; cachexia; cardiac physiology; desensitization; heart rate; pancreatic cancer; sympathetic nervous system
    DOI:  https://doi.org/10.1113/JP290616
  3. Cell Stress. 2026 ;10 49-52
    Polyamine-mediated inhibition of ferroptosis contributes to geroprotection.
    Frank Madeo, Didac Carmona-Gutierrez, Guido Kroemer.
      Geroprotection aims at extending healthspan by delaying age-associated pathologies. Polyamines including spermine and spermidine are interconvertible metabolites whose longevity-promoting effects have traditionally been attributed to autophagy induction. In addition, recent evidence identifies spermine as an endogenous Fe2+ chelator that suppresses ferroptosis, thereby complementing the autophagy-inducing activity of spermidine. Indeed, spermidine inhibits EP300 acetyltransferase activity and supports hypusination-dependent activation of TFEB, both leading to autophagy. However, enhanced autophagic flux may increase susceptibility to ferroptosis through ferritinophagy and lipid remodeling. In parallel, polyamine catabolism generates H2O2 and acrolein, both of which facilitate lipid peroxidation and ferroptotic demise. The discovery that spermine directly chelates redox-active Fe2+ closes a conceptual gap by explaining how polyamine supplementation can promote longevity while avoiding excessive ferroptotic cell loss. Multiple lines of evidence including metabolomics, isotope tracing, cell-free lipid peroxidation systems, Fe2+-binding biophysics, mass spectrometry, Raman spectroscopy, nuclear magnetic resonance and disease models demonstrate that spermine limits labile iron and ferroptosis. Together, these findings support a unified model in which spermidine-driven autophagy and spermine-mediated ferroptosis inhibition cooperate to preserve tissue homeostasis and healthspan.
    Keywords:  Aging; autophagy; cell death; metabolism; spermidine; spermine
    DOI:  https://doi.org/10.15698/cst2026.07.318
  4. J Biol Chem. 2026 Jul 14. pii: S0021-9258(26)02204-0. [Epub ahead of print] 113332
    Conditional dependency of oncogenic KRAS in driving ketone body catabolism and pancreatic cancer growth.
    Runze Wang, Xue Li, Tongxin Zhang, Yinuo Chen, Juanjuan Liu, Yuanjing Wang, Xuanzhe Wang, Lianjing Cao, Zhimin Lu, Leina Ma.
      Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy driven predominantly by oncogenic KRAS mutations, which enforce extensive metabolic reprogramming to support tumor progression. Although ketone body catabolism has emerged as a critical metabolic adaptation in PDAC, the signaling mechanisms that link mutant KRAS to the ketolytic machinery remain largely unexplored. Here, we identify a previously unrecognized, context-dependent role of oncogenic KRAS in driving ketone body utilization. We show that KRAS mutation alone is insufficient to fully activate ketolysis; instead, it primes the ketolytic pathway in a manner that requires cooperative input from additional tumor microenvironment signals. Mechanistically, oncogenic KRAS engages a downstream signaling cascade that leads to specific post-translational modifications of key mitochondrial enzymes. These modifications enhance the flux of ketone body catabolism, thereby increasing acetyl-CoA and ATP production and promoting pancreatic cancer cell proliferation and xenograft tumor growth. In a clinical PDAC cohort, activation of this KRAS-dependent ketolytic axis was elevated in KRAS-mutant tumors compared with KRAS wild-type cases, albeit with a trend that requires further validation. Collectively, our findings define a conditional dependency of mutant KRAS on cooperative signals to drive ketone body catabolism, linking oncogenic signaling to mitochondrial ketone metabolism in PDAC. This study expands our understanding of KRAS-driven metabolic reprogramming and highlights the ketolytic pathway as a context-dependent vulnerability for therapeutic intervention in pancreatic cancer.
    Keywords:  Ketolysis; Metabolic reprogramming; Oncogenic KRAS; PDAC; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.jbc.2026.113332
  5. Biochimie. 2026 Jul 17. pii: S0300-9084(26)00167-7. [Epub ahead of print]
    ER quality control: how cells detoxify their own membrane from lipid stress.
    Helin Elhan, Abdou Rachid Thiam.
      The endoplasmic reticulum (ER) is the principal site of glycerolipid synthesis in eukaryotic cells. The continuous production of lipid intermediates, including phosphatidic acid (PA), diacylglycerol (DAG), and triacylglycerol (TAG), destabilizes the ER membrane when they accumulate. To maintain bilayer integrity, cells deploy two sequential strategies: enzymatic conversion of these intermediates into membrane-compatible phospholipids, and their physical sequestration into lipid droplets (LDs), ER-derived organelles whose biogenesis is actively regulated by the seipin complex. LD growth is further sustained by the relocalization of TAG-synthesizing enzymes to the LD surface and by bridge-like lipid transfer proteins at ER-LD contact sites. When these mechanisms are overwhelmed, the accumulation of non-bilayer lipids drives ER stress and lipotoxicity, thereby contributing to the development of metabolic diseases. Here, we review the molecular logic of ER lipid quality control, from intermediate-driven membrane stress to the regulated responses that neutralize it.
    Keywords:  Diacylglycerol; Kennedy pathway; endoplasmic reticulum; ferroptosis; lipid droplets; lipid quality control; lipotoxicity
    DOI:  https://doi.org/10.1016/j.biochi.2026.07.007
  6. Cancer Discov. 2026 Jul 16.
    First-in-human testing of a mutant KRAS vaccine for pancreatic cancer interception in high-risk cohorts.
    S Daniel Haldar, Amanda L Huff, Hejia Henry Wang, Zirui Zhu, Maureen Berg, Jiayun Lu, Nancy Sun, Elizabeth Abou Diwan, Hassan Sinan, Christopher J Thoburn, Matthew Z Guo, Takeichi Yoshida, Linda C Chu, Anna K Ferguson, Dimitrios N Sidiropoulos, Luciane T Kagohara, Won Jin Ho, Katherine M Bever, Marina Baretti, Mark Yarchoan, Daniel A Laheru, Julie M Nauroth, Amy M Thomas, Hao Wang, Nilofer Saba Azad, Michael G Goggins, Elizabeth M Jaffee, Neeha Zaidi.
