bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2025–08–17
forty-six papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Myc and Kras cooperate in adult acinar cells to drive phenotypic heterogeneity, metastasis, and therapeutic resistance in a novel pancreatic cancer mouse model.
  2. Fast histological assessment of adipose tissue inflammation by label-free mid-infrared optoacoustic microscopy.
  3. PP2A activation drives aberrant macropinocytosis and cell death in pancreatic ductal adenocarcinoma.
  4. Multiple oestradiol functions inhibit ferroptosis and acute kidney injury.
  5. An Iron-regulated Signalling Pathway Controls Adipose Browning and Cancer Cachexia.
  6. ZBTB11 depletion targets metabolic vulnerabilities in KRAS inhibitor-resistant PDAC.
  7. Systematic evaluation of GAPs and GEFs identifies a targetable dependency for hematopoietic malignancies.
  8. ER-phagy and proteostasis defects prime pancreatic epithelial state changes in KRAS-mediated oncogenesis.
  9. CDK8 remodels the tumor microenvironment to resist the therapeutic efficacy of targeted KRAS G12D inhibition in pancreatic ductal adenocarcinoma.
  10. Targeting Cholesterol-Dependent Piezo1 Activation Impairs Amoeboid Migration in Melanoma Cells.
  11. Nothing can replace polyunsaturated lipids.
  12. A porcine model of acute necrotizing pancreatitis.
  13. Technical Recommendation on Multi-Driver Multifrequency MR Elastography for Tomographic Mapping of Abdominal Stiffness With a Focus on the Pancreas and Pancreatic Ductal Adenocarcinoma.
  14. A phase 2 trial of CXCR4 antagonism and PD1 inhibition in metastatic pancreatic adenocarcinoma reveals recruitment of T cells but also immunosuppressive macrophages.
  15. Multi-omics whole-genome characterization of the copy number landscape of metastatic pancreatic ductal adenocarcinoma.
  16. Targeting lipid scrambling potentiates ferroptosis and triggers tumor immune rejection.
  17. Autophagy in the regulation of cancer dormancy.
  18. Mitochondria protect against an intracellular pathogen by restricting access to folate.
  19. Vitamin B2 metabolism promotes FSP1 stability to prevent ferroptosis.
  20. Spontaneous and experimental models of lymph node metastasis.
  21. Clone copy number diversity is linked to survival in lung cancer.
  22. D-cysteine impairs tumour growth by inhibiting cysteine desulfurase NFS1.
  23. Suppression of Cytosolic Phospholipase A2 in the Ventromedial Hypothalamus Induces Hyperphagia and Obesity in Male Mice.
  24. Respiration defects limit serine synthesis required for lung cancer growth and survival.
  25. A pancreatic cancer organoid biobank links multi-omics signatures to therapeutic response and clinical evaluation of statin combination therapy.
  26. Lymph node-targeted, mKRAS-specific amphiphile vaccine in pancreatic and colorectal cancer: phase 1 AMPLIFY-201 trial final results.
  27. PRMT1-mediated metabolic reprogramming promotes leukemogenesis.
  28. A growing problem: the many unsolved mysteries of cell growth.
  29. Using LEXY and LINuS Optogenetics Tools and Automated Image Analysis to Quantify Nucleocytoplasmic Transport Dynamics in Live Cells.
  30. Chemogenetic detection and quantitation of H2O2 in living cells.
  31. Principles of cotranslational mitochondrial protein import.
  32. Causal relationships between immunophenotypes, plasma metabolites, and pancreatic cancer: a mediation Mendelian randomization study.
  33. Ageing, immune fitness and cancer.
  34. Exploring lipid diversity and minimalism to define membrane requirements for synthetic cells.
  35. Energy deprivation in youth and old age.
  36. Genetic mechanisms of resistance to targeted KRAS inhibition.
  37. Bilirubin prevents hyperlipidaemic acute pancreatitis by inhibiting aryl hydrocarbon receptor-mediated acinar cell pyroptosis.
  38. Most autophagic cell death studies lack evidence of causality.
  39. Endothelial Trauma Depends on Surface Charge and Extracellular Calcium Levels.
  40. Mechanisms of cellular fitness and cell competition: Towards an integrated view.
  41. PFOA induces fission of phase-separated phospholipid vesicles.
  42. HuR-regulated extracellular vesicles promote endothelial cell remodeling in pancreatic cancer.
  43. Nanosecond pulsed electric field-empowered physical-chemical cascade ferroptosis therapy for triple-negative breast cancer.
  44. Prevalent mesenchymal drift in aging and disease is reversed by partial reprogramming.
  45. Reversible NIR Ratiometric Probe for Monitoring Redox Homeostasis in Lipid Droplets during Ferroptosis-Driven Liver Injury.
  46. Computationally unmasking each fatty acyl C=C position in complex lipids by routine LC-MS/MS lipidomics.
  1. bioRxiv. 2025 Jul 18. pii: 2025.07.14.664767. [Epub ahead of print]
    Myc and Kras cooperate in adult acinar cells to drive phenotypic heterogeneity, metastasis, and therapeutic resistance in a novel pancreatic cancer mouse model.
    Isabel A English, Patrick J Worth, Kevin Alexander MacPherson-Hawthorne, Macarena Vergara, Katherine Pelz, Ashley L Kiemen, Vidhi Shah, Katie E Blise, Carl Pelz, Motoyuki Tsuda, Michael B Heskett, Amy T Farrell, Brittany L Allen-Petersen, Phillip Jimenez, Meghan Morrison Joly, Mary C Thoma, Jennifer R Eng, Colin J Daniel, Xiaoyan Wang, Melissa Cunningham, Gustavo Salgado-Garza, Jackie L Phipps, Courtney Betts, Shamilene Sivagnanam, Terry K Morgan, Laura D Wood, Lisa M Coussens, Jonathan Brody, Ellen M Langer, Rosalie C Sears.
      Pancreatic ductal adenocarcinoma (PDAc) is a deadly malignancy, most commonly diagnosed in advanced stages when no curative treatments are available. The development of new models that aid ongoing investigation into the mechanisms by which it initiates, disseminates, and evades treatment is of the utmost importance. In vivo models that accurately recapitulate the features and spectrum of human pancreatic cancer are paramount to make a dent in this disease as two decades of the standard-of-care have failed to substantially improve survival. Here, we take advantage of our finding that post-translational stabiliziation of MYC downstream of the canonical PDAc driver, mutant KRAS, is an early event in PDAc progression to design a novel mouse model of PDAc progression based on deregulated, constituitive expression of Myc and mutant Kras in adult pancreatic acinar cells. Tumors from this KMC model histologically and molecularly recapitulate heterogeneity seen in human PDAc, with a high rate of metastasis to the liver. Cell lines derived from KMC autochthonous PDAc provide new models for orthotopic primary tumors that reliably metastasize to the liver and lung, providing important new tools to efficiently study the metastatic cascade and aid in the develoment of new therapeutics addressing metastatic disease. Cell lines represent distinct molecular subtypes with corresponding differential drug sensitivity. Toghether, this model provides a new and additional tool in the study of pancreatic cancer and the means by which it so deftly evades our best efforts at treatment.
    DOI:  https://doi.org/10.1101/2025.07.14.664767
  2. Npj Imaging. 2023 Dec 06. 1(1): 3
    Fast histological assessment of adipose tissue inflammation by label-free mid-infrared optoacoustic microscopy.
    Vito Ko, Marie C Goess, Lukas Scheel-Platz, Tao Yuan, Andriy Chmyrov, Dominik Jüstel, Jürgen Ruland, Vasilis Ntziachristos, Selina J Keppler, Miguel A Pleitez.
