bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2026–05–17
39 papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Inhibition of ceramide synthesis ameliorates body wasting in a cancer cachexia model.
  2. Liver-derived ceramides link metabolism to tissue wasting in cancer cachexia.
  3. Metabolic Control of Membrane Lipid Asymmetry in Cancer.
  4. Galvanin (TMEM154) is an electric-field sensor for directed cell migration.
  5. Targeting Cancer Cachexia: A Mechanistic Evaluation of Anti-GDF-15 Antibody-Based Combination Therapies.
  6. A review of autophagy in the pancreas: normal physiology and pathophysiology.
  7. Antibody subclass deficiency accelerates tumorigenesis in genetically engineered mouse models of pancreatic cancer.
  8. Temperature and lipid composition differentially regulate KRAS assemblies on membranes.
  9. CD300ld on pathologically activated neutrophils promotes tumor immune suppression by binding phosphatidylserine on CD8+ T cells.
  10. Proteolysis activity mapping and substrate discovery platform for identifying tumor-activated biosensors.
  11. Why Do Cells Contain Thousands of Lipid Species? Toward an Integrated Framework for Lipid Diversity in Biological Membranes.
  12. GDF10 exacerbates metastatic burden and cachexia in murine models of cancer.
  13. Whole mouse mapping.
  14. Dietary supplementation with ursolic acid preserves skeletal muscle mass and strength in mouse models of cancer cachexia.
  15. Tumor-derived GDF15 induces CCN3⁺ Schwann cells to promote cancer pain in pancreatic cancer.
  16. Quantifying 3D live-cell membrane dynamics using dynamic metal-induced energy transfer spectroscopy (dynaMIET).
  17. Ki-67 promotes circulating tumor cell intravasation and metastasis in breast cancer.
  18. Cellular mechanometabolism: stimuli and implications.
  19. Flexible high-resolution ECM micropatterning.
  20. ATM Deficiency Induces TGF-β-Mediated Stromal Programming in Pancreatic Cancer.
  21. Adhesion-mediated force transmission regulates cell competition in epithelia.
  22. Genetically targeted mTORC1 inhibitor reveals transcriptional control by nuclear mTORC1.
  23. The multifaceted regulation of autophagy protein ATG16L1 and its implications in human diseases.
  24. Inflammation starves antitumour immunity.
  25. Cu²⁺ triggers lipid phase separation in anionic membranes via a bimodal interfacial mechanism.
  26. Metabolic underpinnings of cuproptosis.
  27. Selective targeting of kinesin on lipid droplets in the liver reduces plasma lipids.
  28. Deep-learning endomicroscope with large field-of-view and depth-of-field for real-time in vivo imaging of epithelial cancer hallmarks.
  29. Ferroptosis inhibition enhances liver and lung graft function.
  30. Simultaneous CRISPR/Cas9-induced double-strand breaks are lethal in models of pancreatic cancer.
  31. Fluorescence tracking live-cell plasma membranes via polarity ultra-sensitive non-ionic probes.
  32. Selective detection of lipophagy with a highly specific lipid droplet probe.
  33. Metastatic tropism of molecularly defined clear-cell renal cell carcinoma clusters.
  34. Heme, copper, and a new way to kill cancer cells.
  35. Golgi pH buffers ferroptosis sensitivity.
  36. Tissue rigidity phase transition shapes morphogen gradients.
  37. The lipidomic atlas for cellular organelles to reveal the central role of mitochondria in organelle communication.
  38. The underexplored complexity of pancreatic cancer: Early dissemination and quiescence.
  39. The role of ATP synthase subunit e (ATP5I) in mediating the metabolic and antiproliferative effects of metformin in cancer cells.
  1. J Clin Invest. 2026 May 15. pii: e194687. [Epub ahead of print]136(10):
    Inhibition of ceramide synthesis ameliorates body wasting in a cancer cachexia model.
    Pauline Morigny, Honglei Ji, Laura Cussonneau, Sabrina Zorzato, Yun Kwon, Fabien Riols, Doris Kaltenecker, Alisa Maier, Vignesh Karthikaisamy, Samantha Corrà, Tanja Krauss, Claudine Seeliger, Syed Qaaifah Gillani, Joël J Tissink, Sandra Lacas-Gervais, Tuna Felix Samanci, Adriano Maida, Raul Terron-Exposito, Angela Trinca, Christine von Toerne, Leonardo Nogara, Melina Claussnitzer, Olga Prokopchuk, Jeannine Bachmann, Mauricio Berriel Diaz, Laure B Bindels, Ondrej Kuda, Hans Hauner, Mark Haid, Stephan Herzig, Carlo Fiore Viscomi, Jerome Gilleron, Anja Zeigerer, Bert Blaauw, Maria Rohm.
      Cachexia is a metabolic wasting syndrome affecting many patients with cancer, with poor survival outcomes. Disturbed lipid metabolism is a hallmark of cachexia, and our previous work has identified increased levels of circulating ceramides, which are bioactive lipids with adverse effects in metabolic diseases, as biomarkers for cachexia in mouse models and patients. Here, we investigated the role of ceramides on cachexia development using the well-established C26 colon carcinoma model. We demonstrated that elevated ceramides in cachexia arose from increased liver synthesis. We showed that ceramides directly contributed to impaired mitochondrial function and energy homeostasis in cachexia target tissues. Targeting ceramide synthesis using miRNA interference, or myriocin, an approved compound targeting the key synthesis enzyme serine palmitoyltransferase (SPT), improved markers of muscle atrophy in cachectic male mice. Importantly, we demonstrated that key enzymes involved in ceramide production were also elevated in livers, but not in other organs, of patients with cancer cachexia, correlating with disease severity. Our data place ceramides as contributors to metabolic dysfunction in cachexia and highlight the suitability of the ceramide synthesis pathway for therapeutic targeting.
    Keywords:  Cancer; Lipidomics; Metabolism; Mitochondria; Oncology
    DOI:  https://doi.org/10.1172/JCI194687
  2. J Clin Invest. 2026 May 15. pii: e206031. [Epub ahead of print]136(10):
    Liver-derived ceramides link metabolism to tissue wasting in cancer cachexia.
    Kerui Huang, Norbert Perrimon, Marcus D Goncalves.
      Cancer cachexia, characterized by weight loss, muscle wasting, and anorexia, complicates cancer treatment and adversely affects patient outcomes. Both tumor-derived and host inflammatory factors are implicated in aspects of cachexia. The search for circulating mediators of cancer cachexia has focused largely on secreted proteins, but metabolites may also drive systemic wasting. In this issue, Morigny, Rohm, and colleagues identified the liver as a major source of circulating ceramides in cachectic mice and patients with cancer and demonstrated that inhibiting ceramide synthesis attenuated muscle wasting and preserved function in cachectic mice. These findings position the liver as an endocrine organ in cachexia and introduce a druggable metabolic pathway with translational potential.
    DOI:  https://doi.org/10.1172/JCI206031
  3. Int J Mol Sci. 2026 Apr 26. pii: 3846. [Epub ahead of print]27(9):
    Metabolic Control of Membrane Lipid Asymmetry in Cancer.
    Kyung-Hee Kim, Byong Chul Yoo.
      The plasma membrane plays essential roles in cellular transport and signaling. One of its fundamental structural features is the asymmetric distribution of lipids between the inner and outer leaflets. This asymmetry is actively maintained by lipid transport systems, including flippases, floppases, and scramblases, and is critical for membrane integrity and signaling regulation. Accumulating evidence indicates that membrane lipid asymmetry is frequently altered in cancer cells, leading to the externalization of normally inner-leaflet phospholipids such as phosphatidylserine and phosphatidylethanolamine. These alterations can influence tumor signaling, immune interactions, and membrane-associated biological processes. Recent studies further suggest that metabolic reprogramming in cancer may play an important role in regulating membrane lipid asymmetry. Changes in cellular energy status, oxidative stress, calcium signaling, and lipid metabolism can modulate lipid transport systems and membrane organization. In addition, tumor metabolism generates diverse circulating metabolites, including lactate, lysophospholipids, and acylcarnitines, which may influence membrane properties and lipid redistribution. These observations raise the possibility that membrane lipid asymmetry functions as a metabolically responsive interface linking intracellular metabolic state to cell surface signaling and tumor-microenvironment interactions. In this review, we propose a conceptual framework in which cancer-associated metabolic reprogramming influences lipid transport systems and membrane organization, thereby reshaping phospholipid distribution across the plasma membrane. We discuss how metabolic perturbations-including changes in energy metabolism, redox balance, calcium signaling, and lipid remodeling-may regulate membrane lipid asymmetry and explore the implications of these processes for tumor signaling, immune interactions, and emerging membrane-targeted therapeutic strategies.