      Pancreatic ductal adenocarcinoma (PDAC) arises from precursor lesions over a decade-plus, offering a window for interception in high-risk individuals, but current surveillance detects a minority of precursors. Mutant KRAS (mKRAS) is present in most PDACs and their precursors, making it an appealing target for immune-based interception. We conducted a phase I, first-in-human study of a peptide vaccine targeting six common KRAS mutations (mKRAS-VAX) in 20 individuals with hereditary PDAC predisposition and a radiographic pancreatic abnormality (NCT05013216) to assess safety, immunogenicity, and T cell persistence. Adverse events were grade 1-2. Vaccination elicited a significant mKRAS-specific T cell response in 18/20 participants (90%). Longitudinal TCR sequencing demonstrated persistence of vaccine-induced mKRAS-specific clonotypes for up to 2 years. Over a median follow-up of 16.5 months, no participants developed PDAC. These findings demonstrate that mKRAS-VAX is safe and generates durable T cell responses, which support the advancement of mKRAS-targeted vaccination for PDAC interception.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-2245
  7. Cancer Res. 2026 Jul 15. 86(14): 3374-3376
    KRAS on Empty: Lipid Oxidation Blockade Reveals a Metabolic Achilles' Heel in Pancreatic Cancer.
    Deborah de la Caridad Delgado Herrera, Christina M Ferrer.
      Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States, driven by its aggressive biology and high metastatic incidence at diagnosis. With a 5-year survival rate of just 8%, PDAC remains one of the most lethal cancers. Mutant KRAS, present in more than 90% of cases, serves as a key driver of tumorigenesis and metabolic reprogramming. In this issue of Cancer Research, Thakur and colleagues uncover a novel metabolic adaptation that PDAC cells use to survive therapeutic stress. Their integrated metabolomic and lipidomic analyses show that ERK inhibition-targeting a key KRAS pathway effector-not only disrupts glycolysis and glutamine metabolism but also triggers a compensatory increase in fatty acid oxidation (FAO). This shift occurs through lipophagy, a lysosome-mediated lipid degradation process, rather than cytosolic lipolysis. Mechanistically, ERK inhibition promotes the nuclear translocation of TFEB, which drives the upregulation of FAO and lipophagy genes. This metabolic reprogramming enables PDAC cells to survive KRAS pathway blockade. Importantly, cotargeting FAO alongside ERK or KRAS inhibitors elicits a potent synergistic antitumor effect in vivo. This dual-target strategy holds promise for overcoming PDAC resistance to KRAS-targeted therapies, laying the groundwork for novel combination treatments. See related article by Thakur et al., p. 3519.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-1877
  8. Mol Metab. 2026 Jul 17. pii: S2212-8778(26)00106-7. [Epub ahead of print] 102422
    Pre-clinical cancer cachexia causes glucose hypermetabolism prior to overt weight loss.
    Emma Frank, Kaspar W Persson, Pauline Morigny, Zakarias Kefil Jensen Ogueboule, Tang Cam Phung Pham, Jonas R Knudsen, Maria Rohm, Lykke Sylow, Steffen H Raun.
       PURPOSE: Cancer cachexia is a life-threatening complication of advanced malignancies, driven by profound systemic metabolic reprogramming and anorexia. Insulin action is markedly impaired in patients with cancer and may contribute directly to cachexia pathogenesis. However, the interplay between weight loss, food intake, and cancer-associated metabolic rewiring in cachexia remains poorly defined. Clarifying this relationship is essential for identifying the fundamental drivers of cachexia and for developing effective therapeutic strategies.
    METHODS: We assessed metabolic rewiring by temporal evaluation of glucose tolerance and isotopic tracers to determine muscle insulin-stimulated glucose uptake in male cachectic and non-cachectic C26- and KPC-tumor-bearing, as well as healthy mice undergoing food restriction.
    RESULTS: Cachectic C26- and KPC-tumor mice showed increased glucose tolerance compared to non-tumor-bearing control mice, and non-cachectic tumor-bearing mice. Increased glucose tolerance appeared prior to overt muscle loss, independent of tumor size and changes in food intake. Ex vivo insulin-stimulated glucose uptake was elevated in soleus (+78%) and extensor digitorum longus (+35%) muscle from cachectic C26-cancer mice with anorexia compared to weight stable C26-cancer mice and control mice. This increase was associated with enhanced AKT signaling. Food restriction in healthy mice increased glucose tolerance, insulin-stimulated glucose uptake ex vivo, and AKT signaling.
    CONCLUSIONS: Our findings suggest that glucose hypermetabolism appears prior to overt weight loss in pre-clinical cachexia, whereas late-stage cachexia with anorexia increased skeletal muscle insulin responsiveness. This highlights AKT signaling as a key node connecting nutrient status with muscle metabolism in cancer cachexia.
    Keywords:  Cancer cachexia; food restriction; glucose metabolism; insulin sensitivity; muscle
    DOI:  https://doi.org/10.1016/j.molmet.2026.102422
  9. Nature. 2026 Jul 15.
    Ketogenic diet mediates intestinal tumorigenesis through lipids not ketones.
    Jessica E S Shay, Fangtao Chi, Constantine N Tzouanas, Shixun Han, Xiao Zhang, Johanna Ten Hoeve, Kevin J Williams, Seda Neptun, Tolga Sever, Isabela Fuentes, Sangeeta N Bhatia, Gizem Calibasi-Kocal, Matthew G Vander Heiden, Alex K Shalek, Ömer H Yilmaz.
      Diet composition shapes tissue function and disease risk by modulating nutrient availability, metabolic state and cellular dynamics1. In the gastrointestinal tract, obesogenic high-fat diets enhance small-intestinal stem cell activity and tumorigenesis2. However, the impact of ketogenic diets (KDs), which contain even higher lipid content but reduce circulating insulin and induce ketogenesis, remains poorly understood3. This is particularly relevant for patients with familial adenomatous polyposis who face a high risk of small-intestinal tumours4. Here we combine dietary, genetic and metabolic manipulations in mouse models of spontaneous intestinal adenoma formation to dissect the role of systemic and epithelial ketogenesis in intestinal cancer. We show that KD accelerates tumour burden and shortens survival, independent of ketone metabolites. Through genetic manipulation of the ketogenic pathway, we modulate the production of local and systemic ketone metabolites; however, neither inhibition nor augmentation of the ketogenic enzyme 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 nor disruption of ketolysis altered tumorigenesis. Combined intestinal loss of PPARα/δ/γ attenuates KD-driven intestinal stem cell expansion, proliferation and clonogenicity, whereas inhibition of downstream fatty acid oxidation through CPT1A loss limits adenoma formation specifically under KD, linking tumour initiation to fatty acid oxidation of dietary lipids rather than lipid accumulation. These findings reveal that dietary lipid content, through fatty acid oxidation rather than ketone metabolism, influences intestinal tumorigenesis and highlight the need for nuanced consideration of dietary strategies for cancer prevention in genetically susceptible populations.
    DOI:  https://doi.org/10.1038/s41586-026-10779-y
  10. Methods Cell Biol. 2026 ;pii: S0091-679X(26)00158-5. [Epub ahead of print]209 91-103
    Ferroptosis induction via genetic approaches - CRISPR/Cas9-based disruption on key anti-ferroptotic genes.