      Conventional histology, as well as immunohistochemistry or immunofluorescence, enables the study of morphological and phenotypical changes during tissue inflammation with single-cell accuracy. However, although highly specific, such techniques require multiple time-consuming steps to apply exogenous labels, which might result in morphological deviations from native tissue structures. Unlike these techniques, mid-infrared (mid-IR) microspectroscopy is a label-free optical imaging method that retrieves endogenous biomolecular contrast without altering the native composition of the samples. Nevertheless, due to the strong optical absorption of water in biological tissues, conventional mid-IR microspectroscopy has been limited to dried thin (5-10 µm) tissue preparations and, thus, it also requires time-consuming steps-comparable to conventional imaging techniques. Here, as a step towards label-free analytical histology of unprocessed tissues, we applied mid-IR optoacoustic microscopy (MiROM) to retrieve intrinsic molecular contrast by vibrational excitation and, simultaneously, to overcome water-tissue opacity of conventional mid-IR imaging in thick (mm range) tissues. In this proof-of-concept study, we demonstrated application of MiROM for the fast, label-free, non-destructive assessment of the hallmarks of inflammation in excised white adipose tissue; i.e., formation of crown-like structures and changes in adipocyte morphology.
    DOI:  https://doi.org/10.1038/s44303-023-00003-1
  3. bioRxiv. 2025 Jul 18. pii: 2025.07.14.664742. [Epub ahead of print]
    PP2A activation drives aberrant macropinocytosis and cell death in pancreatic ductal adenocarcinoma.
    Garima Baral, Claire M Pfeffer, Sara N Filippelli, Indiraa Doraivel, Brittany N Heil, Lauren E Gartenhaus, Kasi Hansen, Joy Wu, Goutham Narla, Emma H Doud, Amber L Mosley, Shalini T Low-Nam, Brittany L Allen-Petersen.
      Pancreatic cancer is highly aggressive with a five-year survival rate of just 13%. Metabolic rewiring in response to oncogenic signals plays a critical role in pancreatic ductal adenocarcinoma (PDAC) survival, tumor growth, and metastasis. These alterations make PDAC tumors dependent on anabolic metabolism for survival, highlighting a unique vulnerability that can be therapeutically exploited. However, during nutrient deprivation, PDAC cells can circumvent this vulnerability by engulfing extracellular fluids to replenish amino acids in a process called, macropinocytosis. This process can be induced downstream of oncogenic KRAS expression, a small GTPase that is almost universally mutated in PDAC patients. The inhibition of macropinocytosis in vivo reduces PDAC tumor growth, emphasizing the importance of this pathway to cancer cell survival. However, the signaling mechanisms that regulate this process remain poorly understood. Protein phosphatase 2A (PP2A) is a heterotrimeric complex that regulates a wide variety of cell signaling pathways, including KRAS, and is commonly dysregulated in human PDAC tumors. Here, we show that acute PP2A activation prevents macropinosome processing leading to cell death. Furthermore, we demonstrate that PP2A posttranslationally regulates the lipid kinase, PIKfyve, a key regulator of macropinosome-lysosome fusion. Finally, we determine that PP2A activating compounds can function synergistically with metabolic inhibitors, supporting a new therapeutic strategy in this aggressive and deadly cancer. Together, our results implicate PP2A as a critical suppressor of PDAC metabolic plasticity and highlight the use of PP2A activating compounds to prevent PDAC nutrient scavenging.
    DOI:  https://doi.org/10.1101/2025.07.14.664742
  4. Nature. 2025 Aug 13.
    Multiple oestradiol functions inhibit ferroptosis and acute kidney injury.
    Wulf Tonnus, Francesca Maremonti, Shubhangi Gavali, Marlena Nastassja Schlecht, Florian Gembardt, Alexia Belavgeni, Nadja Leinung, Karolin Flade, Natalie Bethe, Sofia Traikov, Anne Haag, Danny Schilling, Sider Penkov, Melodie Mallais, Christine Gaillet, Claudia Meyer, Melika Katebi, Anushka Ray, Louisa M S Gerhardt, Anne Brucker, Jorunn Naila Becker, Mirela Tmava, Lisa Schlicker, Almut Schulze, Nina Himmerkus, Andrej Shevchenko, Mirko Peitzsch, Uladzimir Barayeu, Sonia Nasi, Juliane Putz, Kenneth S Korach, Joel Neugarten, Ladan Golestaneh, Christian Hugo, Jan Ulrich Becker, Joel M Weinberg, Svenja Lorenz, Bettina Proneth, Marcus Conrad, Eckhard Wolf, Bernd Plietker, Raphaël Rodriguez, Derek A Pratt, Tobias P Dick, Maria Fedorova, Stefan R Bornstein, Andreas Linkermann.
      Acute tubular necrosis mediates acute kidney injury (AKI) and nephron loss1, the hallmark of end-stage renal disease2-4. For decades, it has been known that female kidneys are less sensitive to AKI5,6. Acute tubular necrosis involves dynamic cell death propagation by ferroptosis along the tubular compartment7,8. Here we demonstrate abrogated ferroptotic cell death propagation in female kidney tubules. 17β-oestradiol establishes an anti-ferroptotic state through non-genomic and genomic mechanisms. These include the potent direct inhibition of ferroptosis by hydroxyoestradiol derivatives, which function as radical trapping antioxidants, are present at high concentrations in kidney tubules and, when exogenously applied, protect male mice from AKI. In cells, the oxidized hydroxyoestradiols are recycled by FSP19,10, but FSP1-deficient female mice were not sensitive to AKI. At the genomic level, female ESR1-deficient kidney tubules partially lose their anti-ferroptotic capacity, similar to ovariectomized mice. While ESR1 promotes the anti-ferroptotic hydropersulfide system, male tubules express pro-ferroptotic proteins of the ether lipid pathway which are suppressed by ESR1 in female tissues until menopause. In summary, we identified non-genomic and genomic mechanisms that collectively explain ferroptosis resistance in female tubules and may function as therapeutic targets for male and postmenopausal female individuals.
    DOI:  https://doi.org/10.1038/s41586-025-09389-x
  5. bioRxiv. 2025 Jul 18. pii: 2025.07.16.664180. [Epub ahead of print]
    An Iron-regulated Signalling Pathway Controls Adipose Browning and Cancer Cachexia.
    Jung Seung Nam, Maya S Dixon, Pardis Ahmadi, Kathrin Schilling, Samuel Pan, Yuxuan Chen, Nal Ae Yoon, Yanping Sun, Jordan Lu, Shu Ichimiya, Jeanine M Genkinger, Thomas C Caffrey, Kelsey A Klute, Benjamin J Swanson, Paul Grandgenett, Michael A Hollingsworth, Kazuki Sugahara, Michael D Kluger, Anthony Ferrante, Sabrina Diano, Iok In Christine Chio.
      The browning and atrophy of white adipose tissue (WAT) are early events in cachexia, a lethal metabolic disorder affecting nearly half of cancer patients, including those with pancreatic ductal adenocarcinoma (PDA). Using patient-derived specimens and PDA mouse models, we identified perturbations in iron metabolism and proteinaceous methionine oxidation as key initiating events of adipose browning. In particular, the iron influxes that accompany WAT browning induce the activity of methionine sulfoxide reductase A (MSRA), an enzyme that reverses the oxidation of proteinaceous methionine residues. Mechanistically, iron coordination by the conserved iron-binding motifs (E203-xx-H206) of two MSRA polypeptides serves to multimerize, stabilize, and enzymatically activate MSRA. This in turns facilitates adipose browning by maintaining the reduced state of two methionines near the ATP-binding site of Protein Kinase A (PKA). Remarkably, in mouse models of PDA, MsrA deletion impairs WAT browning, significantly mitigates cachexia, and improves the overall survival of tumor-bearing animals. By establishing the iron-MSRA-PKA axis as a key nexus of cancer-associated cachexia, our study offers new perspectives for the treatment of this condition.
    DOI:  https://doi.org/10.1101/2025.07.16.664180
  6. Nat Chem Biol. 2025 Aug 11.
    ZBTB11 depletion targets metabolic vulnerabilities in KRAS inhibitor-resistant PDAC.
    Nathan L Tran, Jiewei Jiang, Min Ma, Gillian E Gadbois, Kevin C M Gulay, Alyssa L Verano, Cara R Schiavon, Elena Rebollo, Haowen Zhou, Chun-Teng Huang, Rabi Murad, David A Scott, Uri Manor, Anne G Bang, Herve Tiriac, Andrew M Lowy, Eric S Wang, Fleur M Ferguson.