    Keywords:  cancer metabolism; circulating metabolites; membrane lipid asymmetry; membrane remodeling; membrane-targeted therapy; metabolic reprogramming; phospholipid redistribution; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms27093846
  4. Cell. 2026 May 12. pii: S0092-8674(26)00461-7. [Epub ahead of print]
    Galvanin (TMEM154) is an electric-field sensor for directed cell migration.
    Nathan M Belliveau, Matthew J Footer, Amy Platenkamp, Celeste Rodriguez, Heonsu Kim, Christopher K Prinz, Aaron P van Loon, Yubin Lin, Tara E Eustis, Michelle M Chan, Daniel J Cohen, Julie A Theriot.
      Directed migration of immune and epithelial cells is critical for rapid responses to tissue injury or infection. Endogenous electric fields, generated by disruption of the transepithelial potential across the skin, are thought to guide cells to wound sites. However, how single cells detect these electrical cues remains unclear. We identified Galvanin (TMEM154), a poorly characterized single-pass transmembrane protein, as required for electric-field-guided migration of rapidly moving cells. Expression of Galvanin is sufficient to confer electric-field-guided migration on otherwise non-responsive epithelial cells. Upon electric-field exposure, Galvanin rapidly relocalizes to the anodal side of cells, and in human neutrophils, relocalization is immediately followed by changes in spatial patterns of cellular protrusion and retraction. These data suggest Galvanin acts as a direct sensor of the electric field, transducing spatial information about a cell's electrical environment to the intracellular migratory apparatus to support directed cell migration.
    Keywords:  CRISPR screen; Galvanin; TMEM154; biophysics; cell biology; directed cell migration; electrotaxis; functional genomics; galvanotaxis; neutrophils
    DOI:  https://doi.org/10.1016/j.cell.2026.04.026
  5. J Cachexia Sarcopenia Muscle. 2026 Jun;17(3): e70312
    Targeting Cancer Cachexia: A Mechanistic Evaluation of Anti-GDF-15 Antibody-Based Combination Therapies.
    Danna M Breen, Stephanie Joaquim, Brianna LaCarubba Paulhus, Donald Bennett, Barbara Bernardo, Susie Collins, Ryan M Esquejo, Ja Young Kim-Muller, Laura Lin, Matthew Peloquin, Zhidan Wu, Shuxi Qiao, John C Stansfield, Bei B Zhang, Michelle I Rossulek.
       BACKGROUND: In a recent Phase 2 trial in patients with cancer cachexia, the anti-GDF-15 antibody ponsegromab resulted in increased body weight, appetite, muscle mass and physical activity. This study provides compelling evidence that targeting the GDF-15 pathway may offer a viable therapeutic strategy, while raising new mechanistic questions about how GDF-15 neutralization could be optimally integrated with other interventions to reverse the multifactorial cachexia syndrome. This series of experiments aimed to evaluate the effects of anti-GDF-15 antibody treatment in combination with muscle anabolic (anti-myostatin antibody) or appetite stimulant (ghrelin receptor agonist anamorelin) modulators using mouse cancer cachexia models.
    METHODS: The effects of anti-GDF-15 monoclonal antibody alone and in combination with an anti-myostatin antibody or anamorelin fumarate were examined in GDF-15-dependent (HT-1080 and RENCA) and partially dependent (TOV21G) mouse tumour models. Comprehensive assessments included food intake, body weight, body composition (including fat, lean and muscle mass), muscle function and treadmill running. Circulating myostatin was measured in patient samples from an advanced NSCLC clinical study.
    RESULTS: Anti-myostatin antibody treatment had limited efficacy in improving cachexia in mouse tumour models with high circulating GDF-15 (HT-1080 and RENCA), but improved cachexia (when combined with anti-GDF-15 antibody) in a tumour model with low circulating GDF-15 levels (TOV21G). In the TOV21G model, combining anti-myostatin and anti-GDF-15 antibodies led to even greater increases in body weight and hindlimb muscle mass compared with anti-GDF-15 antibody alone (p < 0.001 for muscle mass); however, the increase in muscle strength and treadmill running did not reach statistical significance over monotherapy. When anamorelin was combined with anti-GDF-15 antibody, body weight was elevated compared with the HT-1080 tumour-bearing vehicle group (p < 0.0001) but did not reach statistical significance over anti-GDF-15 antibody alone. Similar observations of the combination treatment were found for food intake, fat mass and gastrocnemius (p < 0.05). Circulating myostatin was negatively correlated with weight loss in patients with cancer (p < 0.01).
    CONCLUSION: These data provide proof-of-principle that mechanistically distinct approaches targeting muscle anabolism and appetite may act additively with GDF-15 neutralization, particularly in cancer cachexia settings with lower GDF-15 dependence.
    TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01360554.
    Keywords:  GDF‐15; cachexia; ghrelin; mouse tumour models; myostatin
    DOI:  https://doi.org/10.1002/jcsm.70312
  6. Autophagy Rep. 2026 ;5(1): 2665907
    A review of autophagy in the pancreas: normal physiology and pathophysiology.
    Miles Piper, Conan Kinsey.
      Autophagy is a complex cellular process of cellular degradation that is essential for healthy pancreatic function and, when perturbed, can result in pathological states such as pancreatitis, diabetes, and cancer. Extremes in both activation and inhibition can lead to inflammation, cell damage, and organ dysfunction. Pharmacologic targeting of autophagy to restore homeostasis may provide a therapeutic benefit to various pancreatic pathological processes. In this review, we discuss the current understanding of how autophagy maintains normal pancreatic function and is perturbed in various pancreatic disease states, including opportunities for potential therapeutic intervention.
    Keywords:  Autophagy; diabetes; pancreas; pancreatic cancer; pancreatitis
    DOI:  https://doi.org/10.1080/27694127.2026.2665907
  7. JCI Insight. 2026 May 05. pii: e198489. [Epub ahead of print]
    Antibody subclass deficiency accelerates tumorigenesis in genetically engineered mouse models of pancreatic cancer.
    Jeremy B Foote, Sujith Sarvesh, Sameer Al Diffalha, David K Crossman, Changde Cheng, Myng-Hee Kim, Cherlene Hardy, Julienne L Carstens, Kyoko Kojima, Bart J Rose, Christopher A Klug.
      Antibody production by B cells has emerged as an important factor in regulating anti-tumor immunity with both suppressive and promotive roles in cancer. However, the specific impact of antibody deficiency during development of pancreatic ductal adenocarcinoma (PDAC) has not been explored. To address this question, we crossed the well-established KPC mouse model to mice lacking all circulating immunoglobulin (Ig) due to genetic ablation of both Ig secretion and Ig class switching (KPC-μSAID mice). KPC-μSAID mice exhibited a two-fold acceleration in tumor formation, a two-fold reduction in median survival, and increased liver metastases versus KPC-WT control mice. Immunofluorescence analysis of pancreatic tissues from antibody-sufficient KC- and KPC-WT mice showed that IgG was predominantly localized within extracellular matrix (ECM). Furthermore, in both KC- and KPC-μSAID mice, ECM density and podoplanin+ cancer-associated fibroblasts (CAFs) were significantly reduced. In the KPC-μSAID tumor microenvironment (TME), intratumoral myeloid-derived suppressor cells (MDSC) were also increased, while CD4+ and CD8+ T cells decreased, relative to tumor-bearing KPC-WT mice, with macrophage exhibiting a mixed polarization phenotype. These findings were recapitulated in antibody-subclass-deficient, KPC-AID mice, suggesting a potentially novel function of IgG in suppressing PDAC progression, by directly or indirectly regulating pancreatic fibrosis and the density of the ECM.
    Keywords:  B cells; Cancer; Fibrosis; Gastroenterology; Immunology; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.198489
  8. Chem Commun (Camb). 2026 May 13.
    Temperature and lipid composition differentially regulate KRAS assemblies on membranes.
    Ji Kang, Elena Scott, Sangho D Yun, Virginia K James, Jing-Yuan Chang, Hanieh Bahramimoghaddam, James Downing, Kacie Evans, David H Russell, Arthur Laganowsky.