    Jiashuo Zheng, Weijia Zhang, Marcus Conrad.
      Unlike apoptosis, necroptosis, or pyroptosis which are executed by dedicated proteins, ferroptosis is a distinct form of regulated cell death driven by lipid peroxidation downstream of metabolic dysfunction. In most physiological settings, the cyst(e)ine/glutathione/glutathione peroxidase 4 (GPX4) axis constitutes the central anti-ferroptotic machinery, and disruption of this axis is usually sufficient to trigger ferroptosis. For in vitro studies, commonly employed ferroptosis inducers include erastin, which blocks cystine uptake by targeting system xc-, and (1S,3R)-RSL3, which inhibits GPX4 activity. However, both compounds exhibit off-target effects - erastin can activate voltage-dependent anion channels in mitochondria, whereas (1S,3R)-RSL3 affects other selenoproteins in addition to GPX4. Thus, genetic approaches to induce ferroptosis provide a valuable complement to chemical inducers by excluding off-target concerns. Here, we describe an efficient CRISPR/Cas9-based strategy to generate SLC7A11- and GPX4-knockout HT1080 cells. These knockout lines require routine culture in medium supplemented with β-mercaptoethanol or liproxstatin-1, while withdrawal of these supplements readily induces ferroptosis.
    Keywords:  CRISPR/Cas9; Ferroptosis; GPX4; HT1080 cells; Knockout; SLC7A11
    DOI:  https://doi.org/10.1016/bs.mcb.2026.05.002
  11. Methods Cell Biol. 2026 ;pii: S0091-679X(26)00123-8. [Epub ahead of print]209 27-40
    Sensitive detection of lysosomal membrane permeabilization using the galectin puncta assay.
    Konstantinos Danias, Victoria Alexandra Bjerregaard, Marja Jäättelä.
      The Lysosomal Galectin Puncta Assay is a microscopy-based technique able to detect even minor lysosomal leakage with high sensitivity. This protocol describes the detection of galectin puncta as markers of lysosomal membrane permeabilization, a process that relies on the high-affinity binding of the cytosolic galectins to the luminal glycans exposed on damaged lysosomes. Compared to traditional methods, the Galectin Puncta Assay offers high sensitivity, detects subtle lysosomal leakage, and enables analysis at single-lysosome level. Here, we provide a step-by-step protocol for this assay, covering sample preparation, immunostaining, imaging and image quantification.
    Keywords:  Galectin puncta; Lysosomal leakage; Lysosomal membrane permeabilization
    DOI:  https://doi.org/10.1016/bs.mcb.2026.04.002
  12. bioRxiv. 2026 Jul 10. pii: 2026.07.05.735339. [Epub ahead of print]
    Overcoming Daraxonrasib Resistance: Allele-Specific Mechanisms Guide Salvage Therapy in Pancreatic Cancer.
    Daniel Dorbin, Juliannie Herrera, Raven Davidson, Naveen Kumar Chandrashekar, Gabrielle Scheuber, Priyanga Jayakrishnan, Christabelle Rajesh, Grayson Johnson, Jason Yuan, Matthew Sochor, John F Langenheim, Mohammed Aldakkak, Charles Messerly, Jacquelyn Wittmann, Aniko Szabo, Forough Azam Sayahpour, Nathan L Atallah, Francis C Peterson, Brian F Volkman, Mahmoud Ali, Eugene Ke, Douglas B Evans, Susan Tsai, Nikki K Lytle, Y David Seo, Razelle Kurzrock, G Aaron Hobbs, Mandana Kamgar, Thomas McFall.
      Clinical-grade RAS inhibitors raise an unresolved question as to whether KRAS-alleles impose constraints on adaptive resistance that can be exploited therapeutically. Using daraxonrasib (RMC-6236), a multi-selective RAS(ON) inhibitor, we compared resistance mechanisms between KRAS G12D and KRAS G12R, alleles with fundamentally different RAS network dynamics. Daraxonrasib inhibited KRAS MUT primarily through steric occlusion of effector binding, while engaging RAS WT only modestly (∼20%). KRAS G12R is marked by its inability to transactivate RAS WT , and it was observed that daraxonrasib resistant KRAS G12R PDAC cells utilize EGFR/RAS WT -GTP signaling as the dominant adaptive route. In contrast, KRAS G12D resistance arose through retained KRAS G12D -GTP signaling, with a decrease of cyclophilin A (CypA) protein, the binding partner required for daraxonrasib activity. The shift from KRAS G12R dependence to the EGFR/RAS WT conferred sensitivity to trametinib. We confirmed this clinically: a KRAS G12R PDAC patient who progressed after 10 months on daraxonrasib showed intratumoral EGFR/RAS WT activation, and rapid 3D-bioprinted patient-derived toroid modeling predicted sensitivity to trametinib-based combination therapy. Given the aggressive disease trajectory and lack of response to the two immediately preceding lines of therapy, sixth-line trametinib-based combination therapy achieved approximately 5 months of disease control. This patient ultimately achieved 40 months of overall survival, far exceeding the 8-12 month median for metastatic PDAC. Collectively, these data establish a framework in which allele-specific RAS network topology dictates the adaptive resistance landscape, enabling rational selection of targeted therapies with meaningful clinical benefit in metastatic PDAC.
    STATEMENT OF SIGNIFICANCE: Daraxonrasib resistance mechanisms have allele-specific routes: CypA becomes downregulated in KRAS G12D and reliance on EGFR/RAS WT in KRAS G12R . Rapid patient-derived toroids identified sixth-line targeted therapy strategies with an overall survival of 40 months.
    DOI:  https://doi.org/10.64898/2026.07.05.735339
  13. Acta Biomater. 2026 Jul 16. pii: S1742-7061(26)00474-5. [Epub ahead of print]
    Cell Phenotype Phase Separation in Epithelial-Mesenchymal Transition-Mediated Collective Cell Migration.
    Weihao Sun, Rui Xue, Ruiyang Pang, Xiaocen Duan, Hongwei Xu, Chunyang Xiong, Jianyong Huang.