      Over 95% of pancreatic ductal adenocarcinomas (PDACs) harbor oncogenic mutations in KRAS. However, upon treatment with KRAS inhibitors, PDAC cells undergo rapid metabolic reprogramming toward an oxidative phosphorylation (OXPHOS)-dependent, drug-resistant state. Here, we demonstrate that this metabolic shift is associated with upregulation of the transcription factor ZBTB11 and both the metabolic state and resistance to KRAS inhibitors can be attenuated by ZBTB11 depletion. We develop molecular glue degraders of ZBTB11 and demonstrate that they reprogram the aberrant transcriptome, proteome, metabolome and bioenergetics of KRAS inhibitor-resistant PDAC, resensitizing them to KRAS inhibition. ZBTB11 degradation leverages cell-type-specific and cell-state-specific differences in gene-regulatory mechanisms controlling OXPHOS pathway transcripts to selectively target the KRAS inhibitor-resistant state in PDAC while sparing neurons derived from human induced pluripotent stem cells. Together, this work establishes ZBTB11 as a druggable vulnerability in KRAS inhibitor-resistant PDAC and provides a suite of molecular glue degrader tool compounds to investigate its function.
    DOI:  https://doi.org/10.1038/s41589-025-01978-1
  7. Cancer Discov. 2025 Aug 12.
    Systematic evaluation of GAPs and GEFs identifies a targetable dependency for hematopoietic malignancies.
    Pu Zhang, Zhendong Cao, Xiangyu Pan, Yuqiao Liu, Cynthia Castro, Won Jun Kim, Takeshi Fujino, Jennifer Lewis, Jahan Rahman, Sanam Shahid, Jasmine Um, Erin Burns, Bingyi Chen, Winson Cai, Juliana Ortiz-Pacheco, Zhuoning Li, Mara Monetti, Christopher R Vakoc, Anthony F Daniyan, Omar Abdel-Wahab, Junwei Shi.
      GAPs (GTPase-activating proteins) and GEFs (guanine nucleotide exchange factors) play key roles in cancer development, but their large number and potential redundancy have limited systematic evaluation. Here we perform unbiased genetic screens to identify GAPs and GEFs with cancer- and lineage-specific requirements, as well as dual perturbation screens to dissect functionally relevant interactors of GAPs and GEFs. Application to primary acute myeloid leukemia (AML) patient specimens uncovers the GAP ARHGAP45 as a targetable dependency shared across cancers of hematopoietic origin while being dispensable in normal hematopoiesis. We demonstrate that targeting ARHGAP45-expressing cells can be achieved through TCR-CAR T cells directed at an ARHGAP45-encoded minor histocompatibility antigen and that pharmacologic targeting of GAPs required upon ARHGAP45 depletion augments ARHGAP45-directed cell therapies. These studies provide a resource for probing oncogenic and druggable regulators of GTPases and strategies to target a GAP that represents a shared dependency across blood cancers.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-0299
  8. Dev Cell. 2025 Aug 13. pii: S1534-5807(25)00473-3. [Epub ahead of print]
    ER-phagy and proteostasis defects prime pancreatic epithelial state changes in KRAS-mediated oncogenesis.
    Carla Salomó Coll, Marisa Di Monaco, Jocelyn Holkham, Matthew Smith, Morwenna Muir, Philippe Gautier, Hywel Dunn-Davies, Xiaozhong Zheng, Roopesh Krishnankutty, Alain J Kemp, Katie Winnington-Ingram, Alex von Kriegsheim, Jennifer P Morton, Natalia Jimenez-Moreno, Damian Mole, Simon Wilkinson.
      Pre-malignant transformation of pancreatic acinar cells by oncogenic Kras is dependent upon stochastic emergence of metaplastic cell states. Here, we reveal that an early, transcriptionally mediated effect of Kras is sporadic failure of proteostatic endoplasmic reticulum (ER)-phagy. Genetically altered mice deficient in ER-phagy demonstrate that this event cooperates with Kras to drive acinar-ductal metaplasia (ADM) and subsequent cancer. Mechanistically, proteomics and high-resolution imaging uncover pathologic aggregation of a subset of ER proteins, including the injury marker REG3B, resulting from failure to physically interact with the ER-phagy receptor CCPG1. Spatial transcriptomics demonstrate that the appearance of sporadic intracellular aggregates upon Kras activation marks rare acinar cells existing in an injured, ADM-primed state. Importantly, engineered mutants of REG3B establish that aggregate formation is sufficient to directly engender this epithelial cell state. Pancreatic cancer can thus arise from stochastic pathologic protein aggregates that are influenced by, and cooperate with, an oncogene.
    Keywords:  ADM; CANCER; CCPG1; ER-phagy; KRAS; autophagy; inflammation; metaplasia; pancreas; proteostasis
    DOI:  https://doi.org/10.1016/j.devcel.2025.07.016
  9. bioRxiv. 2025 Jul 15. pii: 2025.01.29.635543. [Epub ahead of print]
    CDK8 remodels the tumor microenvironment to resist the therapeutic efficacy of targeted KRAS G12D inhibition in pancreatic ductal adenocarcinoma.
    Kathleen M McAndrews, Krishnan K Mahadevan, Bingrui Li, Amari M Sockwell, Sami J Morse, Patience J Kelly, Sarah I Patel, Michelle L Kirtley, Barbara A Moreno Diaz, Hengyu Lyu, David H Peng, Xunian Zhou, Hikaru Sugimoto, Aaron A Bickert, Lakshmi Kavitha Sthanam, Meagan R Conner, 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 over 40% of PDAC patients presenting with KRAS G12D mutations. The recent development of small molecule inhibitors targeting KRAS G12D has enabled targeting of mutant KRAS signaling and suppression of PDAC; however, the contribution of the tumor microenvironment (TME) to the sustained therapeutic efficacy of KRAS G12D inhibition and mechanism/s of resistance to KRAS G12D suppression remain to be elucidated. Here, we employed spatial transcriptomics, single cell RNA sequencing, and CODEX-based spatial proteomics to evaluate cancer cell intrinsic and extrinsic responses to KRAS G12D inhibition with MRTX1133. While KRAS G12D inhibition initially increases CD11c + cells with impactful T cell infiltration within proximity to cancer cells, long-term treatment with MRTX1133 resulted in reversal of the immune responses leading to KRAS G12D therapy resistance promoted by CDK8, a multiprotein mediator complex associated kinase. CDK8 imparts resistance in part through induction of downstream CXCL2 chemokine secretion, inhibition of FAS expression, and remodeling of the TME to promote immune evasion. Targeting CDK8 by itself and in combination with αCTLA-4 immunotherapy overcomes resistance to KRAS G12D inhibition with prolonged survival with translational implications.
    DOI:  https://doi.org/10.1101/2025.01.29.635543
  10. bioRxiv. 2025 Jul 17. pii: 2025.07.11.664494. [Epub ahead of print]
    Targeting Cholesterol-Dependent Piezo1 Activation Impairs Amoeboid Migration in Melanoma Cells.
    Sylvia Kuang, Alleah Abrenica, Neelakshi Kar, Jeremy S Logue.
      Bleb-based migration enables cancer cells to navigate the heterogeneous tumor microenvironment. Here, we report a phenotypic screen identifying drugs that inhibit bleb formation, a driver of amoeboid migration. Statins, including Fluvastatin and Pitavastatin, suppress amoeboid migration of melanoma cells in confined environments by reducing intracellular cholesterol. This disrupts plasma membrane tension sensing by Piezo1, lowering intracellular Ca 2 + levels. Both cholesterol supplementation and Piezo1 activation rescue migration in confined environments, confirming their functional link. Notably, high cholesterol biosynthesis enzyme levels correlate with reduced patient survival in melanoma. These findings reveal that cholesterol is essential for confinement sensing through Piezo1, identifying cholesterol biosynthesis or uptake as rational therapeutic targets against metastasis.
    Significance Statement: This study builds on a phenotypic drug screen that identified statins as inhibitors of bleb-based migration, a key mode of cancer cell movement through confined spaces. We show that statins reduce membrane cholesterol, disrupting the function of the mechanosensitive channel Piezo1 and impairing melanoma cell migration. Restoring cholesterol or activating Piezo1 rescues this effect, revealing a functional link between cholesterol and confinement sensing. Our findings highlight cholesterol biosynthesis as essential for invasive cell behavior and identify it as a therapeutic vulnerability. Importantly, elevated cholesterol pathway activity correlates with reduced survival in melanoma patients, underscoring the clinical relevance of targeting this pathway to limit metastasis.