      RAS GTPases oligomerize on membranes to regulate signaling, but factors governing this process remain unclear. Using variable-temperature native mass spectrometry and NanoBiT assays, we show KRAS dimerization is lipid- and temperature-dependent, increasing at higher temperatures, whereas NRAS is unaffected. These results indicate entropy-driven KRAS assembly and reveal isoform-specific mechanisms of membrane organization.
    DOI:  https://doi.org/10.1039/d6cc01853j
  9. Nat Cancer. 2026 May 15.
    CD300ld on pathologically activated neutrophils promotes tumor immune suppression by binding phosphatidylserine on CD8+ T cells.
    Chaoxiong Wang, Peixuan Zheng, Anhui Wang, Xinrui Fan, Tianxiang Li, Jingjing Hong, Runze Wang, Chunyan Zhang, Chaogui Luo, Weiwei Yang, Dong Gao, Adili Salai, Min Luo, Zhigang Lu, Dianfan Li, Moubin Lin, Jiayin Peng, Guohui Li, Shuo Han, Yun Zhao.
      The immunosuppressive tumor microenvironment remains a major obstacle to successful immunotherapy. Pathologically activated neutrophils, alternatively termed polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), drive tumor immune evasion primarily by inducing CD8+ T cell tolerance. While direct intercellular contact between neutrophils and CD8+ T cells is essential for immunosuppressive activity, the mechanisms mediating this interaction need deeper understanding. We previously reported that CD300ld is required for recruiting PMN-MDSCs into tumors, suppressing T cell activation. Here we show that CD300ld mediates neutrophil-driven contact-dependent suppression of cytotoxic CD8+ T cells by binding to phosphatidylserine (PS). Mice with mutant CD300ld lacking PS-binding capacity exhibit reduced immunosuppressive activity. Blockade of the CD300ld-PS interaction by neutralizing antibodies demonstrates therapeutic efficacy against established tumors and synergizes with anti-PD1. Our findings establish CD300ld-PS-mediated cell contact as a critical mechanism of neutrophil-driven immune evasion, revealing a targetable checkpoint pathway to overcome tumor immune resistance and improve immunotherapy outcomes.
    DOI:  https://doi.org/10.1038/s43018-026-01169-4
  10. Nat Chem Biol. 2026 May 11.
    Proteolysis activity mapping and substrate discovery platform for identifying tumor-activated biosensors.
    Itay Algov, Audrey Van Heest, Megan Hopton, Frances Liang, Aidan Holmes, Liangliang Hao, Xin Zhou.
      Dysregulated extracellular proteolytic activity is a prominent hallmark of cancer and can thus be exploited for tumor detection and therapeutic development. However, the discovery of tumor-responsive probes has been hindered by the lack of methods to directly screen proteolytic events in specific tissue samples. Here we report PSurf, a platform that enables the identification of tissue-specific protease sensors with tissue specimens. Through differential selection of tumor-specific sequences over healthy tissue, PSurf identifies context-specific tumor-activated probes that precisely distinguish metastatic lesions in lung tissue slices. Using these substrates, we engineered nanobody-targeted biosensors that release urinary reporters upon tumor-specific cleavage in vivo, enabling precise non-invasive tumor detection in a mouse lung metastasis model. PSurf provides a foundation for developing conditionally activated agents through tissue-specific activity mapping and probe discovery.
    DOI:  https://doi.org/10.1038/s41589-026-02218-w
  11. Int J Mol Sci. 2026 May 02. pii: 4089. [Epub ahead of print]27(9):
    Why Do Cells Contain Thousands of Lipid Species? Toward an Integrated Framework for Lipid Diversity in Biological Membranes.
    Kyung-Hee Kim, Byong Chul Yoo.
      Cells contain an unexpectedly large diversity of lipid molecules. Modern lipidomics studies have revealed that even a single cell type can harbor hundreds to thousands of distinct lipid species that differ in headgroup structure, acyl chain length, and degree of unsaturation. While this remarkable diversity is now well established, its biological significance remains incompletely understood. Why do cells maintain such complex lipidomes? In this review, we examine several conceptual frameworks that may help explain the origin and functional significance of lipid diversity. First, the physical properties of biological membranes impose constraints on lipid composition, as variations in lipid structure influence membrane fluidity, curvature, thickness, and phase behavior. Second, lipids can regulate membrane protein function through specific interactions and through the physical environment of the lipid bilayer. Third, lipid metabolism generates signaling molecules that participate in diverse regulatory pathways. Fourth, lipid metabolic networks continuously remodel membrane composition, producing dynamic lipidomes that can adapt to physiological conditions. Finally, evolutionary processes have shaped membrane lipid composition across different domains of life, suggesting that lipid diversity may reflect long-term adaptation to functional and environmental constraints. Taken together, these perspectives suggest that lipid diversity is unlikely to be a simple byproduct of metabolism. Instead, the cellular lipidome may emerge from the interplay of membrane biophysics, metabolic network architecture, protein regulation, and evolutionary pressures. Understanding why cells contain thousands of lipid species therefore represents an important challenge for modern cell biology and may reveal fundamental principles governing the organization of biological membranes.
    Keywords:  biological membranes; lipid diversity; lipid metabolism; lipid signaling; lipidome; lipid–protein interactions; membrane evolution; membrane organization
    DOI:  https://doi.org/10.3390/ijms27094089
  12. Front Physiol. 2026 ;17 1773275
    GDF10 exacerbates metastatic burden and cachexia in murine models of cancer.
    Lauren S James, Alastair A E Saunders, Chris Karagiannis, Hongwei Qian, Robin L Anderson, Rachel E Thomson, Craig A Goodman, Paul Gregorevic.
      Metastasis and cancer-induced cachexia significantly reduce survivorship and quality of life for cancer patients. GDF10 (BMP3b) is a TGF-ß superfamily ligand with little knowledge of its role in cancer progression. Some studies have shown that GDF10 exerts tumor-suppressive effects in a range of cancer types and also plays a protective role against muscle wasting. Basal transcription of GDF10 was described previously to be downregulated in both primary tumors and cachectic muscle. Here, we set out to investigate the therapeutic potential of GDF10 in the 4T1.2 mouse model of breast cancer metastasis and in the C-26 mouse model of cancer cachexia, hypothesizing that GDF10 would ameliorate both metastatic and cachectic disease pathology. Systemic rAAV6:GDF10 administration to mice did not alter primary tumor growth; however, metastatic burden was increased in the mice bearing 4T1.2 tumors. Similarly, increased intramuscular rAAV6:GDF10 expression exacerbated skeletal muscle wasting in C-26 tumor-bearing mice. These results contradicted our initial hypothesis and highlight the complexity of signaling mechanisms utilized by BMP family ligands. Our data point to the need for more research to understand how to target GDF10 in anti-cancer therapy.
    Keywords:  BMP3b; GDF10; adeno-associated virus; cachexia; cancer; metastasis; skeletal muscle
    DOI:  https://doi.org/10.3389/fphys.2026.1773275
  13. Nat Methods. 2026 May;23(5): 872
    Whole mouse mapping.
    Madhura Mukhopadhyay.
      
    DOI:  https://doi.org/10.1038/s41592-026-03107-9
  14. Am J Physiol Cell Physiol. 2026 May 12.
    Dietary supplementation with ursolic acid preserves skeletal muscle mass and strength in mouse models of cancer cachexia.
    Jeremy B Ducharme, Scott M Ebert, Miles E Cameron, Martin M Schonk, Chandler S Callaway, Andrew C D'Lugos, John J Talley, Sarah M Judge, Christopher M Adams, Andrew R Judge.
      Skeletal muscle atrophy is a devastating and defining feature of cancer cachexia that reduces quality of life, treatment tolerance, and survival, but cannot be prevented or reversed by current management strategies. Ursolic acid is a natural dietary compound that has been shown to inhibit atrophy-associated changes in skeletal muscle mRNA expression in rodents and dogs, leading to beneficial changes in skeletal muscle structure and function. We hypothesized that dietary supplementation with ursolic acid might help support skeletal muscle mass and function during cancer. To test this hypothesis, we investigated ursolic acid's effects in five in vivo mouse models of cancer cachexia that are driven by pancreatic, colon, and lung cancer cells of mouse and human origin. We found that dietary supplementation with ursolic acid has broad-spectrum effects towards cancer-induced skeletal muscle atrophy, significantly preserving muscle mass in all five cancer cachexia models. Ursolic acid's positive effects on muscle mass and muscle fiber size led to significant improvements in grip strength and muscle tetanic force, persisted in the presence of chemotherapy, and were not associated with discernable changes in food intake or tumor growth. Ursolic acid appeared to generate its beneficial effects in skeletal muscle by acting directly on muscle cells, inhibiting catabolic effects of tumor-derived secreted factors, and inhibiting > 90% of cancer-induced changes in skeletal muscle mRNA expression. These results strongly nominate ursolic acid as a promising potential nutritional approach for supporting muscle mass and function in individuals with cancer.