      Collective cell migration plays a critically regulatory role in both physiological and pathological processes, e.g., embryonic development, wound healing, cancer progression and metastasis. Nevertheless, spatiotemporal progression of epithelial and mesenchymal cell migration remains poorly understood. Here, we report an epithelial-mesenchymal transition (EMT)-modulated cell phenotype phase separation (CPPS) within spatially confined microenvironments, where the mesenchymal cells display enhanced boundary-directed colonization in a phenotype-dependent manner. Subsequently, we reveal that the CPPS process correlates with the degree of EMT and cytoskeletal inhibition. With the aid of a boundary attraction potential (BAP), we further develop a reaction-diffusion-based model that can quantitatively capture the spatiotemporal evolution of the EMT-related collective migration. Our findings imply that phenotypic heterogeneity among cells is a major determinant of phase separation in collective migration. This work not only uncovers the CPPS phenomenon and its underlying biophysical mechanism in collective cell migration, but also provides a new perspective for dissecting EMT-regulated intratumoral phenotypic heterogeneity. STATEMENT OF SIGNIFICANCE: Collective cell migration drives development, wound healing, and cancer metastasis, yet how phenotypically heterogeneous populations self-organize remains unclear. Using micropatterned substrates and live-cell tracking, we report cell phenotype phase separation (CPPS) during epithelial-mesenchymal transition (EMT)-mediated collective migration. Inspired by the classical Turing's theory, we develop a reaction-diffusion model with a boundary attraction potential that recapitulates the spatiotemporal dynamics of CPPS across micropattern geometries, substrate stiffnesses, and cell compositions. Our findings not only reveal a comprehensive biophysical mechanism linking EMT status to collective migration, which is crucial for dissecting cellular spatial self-organization in tumors and tissue development, but also suggest that CPPS may serve as a potential target for therapeutic intervention and drug screening.
    Keywords:  collective cell migration; epithelial-mesenchymal transition; micropattern; phase separation
    DOI:  https://doi.org/10.1016/j.actbio.2026.07.029
  14. Nat Cell Biol. 2026 Jul 15.
    Lysosomes and lysosomal dysfunction in ageing biology.
    Matthew L Steinhauser, Yuan Liu, Stacey J Sukoff Rizzo, Bill B Chen, Toren Finkel, Jay Xiaojun Tan.
      Lysosomes are essential regulators of cellular homeostasis. Emerging evidence positions lysosomes as both vulnerable targets and active drivers of ageing biology. During ageing, lysosomes exhibit impaired biogenesis, defective acidification, reduced hydrolytic activity and compromised membrane integrity. These defects impair the clearance of damaged organelles and macromolecules and promote cellular stress responses, inflammageing and senescence, causing age-dependent functional decline across tissues. Lysosomal dysfunction has been increasingly linked to age-related diseases, including neurodegeneration, cardiometabolic disorders and increased susceptibility to infection, among others. Thus, lysosomal dysfunction is a hallmark of ageing that drives age-related pathology. Here we review recent progress in lysosomal biogenesis and quality control, discuss how lysosomes intersect with fundamental ageing mechanisms and evaluate emerging therapeutic strategies that target lysosomes to promote healthy ageing and potentially ameliorate age-associated pathologies.
    DOI:  https://doi.org/10.1038/s41556-026-02007-6
  15. Ann Surg Oncol. 2026 Jul 14.
    Prognostic Value of Intratumoral Expression of Claudin 18.2 in Resected Pancreatic Cancer.
    Jun Yoshino, Hakon Blomstrand, Sebastian Fjellander, Johan Svensson, Asif Halimi, Ella Kesti, Hanna Seppänen, Caroline Vilhav, Daniel Öhlund, Caj Haglund, Nils O Elander, Peter Naredi, Malin Sund, Oskar Franklin.
       BACKGROUND: Targeting Claudin-18 isoform 2 (CLDN18.2) improves survival in CLDN18.2 positive advanced gastric cancer and similar trials on metastatic pancreatic ductal adenocarcinoma (PDAC) are ongoing. Here, we aimed to assess the prevalence of CLDN18.2 positivity in resected PDAC including its association with overall survival (OS).
    METHODS: Immunohistochemical analysis on paraffin-embedded primary tumors and lymph node metastases was performed from patients who underwent curative-intent PDAC resection at four centers in Sweden and Finland. In addition, survival outcomes were assessed.
    RESULTS: In total, 599 primary tumors and 197 lymph nodes were analyzed. CLDN18.2 positivity was observed in 138 of 599 of primary tumors (23%) and 35 of 197 metastatic lymph nodes (17.8%). CLDN18.2 positivity in primary tumors was associated with higher tumor grade (p = 0.016). Median OS was longer in patients with CLDN18.2-positive tumors (27.7 vs. 21.1 months). Adjusted analysis identified CLDN18.2 positivity as an independent prognostic variable for OS (hazard ratio 0.79; 95% confidence interval 0.64-0.98).
    CONCLUSIONS: CLDN18.2 is expressed in 23% of primary PDAC tumours, indicating its potential to be used as a therapeutic target in a significant proportion of PDAC patients, and its expression is associated with improved OS in resected PDAC, supporting its role as a prognostic marker.
    Keywords:  CLDN18.2; Immunohistochemistry; Pancreatic ductal adenocarcinoma; Prognosis; Surgical resection
    DOI:  https://doi.org/10.1245/s10434-026-20191-5
  16. Genes Dev. 2026 Jul 17.
    Metabolic adaptations of the tumor macroenvironment and their role in cancer progression and survivorship.
    Devesh Raizada, Ana P Gomes.
      Cancer progression is shaped not only by tumor-intrinsic programs and the local microenvironment but also by profound metabolic rewiring of the host at the organismal scale. Tumors engage in dynamic cross-talk with distant organs, immune and neuroendocrine networks, and systemic nutrient pools, generating a metabolically permissive macroenvironment that fuels tumor growth, supports metastatic dissemination, and undermines therapeutic efficacy. In this review, we synthesize emerging evidence showing how cancer-driven systemic metabolic remodeling reshapes glucose, lipid, and protein metabolism, perturbs immune and hematopoietic homeostasis, and hijacks neuroendocrine circuits governing energy balance and stress responses. We further highlight how these adaptations fuel cellular energetics within tumor cells as well as promote premetastatic niche formation, immune evasion, and therapy resistance, while leaving durable metabolic and inflammatory scars that accelerate biological aging and compromise long-term health in cancer survivors. Together, these findings position tumor-host metabolic cross-talk as a central, targetable axis in cancer biology with broad implications for therapy and survivorship care.
    Keywords:  cancer progression; metabolism; tumor macroenvironment
    DOI:  https://doi.org/10.1101/gad.353830.126
  17. Nat Rev Endocrinol. 2026 Jul 14.
    Reframing cancer cachexia: from malnutrition to treatable disease.
    Gaofei Wei, Jose M Garcia, Maria Rohm.
      
    DOI:  https://doi.org/10.1038/s41574-026-01285-2
  18. Molecules. 2026 Jul 06. pii: 2373. [Epub ahead of print]31(13):
    Lysosomes in Ferroptosis: Regulatory Mechanisms and Molecular Targets.