    DOI:  https://doi.org/10.1101/2025.07.11.664494
  11. Elife. 2025 Aug 11. pii: e108249. [Epub ahead of print]14
    Nothing can replace polyunsaturated lipids.
    Sofia Rodriguez-Gallardo, Takeshi Harayama.
      Genetic studies reveal that polyunsaturated lipids do more than simply increase the fluidity of the cell membrane.
    Keywords:  C. elegans; EGL-9; HIF-1; cell biology; desaturase; forward genetics; polyunsaturated fatty acids
    DOI:  https://doi.org/10.7554/eLife.108249
  12. Pancreatology. 2025 Aug 05. pii: S1424-3903(25)00572-1. [Epub ahead of print]
    A porcine model of acute necrotizing pancreatitis.
    Joerg M Steiner, Hana Algül, Dietrich A Ruess, Ihsan Ekin Demir, Rickmer Braren, Sabine Schwamberger, Marina Lesina, Judith Reiser, Julia Werner, Tanja Groll, Thomas Metzler, Katja Steiger.
       BACKGROUND/OBJECTIVES: Acute necrotizing pancreatitis is a common disease in humans and leads to significant and world-wide morbidity and mortality. Exploration of new pharmaceutical agents for the treatment of this disease frequently rests on rodent models that may not be relevant for spontaneous human disease and also preclude collecting multiple blood samples. Goal of this project was to establish an experimental model for acute necrotizing pancreatitis in pigs that mirrors the development of systemic complications of acute pancreatitis in humans as a prelude to clinical trials in humans.
    METHODS: The accessory pancreatic duct was surgically isolated in domestic pigs and 8 μmol/kg glycodeoxycholic acid were slowly injected into the duct, followed by ligation and cutting the duct. Pigs were repeatedly evaluated clinically and multiple blood samples were collected before the pigs were sacrificed and their organs histopathologically assessed after 1, 5, or 7 days.
    RESULTS: All pigs showed clinical and clinical pathological evidence of pancreatitis after induction of pancreatitis. Pigs showed histopathological evidence of acute necrotizing pancreatitis one day after induction of pancreatitis. At 7 days after induction of pancreatitis, dramatic regeneration could be observed in the pancreas. At 5 days after induction of pancreatitis, evidence of necrotizing pancreatitis was present with less evidence of regeneration.
    CONCLUSIONS: The porcine model for acute necrotizing pancreatitis described here shows many parallels to spontaneous human disease and its systemic complications and may thus serve as a good model to assess the efficacy of novel pharmaceutical agents for the treatment of acute pancreatitis in humans.
    Keywords:  Acute respiratory distress syndrome; Alveolar damage; Glycodeoxycholic acid; Pancreatic necrosis; Systemic inflammatory response syndrome
    DOI:  https://doi.org/10.1016/j.pan.2025.07.415
  13. Invest Radiol. 2025 Aug 14.
    Technical Recommendation on Multi-Driver Multifrequency MR Elastography for Tomographic Mapping of Abdominal Stiffness With a Focus on the Pancreas and Pancreatic Ductal Adenocarcinoma.
    European Consortium of MRE in PDAC
       OBJECTIVES: MR elastography (MRE) offers valuable mechanical tissue characterization for clinical diagnosis. However, conventional single-driver, single-frequency MRE systems are often limited by insufficient coverage of deep-seated organs like the pancreas. This study investigates whether multiplex MRE using multiple drivers and vibration frequencies can overcome these limitations.
    MATERIALS AND METHODS: This prospective study used single-shot spin-echo MRE in 18 healthy volunteers (mean age 30±8 y) targeting the liver, pancreas, kidneys, and spleen. Each healthy volunteer underwent 16 MRE examinations with different sets of 4 vibration frequencies in the range of 30 to 60 Hz and 4 driver combinations, and an additional null experiment without vibrations. In addition, a cohort of 14 patients with pancreatic ductal adenocarcinoma (PDAC, mean age 57±15 y) were retrospectively assessed. The quality of shear-wave fields and stiffness maps were assessed in terms of displacement amplitudes and image sharpness.
    RESULTS: In healthy volunteers, abdominal coverage with displacement amplitudes above the pre-determined noise level of 4 µm varied among the MRE investigated: 24.2% (0.0% to 56.2%, single-driver at 60 Hz), 66.9% (24.8% to 97.7%, single-driver at 30 to 60 Hz), 70.2% (0.0% to 92.5%, multi-driver at 60 Hz), and 99.9% (89.4% to 100%, multi-driver at 30 to 60 Hz). In the pancreas, more than 60% coverage was achieved in all subjects using 4 drivers and multiple frequencies. This was achieved in only 2 of 18 subjects (11%) using single-driver/single-frequency MRE. Superficial organs were adequately assessed with all configurations. In patients with PDAC, multi-driver MRE at 30 to 60 Hz achieved 99.1% (91.4% to 100%) coverage of the pancreas and 96.3% (63.1% to 100%) abdominal coverage, suggesting that tomographic stiffness mapping is clinically feasible.
    CONCLUSION: MRE with at least 4 drivers and multiple vibration frequencies in the range of 30 to 60 Hz enables tomographic mapping of tissue stiffness across the entire abdomen, including the pancreas. Our results thus indicate that multiplex MRE is a promising approach for generating detailed images of abdominal stiffness that can improve clinical diagnosis of abdominal and pancreatic diseases.
    Keywords:  abdomen; magnetic resonance elastography; multi driver; multifrequency; multiplex; pancreas; pancreatic ductal adenocarcinoma; shear wave speed; stiffness
    DOI:  https://doi.org/10.1097/RLI.0000000000001231
  14. Oncoimmunology. 2025 Dec;14(1): 2543614
    A phase 2 trial of CXCR4 antagonism and PD1 inhibition in metastatic pancreatic adenocarcinoma reveals recruitment of T cells but also immunosuppressive macrophages.
    Katherine M Bever, Sarah M Shin, Jennifer N Durham, Hanfei Qi, Alexei Hernandez, Erin M Coyne, Nicole E Gross, Soren Charmsaz, Jayalaxmi Suresh Babu, Diana Carolina Vargas Carvajal, Rohan Verma, Yanyi Sun, Zhehao Zhang, Xuan Yuan, Courtney D Cannon, Sarah N Hughes, Sarah Mitchell, Madeline Figlewski, James M Leatherman, Hao Wang, Robert A Anders, Elizabeth M Jaffee, Dung T Le, Won Jin Ho.
      Pancreatic ductal adenocarcinoma (PDAC) is characterized by dense stroma and myeloid-rich microenvironment that confer resistance to immunotherapies. Previous studies demonstrated that disrupting the immune-stroma CXCR4-CXCL12 axis facilitates T cell recruitment and mobility to collaborate with anti-PD1/PD-L1 therapy. We sought to test the clinical viability of this immunotherapeutic strategy. 21 patients with metastatic PDAC were enrolled and treated in a phase 2 trial evaluating the effects of the plerixafor/AMD3100 and cemiplimab. Primary endpoint was objective response rate. Blood and tissue biospecimens were collected for correlative analyses. Parallel mouse studies were used to determine potential mechanisms of resistance. Treatments were well-tolerated, but only two patients demonstrated a best response of stable disease. Correlative analyses confirmed significant mobilization of immune cells into circulation as well as increased immune infiltration into the tumor. High-parameter imaging revealed higher levels of CD8+ T cells but also granulocytes and macrophages upon treatment. Spatial analysis showed that treatment resulted in closer proximity between macrophages and T cells but not between granulocytes and T cells. Mouse studies revealed that whereas total granulocyte depletion had no effect on immunotherapeutic efficacy, macrophage-targeting yielded significant benefit. Tumor growth measurements and immune profiling of immunotherapeutic combinations incorporating macrophage-targeting showed that despite the increased T cell infiltration, CXCR4 antagonism was in fact associated with enrichment of CD206hiIA/IElo macrophage subtypes and modestly dampened efficacy. Our findings validate the utility of CXCR4 antagonism as an effective immune-recruiting platform but also underscores the need for strategies that better leverage its effects.