    Keywords:  cancer cachexia; muscle atrophy; nutrition; skeletal muscle; ursolic acid
    DOI:  https://doi.org/10.1152/ajpcell.00159.2026
  15. Nat Commun. 2026 May 12.
    Tumor-derived GDF15 induces CCN3⁺ Schwann cells to promote cancer pain in pancreatic cancer.
    Guojun Chen, Weicheng Lu, Meng Liu, Qingqing Ye, Yixin Xu, Yanqun Zhang, Xiangna Guo, Yaqi Ye, Xiaohua Yang, Xiaolin Luo, Wenjun Xin, Jingdun Xie.
      Tumor-neural crosstalk contributes to the remodeling of the tumor microenvironment, yet how tumors engage peripheral glial networks, particularly Schwann cells (SCs), to drive chronic pain remains unclear. Here, we identify a specialized cellular communication network factor 3-positive (CCN3⁺) SC subpopulation that promotes tumor innervation and contributes to pain in pancreatic ductal adenocarcinoma (PDAC). We demonstrate that cancer cell-derived growth differentiation factor 15 (GDF15) drives expansion of CCN3⁺ SCs and induces glycolytic reprogramming via the GDNF family receptor alpha-like (GFRAL) receptor. Mechanistically, GFRAL activation triggers the protein kinase B (AKT)-runt-related transcription factor 2 (RUNX2) cascade, upregulating the glycolytic enzyme muscle-type phosphofructokinase (PFKM) in CCN3⁺ SCs, which enhances tumor innervation and pain sensitization. Targeted inhibition of GDF15-GFRAL signaling in CCN3⁺ SCs significantly alleviates PDAC-associated pain. Together, these findings reveal a perineural-metabolic axis driven by glycolytic reprogramming in SCs and highlight a promising therapeutic strategy for PDAC-associated pain.
    DOI:  https://doi.org/10.1038/s41467-026-72932-5
  16. Sci Adv. 2026 May 15. 12(20): eaed9613
    Quantifying 3D live-cell membrane dynamics using dynamic metal-induced energy transfer spectroscopy (dynaMIET).
    José Ignacio Gallea, Narain Karedla, Dongxia Wang, Bin Zhao, Lizhen Chen, Jörg Enderlein, Tao Chen.
      The dynamic behavior of cellular membranes underpins essential biological processes, including signal transduction, intracellular trafficking, and mechanotransduction. However, simultaneously quantifying lateral molecular diffusion and vertical membrane fluctuations in live cells remains challenging. Here, we present dynamic metal-induced energy transfer spectroscopy (dynaMIET), which integrates metal-induced energy transfer with fluorescence correlation spectroscopy to resolve three-dimensional membrane dynamics with nanometer axial sensitivity and microsecond temporal resolution. dynaMIET enables concurrent measurement of lateral diffusion and vertical undulations within a single acquisition. We validate the method using simulations and model membranes and demonstrate its robustness in living cells, applying it to the plasma membrane, endoplasmic reticulum, and nuclear envelope. By capturing both molecular mobility and membrane fluctuations, dynaMIET provides a powerful, noninvasive tool for probing membrane mechanics and organization. This advance opens avenues for studying membrane-associated phenomena in health and disease, including cancer cell mechanics, protein-membrane interactions, and organelle dynamics.
    DOI:  https://doi.org/10.1126/sciadv.aed9613
  17. Cell Rep. 2026 May 15. pii: S2211-1247(26)00432-8. [Epub ahead of print]45(5): 117354
    Ki-67 promotes circulating tumor cell intravasation and metastasis in breast cancer.
    Yongzhan Zhang, Jianwen Zhou, Karin Strittmatter, Yu Wei Zhang, Maria Waldmeier, Simran Asawa, Marko Vujanovic, Selina Budinjas, Massimo Saini, Ece Su Ildiz, Ana Gvozdenovic, Werner Kovacs, Francesc Castro-Giner, Nicola Aceto.
      Ki-67, a canonical proliferation marker, represents a pivotal prognostic and predictive biomarker in breast cancer. Here, by profiling 88,208 single-cell transcriptomes of circulating tumor cells (CTCs) matched with primary and metastatic lesions in breast cancer mouse models, we uncover a striking enrichment of cell-cycle genes in CTCs, particularly in CTC clusters. Using in vivo CRISPR screens, we identify Ki-67 as an essential regulator of CTC intravasation, whose knockout reduces metastasis. Mechanistically, Ki-67 depletion does not curb proliferation but suppresses genes involved in maintaining cell-cell adhesion, including CD47 and KLF4, thereby linking its expression to collective invasion dynamics. Altogether, decoupling it from its role as a proliferation marker, our findings uncover an unexpected function of Ki-67 as a molecular driver of metastatic competence.
    Keywords:  CP: cancer; Ki-67; breast cancer; circulating tumor cells; intravasation; metastasis
    DOI:  https://doi.org/10.1016/j.celrep.2026.117354
  18. EMBO Rep. 2026 May 09.
    Cellular mechanometabolism: stimuli and implications.
    Ismael Ortiz, Santiago Lopez, Raghu Vamsi Kondapaneni, Jose V Hernandez, Keefer Boone, Cynthia A Reinhart-King.
      While much is known about the effects of the chemical microenvironment on cellular metabolism, mechanical cues have emerged as critical stimuli of intracellular metabolic pathways. Mechanical signals from the extracellular matrix (ECM), neighboring cells, and the microenvironment intersect with key regulators of cellular metabolism, often leading to changes in fundamental cell behaviors, including cell proliferation and migration. Here, we review recent work that has uncovered a role for mechanical cues from microenvironmental factors on cellular metabolism. We discuss how cell-ECM interactions and forces such as shear, tension, and compression affect cellular metabolic requirements and energy production. Importantly, mechanometabolism shapes both physiological homeostasis and pathological states, and further investigation has implications for understanding tissue function and disease progression and uncovering potential therapeutic strategies.
    DOI:  https://doi.org/10.1038/s44319-026-00795-4
  19. Nat Protoc. 2026 May 13.
    Flexible high-resolution ECM micropatterning.
    Alessandro Gandin, Veronica Torresan, Tito Panciera, Gianluca Grenci, Giada Vanni, Anna Citron, Matteo Marchionni, Giusy Battilana, Margherita Pelosin, Rebecca Busetto, Stefano Piccolo, Giovanna Brusatin.
      Spatial cues and cell-cell interactions within in vivo tissue architecture generate physical signals that regulate cell behavior. These mechanical interactions drive processes such as morphogenesis, homeostasis, regeneration and disease progression. To recapitulate these spatial niches in vitro, lithographic micropatterning allows for precise control over the geometry, composition, topography and mechanics of cell-adhesive substrates. Micropatterned cultures have been essential in uncovering key mechanotransduction mechanisms, including YAP/TAZ-mediated signaling, mechanoregulation in cancer, aging and early embryonic development. However, accessible and adaptable micropatterning protocols for conventional cell biology laboratories remain limited. In this protocol, we present a comprehensive procedure for generating flexible, high-resolution micropatterns (down to 10 × 10 µm2), optimized for high-magnification confocal imaging, long-term cell culture, customizable functionalization (proteins, peptides or both) and extended shelf life. This versatile and convenient procedure can be performed by trained PhD students or postdoctoral researchers, does not require prior expertise in photolithography and can be completed within 2 d. In addition, we provide a step-by-step guide to study mechanotransduction using YAP/TAZ functional readouts that can be completed within 5 d. This protocol offers an affordable and scalable solution applicable to a wide range of biological questions, allowing for diverse experimental needs, and represents a valuable tool for advancing mechanobiology and other areas of cell biology.
    DOI:  https://doi.org/10.1038/s41596-026-01360-y
  20. Cancer Res. 2026 May 11.
    ATM Deficiency Induces TGF-β-Mediated Stromal Programming in Pancreatic Cancer.