    Tingrui Luo, Chenyu Wang, Nanhao Zhou, Yuansheng Zhang, Xianbo Mou.
      Ferroptosis is a regulated form of cell death characterized by iron-dependent lipid peroxidation and membrane damage, with broad relevance to human disease. Accumulating evidence suggests that ferroptosis is governed by coordinated organelle-level regulation, among which lysosomes have emerged as central hubs. By controlling endolysosomal iron processing, transport, and degradation pathways, lysosomes shape the intracellular distribution and reactivity of iron, thereby modulating iron-driven lipid peroxidation. The acidic, iron-rich microenvironment and limited local antioxidant capacity render lysosomal membranes highly susceptible to oxidative injury, positioning lysosomes as initiation and amplification sites of lipid peroxidation. Meanwhile, lysosome-dependent selective autophagy pathways actively remodel iron homeostasis, lipid metabolism, and cellular antioxidant defenses, thereby dynamically modulating ferroptotic sensitivity. Mitochondria-lysosome crosstalk further redistributes iron, reactive oxygen species, and lipid substrates, linking lysosomal activity to interorganelle control of ferroptosis. Lysosomal stress-responsive signaling also coordinates metabolic adaptation and redox control. This review summarizes and integrates current evidence on lysosome-centered mechanisms that organize iron metabolism, lipid peroxidation, selective autophagy, organelle crosstalk, and stress-responsive signaling during ferroptosis, and further discusses their disease-specific roles, therapeutic potential, and translational challenges.
    Keywords:  autophagy; ferroptosis; iron metabolism; lysosomes; oxidative stress
    DOI:  https://doi.org/10.3390/molecules31132373
  19. Autophagy. 2026 Jul 16. 1-3
    Regulatory T cell immunosuppressive function requires chaperone-mediated autophagy.
    Ranee Harrison, Floralba Gjergjova, Susmita Kaushik, Yair Botbol, Ana Maria Cuervo, Fernando Macian.
      Regulatory T cells (Tregs) are essential for maintaining immune tolerance. We recently identified chaperone-mediated autophagy (CMA), a selective lysosomal degradation pathway, as a critical regulator of Treg function. Treg activation induces CMA, but this response is markedly diminished with aging. Mice lacking CMA specifically in Tregs develop systemic inflammation, impaired immune tolerance and reduced lifespan. We confirm that CMA is a fundamental mechanism supporting Treg suppressive function as CMA-deficient Tregs are unable to suppress intestinal inflammation in a model of inflammatory bowel disease and fail to block the anti-oncogenic immune response activated in a syngeneic tumor model. Mechanistically, CMA supports metabolic fitness, remodels immune-related protein networks, and promotes degradation of the m6A RNA demethylase FTO, linking lysosomal proteostasis to epitranscriptomic control of IL-2 responsiveness. Restoration of CMA in aged mice improves Treg function, highlighting CMA as a promising therapeutic target for both inflammatory diseases and cancer immunotherapy.
    Keywords:  Anti-oncogenic immune response; Immunotolerance; inflammatory bowel disease; proteostasis; regulatory T cells; selective autophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2700476
  20. Eur J Cancer. 2026 Jul 14. pii: S0959-8049(26)00715-X. [Epub ahead of print]245 116934
    Organotropism-specific circulating tumor cells profiles: Morphology and heterotypic clustering predict metastatic sites in liquid biopsy of solid tumors.
    Michela De Meo, Marco Siringo, Orietta Gandini, Roberta Gareri, Chiara Nicolazzo, Paola Gazzaniga.
       BACKGROUND: While circulating tumor cells (CTCs) are the primary drivers of metastatic dissemination, the mechanisms governing their organotropism remain poorly characterized. CTC morphology, including size and elongation, and cluster configuration (homotypic vs. heterotypic) may encode site-specific metastatic signatures. Characterizing these features could provide critical pre-radiological biomarkers for predicting organ-specific recurrence and refining metastatic risk assessment in clinical.
    METHODS: We analyzed a large retrospective cohort of patients with a single metastatic site (bone, liver, brain, or lung), regardless of primary tumor origin, using the CellSearch® system. CTC were classified by morphological subtypes (canonical, large, elongated) and cluster phenotypes (homotypic versus heterotypic).
    RESULTS: CellSearch® profiling of 8359 CTCs from 82 patients with metastatic cancer uncovered marked site-specific heterogeneity reflective of tumor burden and biological tropisms. Among 34 patients with bone metastases, 7010 CTCs (median 21 [IQR 6-135]) were predominantly canonical (85%) and organized in nearly exclusive homotypic clusters (97.7%). In 26 patients with liver metastases, 1273 CTCs (median 4 [IQR 3-7]) shifted to large CTCs (80%) with mixed homotypic (65.2%) and heterotypic (34.8%) clustering. Conversely, 22 patients with brain/lung metastases yielded 76 CTCs (median 3 [IQR 3-5]), enriched for elongated forms (84%) in exclusively heterotypic clusters (100%). These distinct profiles demonstrated statistically significant disparities (P < 0.001), implicating anatomical and microenvironmental drivers of CTC shedding and dissemination.
    CONCLUSIONS: CTC morphology and heterotypic clustering exhibit organotropism-specific profiles, aligning with microenvironmental cues like capillary shear, endothelial activation, and immune niches. These findings position multimodal CTC analysis as a liquid biopsy tool for early metastasis site forecasting, guiding precision interventions.
    Keywords:  Circulating tumor cell clusters; Circulating tumor cell morphology; Circulating tumor cell organotropism; Circulating tumor cells; Liquid biopsy; Precision oncology
    DOI:  https://doi.org/10.1016/j.ejca.2026.116934
  21. Nature. 2026 Jul 15.
    An encyclopedia of human enhancer-gene regulatory interactions.
    Andreas R Gschwind, Kristy S Mualim, Alireza Karbalayghareh, Maya U Sheth, Kushal K Dey, Evelyn Jagoda, Ramil N Nurtdinov, Wang Xi, Anthony S Tan, James Galante, Hank Jones, X Rosa Ma, David Yao, Dulguun Amgalan, Judhajeet Ray, Chad J Munger, Joseph Nasser, Žiga Avsec, Benjamin T James, Muhammad S Shamim, Neva C Durand, Suhas S P Rao, Ragini Mahajan, Benjamin R Doughty, Kalina Andreeva, Jacob C Ulirsch, Kaili Fan, Elizabeth M Perez, Tri C Nguyen, David R Kelley, Hilary K Finucane, Jill E Moore, Zhiping Weng, Manolis Kellis, Michael C Bassik, Berk Ustun, Alkes L Price, Michael A Beer, Roderic Guigó, John A Stamatoyannopoulos, Erez Lieberman Aiden, William J Greenleaf, Christina S Leslie, Lars M Steinmetz, Anshul Kundaje, Jesse M Engreitz.