    Keywords:  CXCL12; CXCR4; Cancer immunology; checkpoint immunotherapy; mass cytometry; pancreatic cancer; tumor microenvironment
    DOI:  https://doi.org/10.1080/2162402X.2025.2543614
  15. iScience. 2025 Aug 15. 28(8): 113176
    Multi-omics whole-genome characterization of the copy number landscape of metastatic pancreatic ductal adenocarcinoma.
    James T Topham, Joanna M Karasinska, Andrew Metcalfe, Hassan A Ali, Steve E Kalloger, Maya Kevorkova, Emma Titmuss, Gian Luca Negri, Sandra E Spencer, Gun Ho Jang, Grainne M O'Kane, Richard A Moore, Andrew J Mungall, Jonathan M Loree, Faiyaz Notta, Julie M Wilson, Oliver F Bathe, Patricia A Tang, Rachel Goodwin, Gregg B Morin, Jennifer J Knox, Steven Gallinger, Janessa Laskin, Marco A Marra, Steven J M Jones, Daniel J Renouf, David F Schaeffer.
      Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with limited therapeutic options. While genome profiling has benefitted clinical decision-making in many cancer types, PDAC remains among the most lethal solid cancers and has relatively few clinically actionable molecular targets. Using a multi-omics approach, we integrate whole-genome and transcriptome datasets along with proteomics and clinical metadata to identify copy-altered regions with significant impact on expression at the whole-genome scale. This approach identified SMURF1, ARPC1A, ZSCAN25, and BRI3 as focally amplified and over-expressed genes located on chr7q21/22 with expression negatively correlated with patient survival. We extrapolate these results into a pan-cancer analysis to demonstrate that the association between SMURF1 amplification versus expression is strongest in PDAC among 23 other cancer types. Taken together, these data provide a detailed overview of the copy number landscape in PDAC while highlighting chr7q21/22 amplification as a recurrent somatic event impacting both gene expression and patient survival.
    Keywords:  Cancer; Genomics; Proteomics; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2025.113176
  16. Sci Adv. 2025 Aug 15. 11(33): eadx6587
    Targeting lipid scrambling potentiates ferroptosis and triggers tumor immune rejection.
    Mengyun Yang, Ze Yu, Jieming Ping, Yuanchun Duan, Jianlong Tang, Weixiang Liu, Qing He, Yongfeng Lai, Sin Man Lam, Hesen Tang, Zhengjie Liu, Weimin Wang, Min Zhu, Wei Hu, Yunyun Han, Guanghou Shui, Jiqing Hao, Zheng Liu, Ning Wu.
      Despite advances in understanding the metabolic mechanisms of ferroptosis, the molecular events following lipid peroxide accumulation on the plasma membrane (PM) remain unclear. Herein, we identify TMEM16F as a ferroptosis suppressor at the executional phase. TMEM16F-deficient cells display heightened sensitivity to ferroptosis. Mechanistically, TMEM16F-mediated phospholipids (PLs) scrambling orchestrates extensive remodeling of PM lipids, translocating PLs at the lesion sites to reduce membrane tension, therefore mitigating the membrane damage. Unexpectedly, failure of PL scrambling in TMEM16F-deficient cells leads to lytic cell death, exhibiting PM collapse and unleashing substantial danger-associated molecule patterns. TMEM16F-deficient tumors exhibit decelerated progression. Notably, lipid scrambling inhibition synergizes with PD-1 blockade to trigger robust tumor immune rejection. The antiparasitic drug ivermectin enhances the responsiveness to PD-1 blockade by suppressing TMEM16F. Our findings uncover TMEM16F-mediated lipid scrambling as an anti-ferroptosis regulator by relocating PLs on the PM during the final stages of ferroptosis. Targeting TMEM16F-mediated lipid scrambling presents a promising therapeutic strategy for cancer treatment.
    DOI:  https://doi.org/10.1126/sciadv.adx6587
  17. FEBS Lett. 2025 Aug 13.
    Autophagy in the regulation of cancer dormancy.
    Damla Gunes, Alara Ustal, Yusuf Emre Ertem, Yunus Akkoc, Devrim Gozuacik.
      Relapse and metastasis continue to be major factors in cancer patient morbidity and death. Cancer dormancy is one of the reasons why cancer recurs after months or years of treatment. With the ability to reactivate, dormant tumors are transitioning into a growth latency stage that shields them from immune surveillance and traditional chemotherapy medications. Over the past decade, research efforts have concentrated on understanding processes governing the dormant state better. The ultimate goal of these efforts is to improve cancer diagnosis, treatment of metastatic illness, and prevention of relapse. Cancer tolerance to stress may depend on autophagy, a cellular stress and recycling system that promotes cancer growth and survival. Recent studies indicated that autophagy may help cancer cells to survive in primary and metastatic environments, to withstand treatment, to develop a dormant state, and to transition from the dormancy to a proliferative state. In this Review, we will discuss the autophagy-dormancy connection in primary and metastatic cancer.
    Keywords:  autophagy; cancer; cellular stress; metastasis; recurrence
    DOI:  https://doi.org/10.1002/1873-3468.70139
  18. Science. 2025 Aug 14. 389(6761): eadr6326
    Mitochondria protect against an intracellular pathogen by restricting access to folate.
    Tânia Catarina Medeiros, Jana Ovciarikova, Xianhe Li, Patrick Krueger, Tim Bartsch, Silvia Reato, John C Crow, Michelle Tellez Sutterlin, Bruna Martins Garcia, Irina Rais, Kira Allmeroth, Matías D Hartman, Martin S Denzel, Martin Purrio, Andrea Mesaros, Kit-Yi Leung, Nicholas D E Greene, Lilach Sheiner, Patrick Giavalisco, Lena Pernas.
      As major consumers of cellular metabolites, mitochondria are poised to compete with invading microbes for the nutrients that they need to grow. Whether cells exploit mitochondrial metabolism to protect from infection is unclear. In this work, we found that the activating transcription factor 4 (ATF4) activates a mitochondrial defense based on the essential B vitamin folate. During infection of cultured mammalian cells with the intracellular pathogen Toxoplasma gondii, ATF4 increased mitochondrial DNA levels by driving the one-carbon metabolism processes that use folate in mitochondria. Triggered by host detection of mitochondrial stress induced by parasite effectors, ATF4 limited Toxoplasma access to folates required for deoxythymidine monophosphate synthesis, thereby restricting parasite growth. Thus, ATF4 rewires mitochondrial metabolism to mount a folate-based metabolic defense against Toxoplasma.
    DOI:  https://doi.org/10.1126/science.adr6326
  19. bioRxiv. 2025 Aug 06. pii: 2025.08.05.668752. [Epub ahead of print]
    Vitamin B2 metabolism promotes FSP1 stability to prevent ferroptosis.
    Kirandeep K Deol, Cynthia A Harris, Sydney J Tomlinson, Cody E Doubravsky, Alyssa J Mathiowetz, James A Olzmann.
      Ferroptosis, a regulated form of cell death driven by excessive lipid peroxidation, has emerged as a promising therapeutic target in cancer. Ferroptosis suppressor protein 1 (FSP1) is a critical regulator of ferroptosis resistance, yet the mechanisms controlling its expression and stability remain mostly unexplored. To uncover regulators of FSP1 abundance, we conducted CRISPR-Cas9 screens utilizing a genome-edited, dual-fluorescent FSP1 reporter cell line, identifying both transcriptional and post-translational mechanisms that determine FSP1 levels. Notably, we identified riboflavin kinase (RFK) and FAD synthase (FLAD1), enzymes which are essential for synthesizing flavin adenine dinucleotide (FAD) from vitamin B2, as key contributors to FSP1 stability. Biochemical and cellular analyses revealed that FAD binding is critical for FSP1 activity. FAD deficiency, and mutations blocking FSP1-FAD binding, triggered FSP1 degradation via a ubiquitin-proteasome pathway that involves the E3 ligase RNF8. Unlike other vitamins that inhibit ferroptosis by scavenging radicals, vitamin B2 supports ferroptosis resistance through FAD cofactor binding, ensuring proper FSP1 stability and function. This study provides a rich resource detailing mechanisms that regulate FSP1 abundance and highlights a novel connection between vitamin B2 metabolism and ferroptosis resistance with implications for therapeutic strategies targeting FSP1 in cancer.