    Elodie Roger, Hannah M Mummey, Eleni Zimmer, Dharini Srinivasan, Anna Härle, Loïc Moubri, Alica K Michels, Rima Singh, Menar Ekizce, Michael K Melzer, Yun Lee, Austin Silva, Luisa Härle, Thomas Engleitner, Frank Arnold, Mareen Morawe, Benjamin Karem Naggay, Juliane Schneider, Leonard Gilberg, Julia P Mosler, Christina Ludwig, Chen Meng, Maximilian Hirschenberger, Victoria Hunszinger, Klaus Kluck, Martina Kirchner, Anna-Lena Volckmar, Mareike Wirth, Mohamed S S Alhamdani, Jörg D Hoheisel, J-Matthias Löhr, Thomas Seufferlein, Alireza Abaei, Ralf Kemkemer, Roland Rad, Jan Budczies, Medhanie A Mulaw, Patrick C Hermann, Mark M Haenle, Konstantin M J Sparrer, Christopher J Halbrook, Kyle J Gaulton, Konrad Steinestel, Albrecht Stenzinger, Nelson Dusetti, Lukas Perkhofer, Johann Gout, Alexander Kleger.
      The tumor microenvironment (TME) actively contributes to pancreatic ductal adenocarcinoma (PDAC) pathogenesis through dynamic bidirectional tumor-stroma interactions. Here, we demonstrated that ATM-deficient tumor epithelium reprograms the TME in a genotype-specific manner to enhance cancer aggressiveness. In genetically engineered mouse models, pancreatic stellate cell (PSC) and cancer-associated fibroblast (CAF) co-culture systems, single-nucleus multiomics, and human PDAC models, tumoral loss of ATM serine/threonine kinase drove CAFs toward αSMA+ myofibroblastic (myCAF) differentiation, independently of p53 status. The myCAFs, in turn, promoted cancer aggressiveness and chemoresistance. Mechanistically, ATM deficiency increased reactive oxygen species and contractility signaling, enhancing TGF-β1 secretion. Pharmacological TGF-β inhibition reversed myCAF differentiation, sensitized tumors to chemotherapy, and impaired tumor progression in both murine and human ATM-null models. These findings reveal that ATM-deficient tumors shape a cancer-promoting niche via TGF-β signaling and identify dual targeting of intrinsic and extrinsic vulnerabilities as a promising precision oncology strategy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-0138
  21. C R Biol. 2026 May 13. 349 77-84
    Adhesion-mediated force transmission regulates cell competition in epithelia.
    Andreas Schoenit, René Marc Mège, Benoît Ladoux.
      Organs and tissues consist of a precise arrangement of different cell types, all playing a specific role to fulfil the biological function of the tissue. Small changes in cellular phenotypes or behaviour can lead to developmental defects, tissue malfunctions or the emergence of diseases. Therefore, tissue integrity, health and function are maintained through different quality control mechanisms. One highly conserved mechanism is cell competition, through which cells of reduced fitness are eliminated. Cells can employ various strategies to eliminate each other. Those include the exertion of mechanical forces, but its role in determining the competition outcome remains unclear. Here, we report that heterogeneities in force transmission capabilities mediated by cell-cell adhesion differences lead to cell competition. We show that increased force transmission endows collectives of cells with a fitness advantage, as it provides increased resistance to elimination forces. Elimination forces are generated from large stress fluctuations, emerging at the interfaces of competing cell populations. Besides promoting the removal of unfit cells in a wide range of biological conditions where local cell-cell adhesion heterogeneities are observed, this mechanism might be of general importance for the generation and maintenance of tissue boundaries.
    Keywords:  Cell adhesion; Cell competition; Cell extrusion; Force transmission; Mechanobiology; Tissue mechanics
    DOI:  https://doi.org/10.5802/crbiol.194
  22. Nat Chem Biol. 2026 May 14.
    Genetically targeted mTORC1 inhibitor reveals transcriptional control by nuclear mTORC1.
    Yanghao Zhong, Ayse Z Sahan, Zhengyao Shao, Qian-Yi Zhang, Xin Zhou, Jack G Haggett, Keiichi Koshizuka, Samuel A Myers, J Silvio Gutkind, Jin Zhang.
      Mechanistic target of rapamycin complex 1 (mTORC1) is a nutrient sensor that integrates diverse inputs to regulate protein translation and cell growth. While mTORC1 is activated on the lysosome in the classical model, it has become increasingly clear that this multifaceted signaling complex is active at various subcellular locations, such as the nucleus. However, what specific functions mTORC1 serves at these locations and how its signaling is compartmentalized are unclear. To interrogate subcellular pools of mTORC1, we developed TerminaTOR, a genetically encodable inhibitor of mTORC1 that can be targeted to specific subcellular locations. When TerminaTOR is directed to the lysosome, it inhibits canonical lysosomal mTORC1 and induces autophagy. Furthermore, TerminaTOR targeted to the nucleus specifically inhibits nuclear mTORC1, uncovering noncanonical roles of nuclear mTORC1 in regulating the transcription of CCAAT motif-containing genes. Thus, mTORC1 exhibits functional spatial compartmentalization and TerminaTOR serves as a powerful tool for unraveling spatially regulated functions of mTORC1 across different scales.
    DOI:  https://doi.org/10.1038/s41589-026-02188-z
  23. Autophagy. 2026 May 14. 1-20
    The multifaceted regulation of autophagy protein ATG16L1 and its implications in human diseases.
    Fujing Wei, Zhenzhen Liu, Xiaoying Yu, Yinqi Sun, Yuanyuan Zhao, Yu Wang, Ziling Feng, Xiaozhu Zhao, Xiaoxue Ke, Aimin Yang, Hongjuan Cui.
      ATG16L1 (autophagy related 16 like 1) is a core macroautophagy/autophagy protein essential for autophagosome formation. It also functions in non-canonical autophagy pathways such as LC3-associated phagocytosis (LAP) and in other processes including immunity, inflammation, and membrane trafficking. This review synthesizes recent advances and proposes that ATG16L1 functions as a central molecular integrator governed by a multi-layered regulatory code. This framework includes genetic polymorphisms, transcriptional control, and diverse post-transcriptional and post-translational mechanisms. We detail how these regulatory layers collectively fine-tune ATG16L1 function in response to cellular stress. Dysregulation of this network contributes broadly to human diseases including inflammatory bowel disease, cancer, and neurodegenerative disorders. Notably, the functional impact of specific regulatory events is highly context dependent, a principle exemplified by the Crohn disease-associated T300A polymorphism. Deciphering this regulatory landscape and its crosstalk with both autophagy-dependent and autophagy-independent functions positions ATG16L1 as a pivotal node in cellular homeostasis and as an emerging therapeutic target.Abbreviations ATG: autophagy related; CASM: conjugation of Atg8-family proteins to single membranes; CCD: coiled-coil domain; CEBPA/CEBPα: CCAAT enhancer binding protein alpha; CHUK/IKKA: component of inhibitor of nuclear factor kappa B kinase complex; circRNA: circular RNA; CPT1A: carnitine palmitoyltransferase 1A; CREB: cAMP responsive element binding protein; CSNK2: casein kinase 2; FTO: FTO alpha-ketoglutarate dependent dioxygenase; GJA8/connexin 50: gap junction protein alpha 8; H/R: hypoxia-reoxygenation; HDAC: histone deacetylase; KAT2B/PCAF: lysine acetyltransferase 2B; KDM1A: lysine demethylase 1A; LAP: LC3-associated phagocytosis; lncRNA: long non-coding RNA; LRRK2: leucine rich repeat kinase 2; m6A: N6-methyladenosine; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; miRNA/MIR: microRNA; Mtb: Mycobacterium tuberculosis; ncRNA: non-coding RNA; PE: phosphatidylethanolamine; PI3K: phosphoinositide 3-kinase; PRKA/PKA: protein kinase cAMP-activated; PPP1: protein phosphatase 1; RAB33B: RAB33B, member RAS oncogene family; RB1CC1/FIP200: RB1 inducible coiled-coil 1; SETD7: SET domain containing 7, histone lysine methyltransferase; SQSTM1/p62: sequestosome 1; TNF/TNF-α: tumor necrosis factor; ULK: unc-51 like autophagy activating kinase; V-ATPase: vacuolar-type H+-translocating ATPase; VDR: vitamin D receptor; WIPI2B: WD repeat domain, phosphoinositide interacting 2B; YTHDF2: YTH N6-methyladenosine RNA binding protein F2; ZDHHC7: zDHHC palmitoyltransferase 7.