      Identifying transcriptional enhancers and their target genes is essential for understanding gene regulation and the effect of human genetic variation on disease1-6. Here we create and evaluate a resource of more than 92 million enhancer-gene regulatory interactions across 1,458 biosamples covering 369 cell types and tissues, by integrating predictive models, chromatin states, three-dimensional contacts and large-scale genetic perturbations generated by the ENCODE Consortium7. We first create a systematic benchmarking pipeline to compare predictive models, assembling a dataset of 10,356 element-gene pairs measured in CRISPR perturbation experiments, more than 30,000 fine-mapped expression quantitative trait loci and 569 fine-mapped genome-wide association study (GWAS) variants linked to a probable causal gene. Using this framework, we develop ENCODE-rE2G, a predictive model achieving state-of-the-art performance across several prediction tasks, demonstrating that iterative perturbations and supervised machine learning can build increasingly accurate predictive models of enhancer regulation. Using ENCODE-rE2G, we build an encyclopedia of enhancer-gene regulatory interactions in the human genome, revealing global properties of enhancer networks, identifying differences in regulatory complexity across genes and improving analyses linking noncoding variants to target genes and cell types for common complex diseases. By interpreting the model, we find that beyond enhancer activity and three-dimensional enhancer-promoter contacts, additional features that guide enhancer-promoter communication include promoter class and enhancer-enhancer synergy. These genome-wide maps of enhancer-gene regulatory interactions, benchmarking software, predictive models and insights about enhancer function provide a valuable resource for future studies of gene regulation and human genetics.
    DOI:  https://doi.org/10.1038/s41586-026-10781-4
  22. Am J Physiol Cell Physiol. 2026 Jul 16.
    Sex-divergent skeletal muscle remodeling emerges early in cancer cachexia.
    Chris Karagiannis, Alastair A E Saunders, Rachel E Thomson, María Guillán-Fresco, Wayne X Du, Craig A Goodman, Paul Gregorevic.
      Cancer cachexia is characterised by progressive skeletal muscle wasting and dysfunction, yet the early events that precede overt muscle wasting remain poorly defined. Here, we utilised a time-coursed C26 carcinoma model in male and female mice to define the pre-cachectic transcriptomic, proteostatic, immune, and metabolic adaptations between sexes. Males progressed more rapidly to cachexia and exhibited earlier impairments in body composition and grip strength, with shifts in muscle fiber size distribution detectable prior to changes in muscle mass. Transcriptomic analysis of the tibialis anterior muscle identified >6,000 differentially expressed genes, with >60% showing sex-specific regulation at the pre-cachectic stage. Proteostasis pathways were transcriptionally altered in both sexes, however, global muscle protein synthesis was suppressed earlier in males, preceding both measurable muscle mass loss and robust induction of specific E3 ubiquitin ligases. Transcripts related to innate immunity were preferentially elevated in males and accompanied by increased infiltration of myeloid cells, while systemic immune profiles showed limited concordant changes. Females showed preferential enrichment of insulin resistance and metabolic remodeling pathways, accompanied by early impairment of insulin handling and reduced muscle glycogen content at severe cachexia. These results show that cachexia progression in this model is sexually dimorphic and skeletal muscle undergoes extensive remodeling before overt wasting. Males exhibit earlier functional decline and muscle immune remodeling, whereas females show earlier metabolic vulnerability with impaired insulin handling. These findings define sex-divergent pre-cachectic windows that may guide early biomarker discovery and therapeutic strategies aimed at preventing progression and improving quality of life in cancer patients.
    Keywords:  Cancer-cachexia; flow-cytometry; insulin-resistance; protein-metabolism; transcriptomics
    DOI:  https://doi.org/10.1152/ajpcell.00271.2026
  23. Sci Adv. 2026 Jul 17. 12(29): eadz8681
    Iron overload suppresses LKB1 and induces IL36G anti-tumor immunity in PDAC metastasis.
    Douglas E Biancur, Harsha Venkatesh, Amy Crawford, Yealeen Jeong, Albert S W Sohn, Kevin S Kapner, Keisuke Yamamoto, Elaine Y Lin, Robert S Banh, Mohamad Assi, Beny Shapiro, Peter Yu, Soomin C Song, William A Coetzee, Andrew J Aguirre, Alisha N Jones, Alec C Kimmelman, Richard Possemato.
      Pancreatic ductal adenocarcinoma (PDA) is an aggressive cancer that frequently presents with disseminated disease. The PDA metastatic microenvironment imposes distinct metabolic stressors, potentially generating context-dependent vulnerabilities. Therefore, we employed CRISPR-based genetic screening in a model of PDA liver metastasis to identify novel and possibly targetable liabilities. Remarkably, ferritin heavy chain (FTH1) emerged as the most prominent liver-specific dependency - loss of FTH1 suppressed tumor growth specifically in the liver microenvironment. FTH1 deletion and subsequent disruption of iron handling triggers mitochondrial dysfunction and ionic imbalance, including cytosolic calcium overload. These perturbations result in the activation of a transcriptional program that triggers anti-tumor immunity mediated by immunostimulatory cytokine IL36G. Mechanistically, FTH1 deletion and subsequent ionic imbalance causes decreased protein levels of the tumor suppressor Stk11 (LKB1) which we propose to be mediated by an RNA G-quadruplex located in the 5'-UTR of LKB1. The loss of LKB1 protein levels alters signaling cascades resulting in reduced SIK signaling and inhibition of nonsense mediated decay, ultimately leading to Il36g mRNA stabilization. Taken together, this work elucidates novel ionic disruptions that regulate the translation of LKB1 through a previously undescribed quadruplex in the 5'UTR, altering signaling axes that can be targeted to generate an anti-tumor immune response in PDA.
    DOI:  https://doi.org/10.1126/sciadv.adz8681
  24. Nature. 2026 Jul 15.
    Metabolite glues as a means of purine sensing and chemotherapeutic response.
    Samuel R Witus, Megan M Kober, Heegwang Roh, Zhi Yang, Fouad Choueiry, Avani S Ghate, Denis V Titov, Michael Rapé.