    DOI:  https://doi.org/10.1101/2025.08.05.668752
  20. Nat Protoc. 2025 Aug 13.
    Spontaneous and experimental models of lymph node metastasis.
    Cort B Breuer, Zhewen Xiong, Alice Wang, Grayson E Rodriguez, Gita C Abhiraman, K Christopher Garcia, Nathan E Reticker-Flynn.
      Lymph node (LN) metastasis is a conserved feature across most solid organ malignancies and portends worse prognoses. Functionally, LN metastases induce systemic tumor-specific immune tolerance and may serve as a reservoir for distant metastases. Nonetheless, there are relatively few preclinical models for interrogating the biology of LN metastasis and its systemic effects at various stages of metastatic progression. We describe a method for modeling LN metastasis of melanoma tumors in mice that enables assessment of tumor and immune cell phenotypes and the functional roles of nodal involvement on distant metastasis. Our model comprises a family of transplantable syngeneic melanoma tumor cell lines evolved to exhibit enhanced LN metastatic potential, which can be used to probe cancer-immune interactions and test new therapeutics. We present both (i) a spontaneous LN metastasis model involving primary tumor implantation and assessment of LN colonization 21-28 d later and (ii) an experimental metastasis model involving implantation of primary tumors followed by direct intra-LN injections of tumor cells. Both models can be extended to assess the impact of LN metastasis on the development of distant metastases through asynchronous intravenous injections of tumors. Finally, we discuss experimental design considerations including when to use spontaneous or experimental models and troubleshooting consistent LN metastasis, making this model accessible for researchers with basic mouse survival-surgery skills. We highlight how LN metastasis models can be used to profile metastatic immune reprogramming, measure the impact of nodal metastases on distant metastases and assess novel anti-metastatic therapeutics.
    DOI:  https://doi.org/10.1038/s41596-025-01200-5
  21. Nature. 2025 Aug 13.
    Clone copy number diversity is linked to survival in lung cancer.
    Piotr Pawlik, Kristiana Grigoriadis, Abigail Bunkum, Helena Coggan, Alexander M Frankell, Carlos Martinez-Ruiz, Takahiro Karasaki, Ariana Huebner, Andrew Rowan, Jasmin Fisher, Allan Hackshaw, Charles Swanton, Simone Zaccaria, Nicholas McGranahan.
      Both single nucleotide variants (SNVs) and somatic copy number alterations (SCNAs) accumulate in cancer cells during tumour development, fuelling clonal evolution. However, accurate estimation of clone-specific copy numbers from bulk DNA-sequencing data is challenging. Here we present allele-specific phylogenetic analysis of copy number alterations (ALPACA), a method to infer SNV and SCNA coevolution by leveraging phylogenetic trees reconstructed from multi-sample bulk tumour sequencing data using SNV frequencies. ALPACA estimates the SCNA evolution of simulated tumours with a higher accuracy than current state-of-the-art methods1-4. ALPACA uncovers loss-of-heterozygosity and amplification events in minor clones that may be missed using standard approaches and reveals the temporal order of somatic alterations. Analysing clone-specific copy numbers in TRACERx421 lung tumours5,6, we find evidence of increased chromosomal instability in metastasis-seeding clones and enrichment for losses affecting tumour suppressor genes and amplification affecting CCND1. Furthermore, we identify increased SCNA rates in both tumours with polyclonal metastatic dissemination and tumours with extrathoracic metastases, and an association between higher clone copy number diversity and reduced disease-free survival in patients with lung cancer.
    DOI:  https://doi.org/10.1038/s41586-025-09398-w
  22. Nat Metab. 2025 Aug 12.
    D-cysteine impairs tumour growth by inhibiting cysteine desulfurase NFS1.
    Joséphine Zangari, Oliver Stehling, Sven A Freibert, Kaushik Bhattacharya, Florian Rouaud, Veronique Serre-Beinier, Kinsey Maundrell, Sylvie Montessuit, Sabrina Myriam Ferre, Evangelia Vartholomaiou, Vinzent Schulz, Karim Zuhra, Víctor González-Ruiz, Sahra Hanschke, Takashi Tsukamoto, Michaël Cerezo, Csaba Szabo, Serge Rudaz, Michal T Boniecki, Miroslaw Cygler, Roland Lill, Jean-Claude Martinou.
      Selective targeting of cancer cells is a major challenge for cancer therapy. Many cancer cells overexpress the cystine/glutamate antiporter xCT/CD98, an L-cystine transport system that strengthens antioxidant defences, thereby promoting tumour survival and progression. Here, we show that the D-enantiomer of cysteine (D-Cys) is selectively imported into xCT/CD98-overexpressing cancer cell lines and impairs their proliferation, particularly under high oxygen concentrations. Intracellular D-Cys specifically inhibits the mitochondrial cysteine desulfurase NFS1, a key enzyme of cellular iron-sulfur protein biogenesis, by blocking sulfur mobilization due to steric constraints. NFS1 inhibition by D-Cys affects all cellular iron-sulfur cluster-dependent functions, including mitochondrial respiration, nucleotide metabolism and maintenance of genome integrity, leading to decreased oxygen consumption, DNA damage and cell cycle arrest. D-Cys administration diminishes tumour growth of human triple-negative breast cancer cells implanted orthotopically into the mouse mammary gland. Hence, D-Cys could represent a simple therapy to selectively target those forms of cancer characterized by overexpression of xCT/CD98.
    DOI:  https://doi.org/10.1038/s42255-025-01339-1
  23. Int J Mol Sci. 2025 Aug 04. pii: 7532. [Epub ahead of print]26(15):
    Suppression of Cytosolic Phospholipase A2 in the Ventromedial Hypothalamus Induces Hyperphagia and Obesity in Male Mice.
    Takashi Abe, Taiga Ishimoto, Yudai Araki, Ziwei Niu, Changwen Li, Jinxiao He, Samson Ngurari, Chitoku Toda.
      We recently reported that phospholipase A2 (PLA2)-mediated production of prostaglandins within the ventromedial hypothalamus (VMH) plays a critical role in systemic glucose homeostasis. However, the role of PLA2 in the VMH in regulating food intake is still unclear. Here, we attempted to investigate the role of PLA2 in regulating food intake and body weight in male mice. We injected an adeno-associated virus encoding short hairpin RNA (AAV-shRNA) targeting cytosolic phospholipase A2 (shPla2g4a) into the VMH. We assessed food intake, body weight, oxygen consumption, glucose tolerance, and insulin sensitivity. Three weeks after the AAV injection, the shPla2g4a group exhibited increased food intake and body weight gain compared to controls (shSCRM). Energy expenditure, oxygen consumption, and respiratory quotient (RQ) were comparable between groups. Our findings suggest that the cPLA2-mediated pathway in the VMH is critical for feeding behavior and maintaining energy homeostasis. Further investigation is needed to elucidate the underlying mechanisms.
    Keywords:  VMH; appetite; body weight; overeating; phospholipid; prostaglandins
    DOI:  https://doi.org/10.3390/ijms26157532
  24. Nat Commun. 2025 Aug 15. 16(1): 7621
    Respiration defects limit serine synthesis required for lung cancer growth and survival.
    Eduardo Cararo Lopes, Fuqian Shi, Akshada Sawant, Maria Ibrahim, Maria Gomez-Jenkins, Zhixian Hu, Pranav Manchiraju, Vrushank Bhatt, Wenping Wang, Christian S Hinrichs, Douglas C Wallace, Xiaoyang Su, Joshua D Rabinowitz, Chang S Chan, Jessie Yanxiang Guo, Shridar Ganesan, Edmund C Lattime, Eileen White.