    Keywords:  ATG16L1; T300A polymorphism; autophagy; non-canonical autophagy; post-translational modifications; transcriptional regulation
    DOI:  https://doi.org/10.1080/15548627.2026.2672698
  24. Nat Cell Biol. 2026 May;28(5): 846-847
    Inflammation starves antitumour immunity.
    Dominic Denk, Michael Karin.
      
    DOI:  https://doi.org/10.1038/s41556-026-01933-9
  25. Colloids Surf B Biointerfaces. 2026 May 07. pii: S0927-7765(26)00374-7. [Epub ahead of print]265 115786
    Cu²⁺ triggers lipid phase separation in anionic membranes via a bimodal interfacial mechanism.
    Jinjin Zhang, Yadi Wang, Jianrong Zeng, Chao Tang, Yiwen Li, Yaobo Huang, Jun Hu, Junhong Lü.
      The cellular membrane serves as the primary interface for sensing environmental cues, yet how it decodes the concentration-dependent toxicity of essential metal ions like copper remains a fundamental question. Here, we unveil a bimodal molecular switching mechanism by which Cu²⁺ reorganizes anionic lipid membranes, suggesting that the cell membrane could act as a sensor for copper concentration. Using an integrative biophysical approach on phosphatidylcholine/phosphatidylglycerol membranes, we demonstrate that at low concentrations, Cu²⁺ binds individually to anionic lipids, reorienting headgroups and priming the membrane for separation (Stage I). Crucially, beyond a critical threshold, adjacent membrane-bound Cu²⁺ ions form metal-metal bonds, creating rigid [PG-Cu-Cu-PG] bridges that act as molecular clamps (Stage II). This cooperative bridging event forcefully squeezes lipids together, driving extensive phase separation and the formation of Cu-rich domains with markedly enhanced thermodynamic stability. We provide evidence through atomic force microscopy, X-ray scattering, and calorimetry, complemented by the spectroscopic signature of ESR-silent Cu-Cu pairs. This bimodal switch model provides a physicochemical basis for copper's dual biological identity, with direct implications for understanding its antimicrobial mechanism and its potential role in neurotoxicity. Our findings establish a new paradigm for how transition metal coordination chemistry can programmatically control membrane architecture.
    Keywords:  Bimodal molecular switch; Copper toxicity; Jahn-Teller effect; Lipid phase separation; Membrane biophysics
    DOI:  https://doi.org/10.1016/j.colsurfb.2026.115786
  26. Cell Chem Biol. 2026 May 14. pii: S2451-9456(26)00144-3. [Epub ahead of print]
    Metabolic underpinnings of cuproptosis.
    Dadi Jiang, Li Zhuang, Albert C Koong, Boyi Gan.
      Cuproptosis is a recently defined form of regulated cell death (RCD) driven by copper-induced mitochondrial proteotoxic stress. Distinct from other RCD pathways such as apoptosis and ferroptosis, cuproptosis arises when copper binds to lipoylated metabolic enzymes in mitochondria, leading to their aggregation, loss of iron-sulfur cluster proteins, and metabolic collapse. This discovery establishes a mechanistic link between metal homeostasis and mitochondrial metabolism, positioning cuproptosis as a "cell-sabotage" pathway in which essential metabolic processes become self-destructive when dysregulated. In this review, we synthesize recent advances in understanding the molecular and metabolic basis of cuproptosis, its intersection with other metabolic cell death pathways such as ferroptosis, and its emerging therapeutic relevance in cancer. We further discuss the potential involvement of cuproptosis-like mechanisms in neurodegenerative disorders and highlight the outstanding questions and translational challenges that will guide future efforts to exploit this unique metabolic vulnerability for disease intervention.
    Keywords:  cancer; cell metabolism; copper; cuproptosis; mitochondria
    DOI:  https://doi.org/10.1016/j.chembiol.2026.04.009
  27. Proc Natl Acad Sci U S A. 2026 May 19. 123(20): e2528332123
    Selective targeting of kinesin on lipid droplets in the liver reduces plasma lipids.
    Subham Kumar Tripathy, Archisman Mahapatra, Ojal Saharan, Hindol Chatterjee, Neelanjana Sengupta, Siddhesh Kamat, Sreelaja Nair, Roop Mallik.
      The liver controls plasma lipids by secreting lipid-rich very low density lipoproteins (VLDL) into blood. Inside hepatocytes in the liver, Lipid Droplets (LDs) are transported to the Smooth Endoplasmic Reticulum by kinesin-1 motors, where they are catabolized to supply lipids for VLDL assembly. Here we find that kinesin-1 uses its tail domain to bind the monolayer phospholipid membrane of LDs, but alternative mechanisms to bind cellular organelles with bilayer membranes. A peptide corresponding to the tail domain of kinesin-1 therefore competes with and removes kinesin-1 selectively from LDs with minimal effect on other organelles. Delivery of lipids for VLDL assembly is consequently reduced, causing a remarkable reduction of ~50% of secreted lipids (triglycerides and cholesterol) in cell culture. Strikingly, the peptide causes no unwanted accumulation of lipids inside cells because it redistributes LDs across the cell, enhancing LD-to-mitochondria lipid trafficking for mitochondrial lipid utilization. Further, we show that egg-liposomes can be used to orally deliver the kinesin tail domain peptide to zebrafish. The peptide accumulates in the zebrafish liver, and reverses diet-induced hyperlipidemia to bring zebrafish back to a normolipidemic state. Reflecting its effects in cell culture, the peptide causes no unwanted hepatic accumulation of lipids, no toxicity, and no developmental or behavioral defects in zebrafish. Using a peptide to displace proteins (e.g., kinesin) selectively from LDs provides a radically different approach against lipid disorders. This monolayer-vs.-bilayer strategy can potentially be extended to target other LD-bound proteins that function as key regulators of Lipid metabolism.
    Keywords:  VLDL; hyperlipidaemia; kinesin; lipid droplets; lipoproteins
    DOI:  https://doi.org/10.1073/pnas.2528332123
  28. Proc Natl Acad Sci U S A. 2026 May 19. 123(20): e2602705123
    Deep-learning endomicroscope with large field-of-view and depth-of-field for real-time in vivo imaging of epithelial cancer hallmarks.
    Huayu Hou, Jimin Wu, Jinyun Liu, Vivek Boominathan, Argaja Shende, Karthik Goli, Jennifer Carns, Richard A Schwarz, Ann M Gillenwater, Preetha Ramalingam, Mila P Salcedo, Kathleen M Schmeler, Tomasz S Tkaczyk, Jacob T Robinson, Ashok Veeraraghavan, Rebecca R Richards-Kortum.
      In vivo microscopy (IVM) has shown great promise to improve early detection of epithelial precancer, but it suffers from fundamental trade-offs that limit the resolution, field-of-view (FOV) and depth-of-field (DOF). Here, we present PrecisionView, a compact, deep learning-enabled endomicroscope that breaks these constraints and achieves 20 mm2 FOV and 500 µm DOF with 4 µm resolution, representing approximately 5× increase in FOV and 8× larger DOF compared to conventional IVM with similar resolution. PrecisionView integrates a deep learning-optimized phase mask and real-time reconstruction, enabling rapid in vivo assessment of two key hallmarks of cancer: epithelial cell nuclear morphology and subsurface microvasculature through fluorescence and reflectance imaging. By imaging the oral cavity of healthy volunteers and cervical specimens with precancerous lesions, PrecisionView generates large-scale (1 to 3 cm2) coregistered maps of cellular and vascular structures, revealing distinct microscopic patterns associated with anatomic structures and precancerous lesions. Our results suggest the potential of this computational endomicroscope to address the unmet need for early cancer detection at the point of care.
    Keywords:  deep learning; endomicroscopy; extended depth-of-field; in vivo imaging; large field-of-view
    DOI:  https://doi.org/10.1073/pnas.2602705123
  29. Cell. 2026 May 08. pii: S0092-8674(26)00459-9. [Epub ahead of print]
    Ferroptosis inhibition enhances liver and lung graft function.