      Molecular glues stabilize weak interactions to impart new functionalities to complexes1-3. Although molecular glues have been described in plant signalling and as human therapeutics4,5, it is unclear whether this modality provides endogenous regulation in human cells. Here we show that purine nucleotides are molecular glues that tether the rate-limiting enzyme in purine biosynthesis-phosphoribosyl pyrophosphate amidotransferase (PPAT)-to its inhibitor NUDT5. This mechanism allows cells to sense the levels of purines and to establish essential feedback control of their synthesis. We refer to such molecules as metabolite glues. Thiopurine chemotherapeutics6, which have been in clinical use since the 1950s, glue the same complex but adopt distinct orientations for enhanced function. Unlike most known glues, the PPAT-NUDT5 metabolite-glue pocket can adjust its conformation to notable compound alterations, enabling increased glue potency and improved on-target activity. We therefore identify endogenous metabolite glues as a mode of nutrient sensing that can be exploited for therapeutic benefit.
    DOI:  https://doi.org/10.1038/s41586-026-10790-3
  25. bioRxiv. 2026 Jul 06. pii: 2026.07.04.736063. [Epub ahead of print]
    ELDR-Glo, a biosensor for cell age and quiescence depth.
    Martha S Johnson, Sapna Kamath, Dalia Fleifel, Tessa Hill, Liu Mei, Neha Das, Mary Linares, Wenyih Aw, Victoria L Bautch, Jeanette Gowen Cook.
      Fluorescent reporters are powerful tools to reveal intercellular heterogeneity among proliferating cells. However, there are few tools to analyze differences among quiescent (G0) cells, though such differences are relevant for development, tissue maintenance, and cancer cell behavior. Quiescence heterogeneity, also known as quiescence depth, typically correlates with time after cell cycle arrest, yet directly measuring cell age is not feasible for all cell types or most tissues. Here, we describe ELDR-Glo, a genetically-encoded fluorescent biosensor that estimates relative cell age, i.e., time since the last cell cycle. The biosensor integrates replication-coupled degradation in S phase with a slow-maturing mCherry and a normalization module. We demonstrate that ELDR-Glo signal correlates with true cell age by both live-cell imaging and in fixed cells. ELDR-Glo distinguishes early and late G0 cells and functions as a relative quiescence depth reporter in situ. The biosensor is compatible with multiplexed immunofluorescence and flow cytometry. ELDR-Glo provides a unique and scalable tool to investigate cell proliferation control.
    DOI:  https://doi.org/10.64898/2026.07.04.736063
  26. Nat Biotechnol. 2026 Jul 15.
    Multiscale in vivo imaging of tumor evolution using a germline conditional triple-reporter mouse.
    Ximena L Raffo-Iraolagoitia, Abdullah Alyamani, Stephanie May, David Stevenson, Agata Mackintosh, Lynn McGarry, Jayanthi Anand, Dmitry Soloviev, Gavin Brown, Colin Nixon, Chrysa Kapeni, Maike De La Roche, Karen Blyth, Thomas Graham Bird, Douglas Strathdee, Scott K Lyons, Gilbert Fruhwirth, Leo M Carlin, David Y Lewis.
      Imaging reporter genes are essential tools in cancer research for monitoring tumor evolution, cell dissemination, gene activation and treatment response. However, germline reporter models typically rely on single imaging modalities operating over limited spatial scales. To address these limitations, we developed an inducible triple-reporter mouse model (Rosa26LSL-NRL) that integrates three reporters for complementary imaging modalities, fluorescence, bioluminescence and positron emission tomography (PET), along with inducible Cre-lox functionality for precise spatiotemporal control of reporter expression in genetically engineered mouse models. Using a multiscale, multimodal approach, we visualize deep tissue oncogenesis in models of hepatocellular carcinoma and lung adenocarcinoma and, guided by whole-body imaging with bioluminescence and [18F]tetrafluoroborate PET/magnetic resonance imaging (MRI), resolve cell-cell interactions within tumor microenvironments using in situ microscopy. This triple-reporter system enables multiscale investigation of biological processes within whole animals, facilitating sensitive, tissue-specific, in vivo cell tracking from whole-body to cellular resolution.
    DOI:  https://doi.org/10.1038/s41587-026-03184-3
  27. Sci Adv. 2026 Jul 17. 12(29): eaec9227
    Ridge-assisted micro positioning of cells in a channel.
    Adriana Payan-Medina, Victor R Putaturo, Sajad R Bazaz, Quinn E Cunneely, Varun Kulkarni, Mehmet Toner, Avanish Mishra.
      The ability to deterministically and precisely control the lateral position of focused cell streams within a microchannel enables a wide range of biomedical applications, including cell concentration, sorting, and sensing. By leveraging engineered microvortices generated by channel ridges and fluidic lift forces, we present a microfluidic method for deterministically positioning focused cell streams to desired streamlines. Unlike inertial focusing, ridge-assisted micro positioning (RAMP) is independent of particle size and flow rate, enabling polydisperse particles to be focused to the same streamline across a broad range of flow rates. The focusing position can be precisely adjusted by altering the ridge placement and geometry, allowing for micron-level lateral shifts in a controlled manner. Applying the RAMP concept, we demonstrate clog-free microfluidic cell concentrators that can enrich single cells and clusters to desired concentration factors and show the ability to focus particles in undiluted whole blood. Together, these results establish RAMP as a versatile platform for precise cell positioning in complex biological fluids.
    DOI:  https://doi.org/10.1126/sciadv.aec9227
  28. J Natl Cancer Inst. 2026 Jul 10. pii: djag235. [Epub ahead of print]
    Benefit of adjuvant chemotherapy for resected pancreatic cancer following neoadjuvant FOLFIRINOX or Gemcitabine-Nab-paclitaxel: a multinational analysis.
    Victor Lopez-Lopez, Tanja Hasse, Philipp Houben, Michael C Frey, Elena Rangelova, Luana Genova, Giuseppe Malleo, Gabriella Lionetto, So Heun Lee, Sarvar Abdurakhmonov, Sameer H Patel, Gregory C Wilson, Syed A Ahmad, Ryan K Schmocker, Magdalena Lüthy, Ralph Fritsch, Russell F Palm, Sarah E Hoffe, Jin He, Alex Gordon-Weeks, Adil Lakha, Ning Pu, Liang Liu, Simon Owuor, Patricia Sánchez-Velazquez, Benedetto Ielpo, Pablo Beltrán, M J Pérez-Benito, Iago Justo Alonso, Anisa Nutu, Jasur Sobirov, Gema Marin Zafra, Ricardo Robles-Campos, Timothy M Pawlik, Andreas Pascher, Changhoon Yoo, Jose Oberholzer, Dilmurodjon Eshmuminov.
       BACKGROUND: The survival benefit of adjuvant chemotherapy (AC) for pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant therapy (NAT) and resection remains controversial. Previous studies often pooled diverse disease stages or chemotherapy regimens, potentially obscuring regimen-specific outcomes. We sought to investigate the association of AC with overall survival (OS) among patients with resected borderline resectable (BRPC) or locally advanced pancreatic cancer (LAPC), stratified by specific neoadjuvant and adjuvant regimens.