      Mitochondrial function supports energy and anabolic metabolism. Pathogenic mitochondrial DNA (mtDNA) mutations impair these processes, causing mitochondrial diseases. Their role in human cancers is less clear; while some cancers harbor high mtDNA mutation burden, others do not. Here we show that a proofreading mutant of DNA polymerase gamma (PolGD256A) increases the mtDNA mutation burden in non-small-cell lung cancer (NSCLC). This mutation promotes the accumulation of defective mitochondria, reduces tumor cell proliferation and viability, and improves cancer survival. In NSCLC, pathogenic mtDNA mutations enhance glycolysis and create a glucose dependency to support mitochondrial energy, but at the expense of a lower NAD+/NADH ratio that hinders de novo serine synthesis. Thus, mitochondrial function in NSCLC is essential for maintaining adequate serine synthesis, which in turn supports the anabolic metabolism and redox homeostasis required for tumor growth, explaining why these cancers preserve functional mtDNA.
    DOI:  https://doi.org/10.1038/s41467-025-62911-7
  25. Cell Stem Cell. 2025 Aug 05. pii: S1934-5909(25)00265-6. [Epub ahead of print]
    A pancreatic cancer organoid biobank links multi-omics signatures to therapeutic response and clinical evaluation of statin combination therapy.
    Yunguang Li, Shijie Tang, Huan Wang, Hongwen Zhu, Yurun Lu, Yehan Zhang, Shiwei Guo, Juan He, Yikai Li, Yi Zhang, Xiaohan Shi, Yuanxiang Miao, Chaoliang Zhong, Yiqin Zhu, Yi Ju, Yuejia Liu, Maoyuan Sun, Yong Wang, Luonan Chen, Hu Zhou, Gang Jin, Dong Gao.
      Chemotherapy remains the primary treatment for pancreatic ductal adenocarcinoma (PDAC), but most patients ultimately develop resistance. Here, we established 260 pancreatic cancer organoid lines, followed by extensive multi-omics profiling and therapeutic sensitivity assessments. Integrated analyses uncovered 6 novel coding and 35 noncoding driver candidates. We discovered 2,794 multi-omics features associated with drug sensitivity and 322 features linked to radiation sensitivity. Pharmacogenomic analyses revealed that chemoresistant organoids exhibited enrichment in protein glycosylation and cholesterol metabolism pathways. Notably, statins effectively targeted chemoresistant PDAC organoids. Statin treatment attenuated protein glycosylation, cholesterol levels, and the epithelial-to-mesenchymal transition (EMT) signature in PDAC organoids. We conducted a single-center, single-arm, phase 2 clinical trial (NCT06241352) combining atorvastatin with chemotherapy in patients with advanced pancreatic cancer. Among 37 patients, 26 (70.3%) demonstrated a response, with tumor markers decreasing by more than 20%, suggesting durable responses and potential clinical benefits in this challenging patient population.
    Keywords:  chemoresistance signature; driver candidates; multi-omics; organoid; pancreatic cancer; pharmacogenomics; statin combination therapy
    DOI:  https://doi.org/10.1016/j.stem.2025.07.008
  26. Nat Med. 2025 Aug 11.
    Lymph node-targeted, mKRAS-specific amphiphile vaccine in pancreatic and colorectal cancer: phase 1 AMPLIFY-201 trial final results.
    Zev A Wainberg, Colin D Weekes, Muhammad Furqan, Pashtoon M Kasi, Craig E Devoe, Alexis D Leal, Vincent Chung, James R Perry, Thian Kheoh, Lisa K McNeil, Esther Welkowsky, Peter C DeMuth, Christopher M Haqq, Shubham Pant, Eileen M O'Reilly.
      Cellular immunity, mediated by tumor antigen-specific CD4+ and CD8+ T cells, has a critical role in the success of cancer immunotherapy by targeting intracellular driver and passenger tumor mutations. We present the final results of the phase 1 AMPLIFY-201 trial, in which patients who completed standard locoregional treatment, with minimal residual mKRAS disease (n = 25, 20 pancreatic cancer and 5 colorectal cancer), received monotherapy vaccination with lymph node-targeting ELI-002 2P, including mutant KRAS (mKRAS) amphiphile-peptide antigens (G12D, G12R) and amphiphile-adjuvant CpG-7909. At a median follow-up of 19.7 months, efficacy correlated with mKRAS-specific T cell responses above or below a threshold 9.17-fold increase over baseline, with median radiographic relapse-free survival not reached, versus 3.02 months (hazard ratio (HR) = 0.12, P = 0.0002) and median overall survival not reached versus 15.98 months (HR = 0.23, P = 0.0099). Seventy-one percent of evaluable patients induced both CD4+ and CD8+ subsets, with sustained immunogenicity. Following ELI-002 2P treatment, antigen spreading was observed in 67% of patients, with increased T cells reactive to personalized, tumor antigens absent from the ELI-002 2P vaccine. Therefore, lymph node-targeting amphiphile vaccination induces persistent T cell responses targeting oncogenic driver KRAS mutations, alongside personalized, tumor antigen-specific T cells, which may correlate to clinical outcomes in pancreatic and colorectal cancer. ClinicalTrials.gov registration: NCT04853017 .
    DOI:  https://doi.org/10.1038/s41591-025-03876-4
  27. Elife. 2025 Aug 13. pii: RP105318. [Epub ahead of print]14
    PRMT1-mediated metabolic reprogramming promotes leukemogenesis.
    Hairui Su, Yong Sun, Han Guo, Chiao-Wang Sun, Qiuying Chen, Szumam Liu, Anlun Li, Min Gao, Rui Zhao, Glen Raffel, Jian Jin, Cheng-Kui Qu, Michael Yu, Christopher A Klug, George Y Zheng, Scott Ballinger, Matthew Kutny, Long X Zheng, Zechen Chong, Chamara Senevirathne, Steven Gross, Yabing Chen, Minkui Luo, Xinyang Zhao.
      Copious expression of protein arginine methyltransferase 1 (PRMT1) is associated with poor survival in many types of cancers, including acute myeloid leukemia. We observed that a specific acute megakaryocytic leukemia (AMKL) cell line (6133) derived from RBM15-MKL1 knock-in mice exhibited heterogeneity in Prmt1 expression levels. Interestingly, only a subpopulation of 6133 cells expressing high levels of Prmt1 caused leukemia when transplanted into congenic mice. The PRMT1 inhibitor, MS023, effectively cured this PRMT1-driven leukemia. Seahorse analysis revealed that PRMT1 increased the extracellular acidification rate and decreased the oxygen consumption rate. Consistently, PRMT1 accelerated glucose consumption and led to the accumulation of lactic acid in the leukemia cells. The metabolomic analysis supported that PRMT1 stimulated the intracellular accumulation of lipids, which was further validated by fluorescence-activated cell sorting analysis with BODIPY 493/503. In line with fatty acid accumulation, PRMT1 downregulated the protein level of CPT1A, which is involved in the rate-limiting step of fatty acid oxidation. Furthermore, administering the glucose analog 2-deoxy-D-glucose delayed AMKL progression and promoted cell differentiation. Ectopic expression of Cpt1a rescued the proliferation of 6133 cells ectopically expressing PRMT1 in the glucose-minus medium. In conclusion, PRMT1 upregulates glycolysis and downregulates fatty acid oxidation to enhance the proliferation capability of AMKL cells. .
    Keywords:  CPT1A; PRMT1; cancer biology; cell biology; fatty acids; glycolysis; leukemia; mitochondria; mouse
    DOI:  https://doi.org/10.7554/eLife.105318
  28. Mol Biol Cell. 2025 Aug 13. mbcE21070359
    A growing problem: the many unsolved mysteries of cell growth.
    Douglas R Kellogg.
      Growth is the essential vital process that drives life forward and always occurs within cells. Cell growth fuels the cell divisions that drive proliferation of single-celled organisms and growth of multi-cellular organisms. Mechanisms that control the extent and location of growth within cells generate the extraordinary diversity of cell sizes and shapes seen across the tree of life and within the human body, and nearly all cancers show profound defects in control of cell growth that lead to severe aberrations in cell size and shape. Yet we know little about how cell growth occurs or how it is controlled. For decades we have known how basic building blocks such as amino acids and lipids are built, but an enormous gap has always remained in our understanding of how these building blocks are used to build out cells of highly diverse sizes and shapes under varying environmental conditions and in diverse developmental contexts. Given the fundamental importance of growth in biology and cancer, our minimal understanding of cell growth is a growing problem. Here, a few of the intriguing and important questions about cell growth are considered.