    Geraldine Veeckmans, Lene Devos, Nicholas Gilbo, Dieter Van Beersel, Camilla Scarpellini, Joris Blondeel, Magali Walravens, Greta Klejborowska, Caroline Lanthier, Michele Wölk, Sebastian Müller, Christine Gaillet, Ludovic Colombeau, Behrouz Hassannia, Matthias Längin, Martin Bender, Jan-Michael Abicht, Bruno Reichart, Hans De Winter, Maria Fedorova, Raphaël Rodriguez, Jacques Pirenne, Laurens J Ceulemans, Ina Jochmans, Koen Augustyns, Diethard Monbaliu, Arne Neyrinck, Tom Vanden Berghe.
      Ischemia-reperfusion injury (IRI) is a major clinical challenge in transplantation, vascular surgeries, myocardial infarction, and stroke. Disruption of energy and redox homeostasis triggers ferroptosis, a regulated, iron-dependent form of cell death, leading to organ dysfunction. We identify an early and transient increase of lipid peroxidation in human liver transplants and validate it as a therapeutic target. FXT-001, a ferroptosis inhibitor with dual radical and iron-trapping activity, provides robust protection in preclinical models, including ex situ perfusion of porcine liver and lung grafts. In a split ex vivo machine perfusion setting using declined human donors, FXT-001 treatment preserves graft viability, whereas untreated lungs deteriorate. We also develop FXT-002 and FXT-003 with enhanced pharmacokinetic and safety profiles. These findings support the use of ferroptosis inhibitors as a therapeutic strategy in transplantation and other IRI-associated conditions.
    Keywords:  FXT-001; ex situ machine perfusion; ferroptosis; human graft; iron; ischemia-reperfusion injury; liver; lung; porcine graft; radical-trapping antioxidant
    DOI:  https://doi.org/10.1016/j.cell.2026.04.024
  30. J Clin Invest. 2026 May 15. pii: e190121. [Epub ahead of print]136(10):
    Simultaneous CRISPR/Cas9-induced double-strand breaks are lethal in models of pancreatic cancer.
    Selina Shiqing K Teh, Akhil Kotwal, Alexis Bennett, Eitan Halper-Stromberg, Laura Morsberger, Saum Zamani, Yanan Shi, Alyza Skaist, Qingfeng Zhu, Kirsten Bowland, Hong Liang, Ralph H Hruban, Chien-Fu Hung, Robert A Anders, Nicholas J Roberts, Robert B Scharpf, Michael Goldstein, Ying S Zou, James R Eshleman.
      While radiation is an effective oncologic therapy, killing cancer by inducing DNA double-strand breaks (DSBs), it lacks specificity for neoplastic cells. We have previously adapted the CRISPR/Cas9 gene-editing technology as a cancer-specific treatment modality targeting somatic mutations in pancreatic cancer (PC). However, its tumoricidal potential remains unclear, especially in comparison with therapeutic doses of radiation. Here, we demonstrate that CRISPR/Cas9-induced DSBs are more cytotoxic in PCs than a comparable number of radiation-induced DSBs. We observed more than 90% tumor growth inhibition by targeting 9 sites with cancer-specific sgRNAs. Through both bioinformatics and cytogenetics analyses, we found that CRISPR/Cas9-induced DSBs triggered ongoing chromosomal rearrangements, with 87% of structural variants not directly produced from the initial CRISPR/Cas9-induced DSBs, and chromosomal instability peaking before cell death. By comparing the cytotoxicity of CRISPR/Cas9- and radiation-induced DSBs, we demonstrated that the number of DSBs required to achieve equitoxic effects was approximately 3 times higher for radiation than CRISPR/Cas9. Finally, we showed that PC cells that had survived CRISPR/Cas9 targeting retained susceptibility to subsequent CRISPR/Cas9-induced DSBs at different genomic sites with more than 87% growth inhibition. Together, our data support the therapeutic potential of CRISPR/Cas9 as an anticancer strategy.
    Keywords:  Cancer gene therapy; Genetic instability; Genetics; Oncology; Radiation therapy
    DOI:  https://doi.org/10.1172/JCI190121
  31. Spectrochim Acta A Mol Biomol Spectrosc. 2026 May 08. pii: S1386-1425(26)00621-9. [Epub ahead of print]360 128050
    Fluorescence tracking live-cell plasma membranes via polarity ultra-sensitive non-ionic probes.
    Xiaotong Xia, Yuqin Li, Haojia Liang, Junxuan Liang, Yahui Xu, Pengwei Zhang, Kun Wang, Fang Liu.
      Small-molecule fluorescent probes provide simple and convenient tools to visualize the cell plasma membrane, offering essential information for cellular-level studies. Most existing plasma membrane probes rely on the incorporation of highly charged moieties and long hydrophobic alkyl chains, and there has been scarce exploration of non-ionic probes that lack highly hydrophobic alkyl substituents. In this work, we exploited (2H)-benzofuran-3-one (3-coumaranone), a scaffold that combines an electron-withdrawing moiety with an active methylene unit, to construct eight D-π-A type fluorescent probes (CMO-1 ∼ CMO-8) with typical intramolecular charge transfer (ICT) characteristics via straightforward condensation and alkylation reactions. Experimental measurements and theoretical calculations consistently show that both the fluorescence intensity and peak position of these probes respond with ultra-high sensitivity to the changes of environmental polarity. Importantly, the representative probe CMO-2 enables wash-free and long-term fluorescence tracking of the plasma membrane and exhibits superior membrane-anchoring compared with the commercial probe DiD. Unlike the most reported membrane probes, this class of probes is non-ionic at physiological pHs, providing useful alternatives for wash-free live-cell plasma membrane imaging.
    Keywords:  Fluorescence probe; Intramolecular charge transfer (ICT) dyes; Non-ionic design; Plasma membrane imaging; Wash-free imaging
    DOI:  https://doi.org/10.1016/j.saa.2026.128050
  32. Analyst. 2026 May 11.
    Selective detection of lipophagy with a highly specific lipid droplet probe.
    Shixiong Wen, Xiaoxue Zou, Jianing Liu, Jiahuai Han, Shoufa Han.
      Lipophagy, the autophagic degradation of lipid droplets (LDs) by lysosomes, is an important route for maintaining LD homeostasis. Tools for lipophagy detection facilitate research in LD biology. Herein, we report LD-Blue, a highly specific LD probe, for tracking dynamic formation of LDs and detection of lipophagy. Upon lipophagy, LD-Blue chaperoning host LDs is delivered into lysosomes. By using the co-localization co-efficiency of LD-Blue and LysoTracker Red as the readout of lipophagy, we observed lipophagy induced by serum deprivation but not acute nutrient starvation as well as lipophagy inhibition by chloroquine and Bafilomycin A1. With the established fidelity of the LD-Blue-based co-localization assay for lipophagy, monensin is identified to be a potent inducer of lipophagy.
    DOI:  https://doi.org/10.1039/d5an01241d
  33. J Clin Invest. 2026 May 15. pii: e195288. [Epub ahead of print]136(10):
    Metastatic tropism of molecularly defined clear-cell renal cell carcinoma clusters.
    Gaelle Haddad, Junyu Guo, Yin Xi, Emin Albayrak, Mahrukh Huseni, Habib Hamidi, Romain Banchereau, Edward Kadel, Sarita Dubey, Corey Carter, Payal Kapur, James Brugarolas, Ivan Pedrosa.
      BACKGROUNDThe relationship between molecular subgroups in clear-cell renal cell carcinoma (ccRCC) and metastatic tropism is poorly understood.METHODSWe analyzed over 5,000 metastatic sites from 305 treatment-naive ccRCC patients in the IMmotion150 phase II clinical trial, where patients were randomized to atezolizumab, atezolizumab/bevacizumab, or sunitinib.RESULTSAngiogenic tumors (clusters 1 and 2) had a higher rate of pancreatic (21% vs. 6.9%; P = 0.002) and lower absolute number of lymph node (2.5 vs. 4.2; P = 0.006) metastases. In contrast, proliferative tumors (clusters 4 and 5) exhibited a higher absolute number of lymph node metastases (5.5 vs. 3.5; P = 0.019). Patients with pancreatic metastases receiving sunitinib had higher odds of overall response (OR, 7.13; 95% CI, 1.81-28.07; P = 0.0049) and longer progression-free survival than those without pancreatic metastases (P = 0.02).CONCLUSIONccRCC metastatic tropism relates to molecular clusters that predict response to therapy for tumors that metastasize to the pancreas.TRIAL REGISTRATIONClinicalTrials.gov NCT01984242FUNDINGNIH grants R01CA154475 and P50CA196516.