    METHODS: This multinational, retrospective cohort study included 834 patients with BRPC/LAPC who underwent curative-intent resection following NAT with either FOLFIRINOX or gemcitabine plus nab-paclitaxel (Gem/Nab). Propensity score matching (1:1) was utilized to minimize selection bias. The primary outcome was OS, analyzed using Kaplan-Meier methods and Cox proportional hazards models.
    RESULTS: Among 834 patients, 605 received neoadjuvant FOLFIRINOX and 229 received neoadjuvant Gem/Nab. In the matched analysis for the neoadjuvant FOLFIRINOX cohort, continuation of adjuvant FOLFIRINOX was associated with longer OS compared with no AC (median OS, 42.0 vs. 25.8 months; HR, 0.58; 95% CI, 0.43-0.79; p < 0.001). In contrast, switching to adjuvant Gem/Nab did not confer a survival benefit in this group (HR, 0.84; 95% CI, 0.61-1.15; p = 0.27). For patients receiving neoadjuvant Gem/Nab, adjuvant Gem/Nab or other regimens was not associated with improved OS (HR, 0.92; 95% CI, 0.64-1.34; p = 0.69).
    CONCLUSIONS: Survival benefits of adjuvant chemotherapy in resected BRPC/LAPC may be regimen-dependent. Postoperative continuation of FOLFIRINOX appeared to be associated with a survival advantage, whereas regimen de-escalation or adjuvant chemotherapy following neoadjuvant Gem/Nab demonstrated no clear benefit.
    DOI:  https://doi.org/10.1093/jnci/djag235
  29. Immunity. 2026 Jul 17. pii: S1074-7613(26)00271-2. [Epub ahead of print]
    Autophagy maintains high endothelial venule identity and function during inflammation.
    Kathryn A Jacobs, Yichao Hua, Apostolos Panagiotis Nikolakopoulos, Swati Gupta, Gerlanda Vella, Ana Filipa Domingues Laranjeiro, Julie Bonnereau, Mélanie Guyot, Maria Livia Sassano, Larissa Mourao, Feyza Cansiz, Gabriele Allies, Nicolas Van Baren, Sophie Lucas, Hiroto Kawashima, Wiebke Sondermann, Florian Rambow, Alpaslan Tasdogan, Colinda Scheele, Patrizia Agostinis, Gabriele Bergers.
      High endothelial venules (HEVs) play a crucial role in adaptive immune responses in secondary lymphoid organs (SLOs). They are equipped with high amounts of peripheral node addressin (PNAd), harboring carbohydrate structures that serve as L-selectin ligands to efficiently facilitate lymphocyte homing. During inflammation, the HEV network expands in SLOs, increasing lymphocyte infiltration, but the underlying mechanisms that maintain HEVs remain underexplored. Here, we report that autophagy is essential for HEV function and expansion. Using single-cell transcriptomics, unbiased proteomics, intravital imaging, and an inducible HEV tracer system in mice, we demonstrate that autophagy deficiency compromises lymphotoxin beta receptor (LTβR) signaling and the unfolded protein response in HEVs, leading to disrupted PNAd production, dedifferentiation, and reduced lymphocyte homing. Autophagy deficiency and LTβR blockade impair HEV function and reduce skin inflammation in psoriasis-affected mice by limiting immune infiltration and cytokine release. Our work reveals that autophagy safeguards HEV identity and function during inflammation.
    Keywords:  HEV; UPR; autophagy; high endothelial venules; inflammation; lymph node; lymphotoxin-beta receptor; peripheral node addressin; psoriasis; unfolded protein response
    DOI:  https://doi.org/10.1016/j.immuni.2026.06.020
  30. Trends Mol Med. 2026 Jul 17. pii: S1471-4914(26)00169-3. [Epub ahead of print]
    Lysosome as a central hub in ferroptosis-driven pathologies.
    Siyu Li, Bavid Qiu, Xin Yi, Ding-Sheng Jiang.
      Ferroptosis is a unique form of programmed cell death that involves multiple organelles. Although traditionally viewed as a 'degradation workshop', accumulating evidence reveals that the lysosome serves as a central hub for iron metabolism and signal transduction, orchestrating the overall fate of cellular ferroptosis across spatiotemporal dimensions. In this review, we propose the concept of the 'lysosome-ferroptosis axis' and outline its roles in metabolic signaling, autophagy, and lysosomal membrane permeabilization. We further discuss the involvement of this axis in neurodegenerative, tumor, and cardiometabolic diseases, with the aim of providing new insights for targeted therapeutic strategies.
    Keywords:  cancer; cardiometabolic disorder; ferroptosis; lysosome; neurodegenerative disorder
    DOI:  https://doi.org/10.1016/j.molmed.2026.06.016
  31. J Colloid Interface Sci. 2026 Jul 10. pii: S0021-9797(26)01293-2. [Epub ahead of print]724(Pt 1): 141116
    Myelin basic protein binding is modulated by leaflet asymmetry and lipid composition.
    Julio M Pusterla, Alexandros Koutsioubas, Nicolò Paracini, Philipp Gutfreund, Maximilian W A Skoda, Stephen Hall, Igor Graf von Westarp, Irina Apanasenko, Sabine Dieluweit, Guillermo Beltramo, Marina Cagnes, Stephan Förster, Andreas M Stadler.
      Compositional asymmetry between lipid bilayer leaflets is a defining feature of biological membranes and can modulate protein binding. Here, we investigate how leaflet-specific composition affects the interaction between Myelin Basic Protein and biomimetic myelin membranes using neutron reflectometry. Asymmetric supported myelin bilayers containing deuterated cholesterol in the cytoplasmic leaflet enabled resolution of structural asymmetry. Neutron reflectometry measurements show that Myelin Basic Protein binds preferentially to asymmetric supported bilayers mimicking native myelin, whereas Experimental Autoimmune Encephalomyelitis-modified compositions exhibit weaker binding and more pronounced protein insertion. Disruption of asymmetry-either by thermally induced lipid redistribution or by using symmetric cytoplasmic myelin-leads to a marked reduction in Myelin Basic Protein binding, despite increased membrane charge. Following vesicle adsorption and formation of a second bilayer, the protein layer narrows to near in vivo thickness in both systems, with the diseased condition exhibiting a wider inter-bilayer spacing. These results underscore the relevance of lipid asymmetry and composition in governing protein-membrane interactions, with implications for the molecular basis of myelin stability and demyelination.
    Keywords:  Membrane asymmetry; Myelin; Myelin basic protein; Neutron reflectometry; Selective deuteration; Supported lipid bilayer
    DOI:  https://doi.org/10.1016/j.jcis.2026.141116
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