    Keywords:  Cancer; Clinical Research; Diagnostic imaging; Molecular genetics; Oncology; Public Health
    DOI:  https://doi.org/10.1172/JCI195288
  34. EXO. 2026 ;pii: 202605. [Epub ahead of print]1(1):
    Heme, copper, and a new way to kill cancer cells.
    Xi Zhao, Li Zhuang, Boyi Gan.
      Heme homeostasis influences mitochondrial metabolism and leukemia stem cell biology in acute myeloid leukemia. Lewis et al. uncover a surprising metabolic vulnerability in acute myeloid leukemia: suppression of heme biosynthesis primes leukemic cells for cuproptosis, a form of copper-dependent cell death. By linking heme depletion to mitochondrial cytochrome c oxidase (Complex IV) dysfunction, copper accumulation, and cuproptosis, the study integrates transcriptional regulation, mitochondrial metabolism, and metal homeostasis into a unified framework for selective cancer cell killing.
    Keywords:  BTB and CNC homology 1; Heme; acute myeloid leukemia; copper; cuproptosis
    DOI:  https://doi.org/10.70401/EXO.2026.0004
  35. Nat Cancer. 2026 May 11.
    Golgi pH buffers ferroptosis sensitivity.
    Vasanthi S Viswanathan, John K Eaton.
      
    DOI:  https://doi.org/10.1038/s43018-026-01170-x
  36. Nat Cell Biol. 2026 May 14.
    Tissue rigidity phase transition shapes morphogen gradients.
    Camilla Autorino, Diana Khoromskaia, Louise Harari, Elisa Floris, Harry Booth, Cristina Pallares-Cartes, Vesta Petrasiunaite, Michael Dorrity, Bernat Corominas-Murtra, Zena Hadjivasiliou, Nicoletta I Petridou.
      During development, local mechanochemical cues within the cell microenvironment are translated into signalling pathways that drive cell fate decisions. Yet, as cells differentiate collectively, how global tissue-level properties shape these instructive cues remains unclear. Here we show that a tissue-scale rigidity transition guides patterning by tuning the length scales and timescales of morphogen signalling. By combining rigidity percolation theory, reaction-diffusion modelling, quantitative imaging and optogenetics in zebrafish, we uncover dynamical global tissue rigidity patterns that actively shape the Nodal morphogen gradient by locally changing its concentration and accelerating its signalling activity. In this self-generated mechanism, Nodal, besides instructing meso-endoderm fate specification, increases cell-cell adhesion strength via regulating planar cell polarity genes. Once the adhesion strength reaches a critical point, it triggers a rigidity transition which, in turn, induces the collapse of tissue porosity. The abrupt tissue reorganization negatively feeds back on Nodal signalling, impacting both its length scales, by restricting Nodal diffusivity, and its timescales, by speeding up the expression of its antagonist Lefty, thereby ensuring timely signal termination and robust patterning. Overall, we uncover a multiscale regulatory mechanism by which positional information and tissue material properties dynamically tune one another.
    DOI:  https://doi.org/10.1038/s41556-026-01954-4
  37. Sci China Life Sci. 2026 May 07.
    The lipidomic atlas for cellular organelles to reveal the central role of mitochondria in organelle communication.
    Wenjuan Qian, Qinsheng Chen, Haoran Hu, Shuaiyao Wang, Hongyan Yao, Huiru Tang.
      Intracellular organelles are pivotal for maintaining cellular homeostasis, with lipids serving as key mediators of inter-organellar contact and communication. However, the limited understanding of lipid chemical diversity and composition has constrained research into lipid-mediated organellar functions. The A549 cell lines, a widely used human non-small cell lung cancer model in both basic research and drug discovery, provide an ideal system for investigations. In this study, we generated the quantitative lipidomic atlas covering seven subcellular compartments, including mitochondria, ER, Golgi apparatus, nucleus, exosome, lysosome and plasma membrane in A549 cells. This atlas encompasses appropriately 1,400 lipid species across 40 subclasses and systematically characterizes the proportional composition and distinct features of each organelle. We analyzed the key features, including lipid species distribution, unsaturation and chain length patterns, as well as the ratios of polyunsaturated fatty acids to monounsaturated and saturated fatty acids (PUFA:MUFA+SFA) and cylindrical to non-cylindrical lipids. Causal connection and pair-by-pair correlation analyses revealed that the ER acts as the primary source of lipid flow, with mitochondria as its terminal. Specifically, glycosylceramide and dihexosylceramides (Hex2Cer) emerge as central hubs exhibiting significant correlations with other lipids across the seven subcellular lipidomes. Taken together, this study establishes a reference lipidome for seven major organelles, maps their distinct lipidomic characteristics and the correlations of lipid-mediated interorganelles, and provides new insights into the lipid-based communication networks in cancer cells.
    Keywords:  A549 cell; inter-organellar network; lipid distribution; lipid hub; organelle; subcellular lipidome
    DOI:  https://doi.org/10.1007/s11427-025-3222-4
  38. Biochim Biophys Acta Rev Cancer. 2026 May 13. pii: S0304-419X(26)00078-8. [Epub ahead of print] 189606
    The underexplored complexity of pancreatic cancer: Early dissemination and quiescence.
    Nivedeta Krishna Kumar, Annant Bir Kaur, Surinder K Batra, Moorthy P Ponnusamy.
      Pancreatic cancer has been renowned for its aggressive nature and occasionally manifests periods of dormancy, presenting a perplexing challenge in studying disease progression. Despite surgery, many patients relapse due to dormancy and chemoresistance, resulting in recurrence and death within a few years. Studies also suggest that pancreatic cancer disseminates early on, spreading to secondary organs with no evidence of disease. The lingering question is: how, where, and when does pancreatic cancer recur and spread? Herein, we explore evidence for clinically dormant pancreatic cancer cells, examining the roles of quiescence and stemness populations and their interactions with the tumor microenvironment. Understanding the molecular factors that control dormancy is crucial for addressing disease heterogeneity and offers opportunities for targeted interventions to enhance pancreatic cancer outcomes.
    Keywords:  Disseminated cancer cells; Pancreatic cancer dormancy; Quiescence; Stroma; cancer stemness
    DOI:  https://doi.org/10.1016/j.bbcan.2026.189606
  39. Elife. 2026 May 15. pii: RP102680. [Epub ahead of print]13
    The role of ATP synthase subunit e (ATP5I) in mediating the metabolic and antiproliferative effects of metformin in cancer cells.
    Guillaume Lefrançois, Emilie Lavallée, Marie-Camille Rowell, Véronique Bourdeau, Farzaneh Mohebali, Thierry Bertomeu, Ana Maria Duman, Maya Nikolova, Mike Tyers, Simon-Pierre Gravel, Andreea R Schmitzer, Gerardo Ferbeyre.
      Here, we identify the subunit e of F₁F₀-ATP synthase (ATP5I) as a target of metformin, a first-in-class antidiabetic biguanide. ATP5I maintains the stability of F₁F₀-ATP synthase dimers, which is crucial for shaping cristae morphology. We demonstrate that ATP5I interacts with a biguanide analogue in vitro, and disabling its expression by CRISPR-Cas9 in pancreatic cancer cells leads to the same phenotype as biguanide-treated cells, including mitochondrial morphology alterations, reduction of the NAD+/NADH ratio, inhibition of oxidative phosphorylation (OXPHOS), rescue of respiration by uncouplers, and a compensatory increase in glycolysis. Notably, metformin disrupts F₁F₀-ATP synthase oligomerization, leading to the accumulation of vestigial assembly intermediates in pancreatic and osteosarcoma cancer cells, a phenotype also observed upon ATP5I inactivation in pancreatic cancer cells. Moreover, ATP5I knockout (KO) cells exhibit resistance to the antiproliferative effects of biguanides, but reintroduction of ATP5I rescues the metabolic and antiproliferative effects of metformin and phenformin. Finally, a genome-wide CRISPR screening in NALM-6 lymphoma cells revealed that metformin-treated cells exhibit genetic interaction profiles similar to those observed with the F₁F₀-ATP synthase inhibitor oligomycin, but not with the complex I inhibitor rotenone. This provides unbiased support for the relevance of the newly proposed target.
    Keywords:  ATP5I; F1ATPase; NAD metabolism; biguanides; biochemistry; chemical biology; human; mitochondria; pancreatic cancer
    DOI:  https://doi.org/10.7554/eLife.102680
This page is being maintained by Thomas Krichel. It was last updated on 2026‒05‒17 at 14:49.