    DOI:  https://doi.org/10.1091/mbc.E21-07-0359
  29. J Vis Exp. 2025 Jul 22.
    Using LEXY and LINuS Optogenetics Tools and Automated Image Analysis to Quantify Nucleocytoplasmic Transport Dynamics in Live Cells.
    Axelle Donjon, Charlene Boumendil.
      Nucleocytoplasmic transport (NCT) is essential for maintaining cellular homeostasis, and its disruption is involved in various diseases, including neurodegenerative disorders and amyotrophic lateral sclerosis. This underscores the need to develop tools to monitor and quantify NCT. Amongst these tools, the fast and reversible optogenetics probes, LEXY (light-inducible nuclear export system) and LINuS (light-inducible nuclear localization signal), allow the measurement of NCT dynamics in live cells. The original publications describe manual segmentation and quantification of the fluorescent probe signal in the nucleus and cytosol upon transfection of LEXY and LINuS constructs in live-cell imaging. However, both transfection and manual segmentation limit the number of cells that can be analyzed and are subject to imprecision due to potential user-dependent errors. While the high speed and reversibility provided by optogenetics should, in principle, allow for high sensitivity in detecting changes in NCT dynamics, it depends on the acquisition parameters and analysis of a sufficient number of cells. We have therefore established lentiviral vectors expressing LEXY and LINuS to create stable cell lines, tested live imaging markers and control conditions, and implemented a semi-automated image analysis pipeline that allows for the analysis of hundreds of cells. This analysis method uses the open-access software FIJI, is accessible to beginners in bioinformatics, and does not require advanced computer setups. Here we provide a step-by-step protocol to set up LEXY as an example of these optogenetic tools to monitor nuclear export, from preparation of the samples to live-cell imaging acquisition and automated analysis, while demonstrating how to adapt the protocol for other conditions, controls, or models in any lab. All plasmids and cell lines used in this protocol will be made available to the scientific community, therefore further increasing the accessibility of the method.
    DOI:  https://doi.org/10.3791/68585
  30. Nat Protoc. 2025 Aug 11.
    Chemogenetic detection and quantitation of H2O2 in living cells.
    Mohammad Eid, Uladzimir Barayeu, Tobias P Dick.
      Hydrogen peroxide (H2O2) is a natural product of aerobic metabolism. It acts as a signaling molecule and regulates fundamental cellular functions. However, it has remained difficult to measure intracellular H2O2 with high specificity and in a quantitative manner. Here, we present a detailed protocol for a chemogenetic method that enables the detection and quantitation of H2O2 in living cells by converting intracellular H2O2 into fluorescent or luminescent signals. This is achieved by expressing the engineered heme peroxidase APEX2 in cells and subcellular locations of interest and by providing an appropriate fluorogenic or luminogenic substrate from outside. This method differs fundamentally from previously developed genetically encoded H2O2 probes; those are reversible and measure the balance between probe thiol oxidation and reduction. By contrast, APEX2 turns over its substrate irreversibly and therefore directly measures endogenous H2O2 availability. Our detailed step-by-step protocol covers the generation of APEX2-expressing cell lines, the implementation of fluorescent and luminescent measurements and examples for application. Ectopic expression of APEX2 can be achieved in 3 days, while the actual measurements typically require 1-2 h. This protocol is intended for entry-level scientists.
    DOI:  https://doi.org/10.1038/s41596-025-01226-9
  31. Cell. 2025 Aug 07. pii: S0092-8674(25)00811-6. [Epub ahead of print]
    Principles of cotranslational mitochondrial protein import.
    Zikun Zhu, Saurav Mallik, Taylor A Stevens, Riming Huang, Emmanuel D Levy, Shu-Ou Shan.
      Nearly all mitochondrial proteins are translated on cytosolic ribosomes. How these proteins are subsequently delivered to mitochondria remains poorly understood. Using selective ribosome profiling, we show that nearly 20% of mitochondrial proteins can be imported cotranslationally in human cells. Cotranslational import requires an N-terminal presequence on the nascent protein and contributes to localized translation at the mitochondrial surface. This pathway does not favor membrane proteins but instead prioritizes large, multi-domain, topologically complex proteins, whose import efficiency is enhanced when targeted cotranslationally. In contrast to the early onset of cotranslational protein targeting to the endoplasmic reticulum (ER), the presequence on mitochondrial proteins is inhibited from initiating targeting early during translation until a large globular domain emerges from the ribosome. Our findings reveal a multi-layered protein sorting strategy that controls the timing and specificity of mitochondrial protein targeting.
    Keywords:  NAC; TOM complex; cotranslational protein import; localized translation; mitochondria; mitochondrial targeting sequence; nascent polypeptide-associated complex; protein folding; protein targeting; ribosome profiling
    DOI:  https://doi.org/10.1016/j.cell.2025.07.021
  32. J Leukoc Biol. 2025 Aug 14. pii: qiaf120. [Epub ahead of print]
    Causal relationships between immunophenotypes, plasma metabolites, and pancreatic cancer: a mediation Mendelian randomization study.
    Jiawei Liu, Jian Zhou, Hongyu Bie, Xin Li, Cihui Yan, Xiubao Ren.
      Existing studies examining the relationships among immunological cell phenotype, plasma metabolites, and pancreatic cancer susceptibility are limited. More comprehensive research is required to elucidate the complex interactions underlying these associations. Genetic instruments for 731 immune phenotypes (N = 3,757), 1,400 circulating metabolites (N = 8,299), and pancreatic cancer (N = 1,196) were derived from a genome-wide association studies (GWAS) meta-analysis. A two-step, two-sample Mendelian randomization (MR) study using the IVW method was conducted to investigate the causal influence of immune cell phenotypes on pancreatic cancer and to assess the intermediary role of circulating metabolites. Sensitivity analyses were carried out to verify the robustness, potential heterogeneity, and pleiotropy. MR analyses identified protective effects of CD64 on monocyte (OR = 0.859, 95%CI 0.802-0.920, P = 1.65 × 10-5, PBonferroni = 0.012) against pancreatic cancer. Moreover, 68 metabolites were suggestively associated with pancreatic cancer. Notably, mediation MR revealed that the causal role of CD64 on monocyte in pancreatic cancer was largely mediated by 1-palmitoleoylglycerol (16:1) level (OR = 0.0089, 95%CI 0.00121-0.0167, P = 0.023), accounting for 5.91% of the total effect. These findings establish a causal relationship between CD64 on monocytes and pancreatic cancer, possibly operating through circulating metabolites. The research advances knowledge of the interplay between immune responses and the risk of pancreatic cancer, providing important implications for immunologically targeted treatment approaches.
    Keywords:  GWAS; immune cell; mendelian randomization; metabolites; pancreatic cancer
    DOI:  https://doi.org/10.1093/jleuko/qiaf120
  33. Nat Rev Cancer. 2025 Aug 14.
    Ageing, immune fitness and cancer.
    Melissa Dolan, Kendra A Libby, Alison E Ringel, Peter van Galen, Sandra S McAllister.
      The immune system undergoes substantial changes throughout life, with ageing broadly impacting immune cell composition, function and regenerative capacity. Emerging evidence suggests that age-associated changes in immune fitness - the ability to respond to and eliminate infection, pathogens and malignancy while maintaining self-tolerance - reshape antitumour immunity and influence the efficacy of immunotherapies. Technological advances in high-dimensional immunoprofiling have begun to reveal the complex interplay between ageing, immune fitness and cancer biology, uncovering new therapeutic vulnerabilities and challenges. In this Review, we discuss recent insights derived from age-resolved immunoprofiling of the human tumour microenvironment, how ageing haematopoiesis affects immune cells that contribute to the microenvironment and impact cancer progression, and what is known from preclinical modelling about the functional consequences of immune ageing on tumour control. We further highlight emerging age-stratified analyses of treatment responses, which are beginning to inform hypotheses about how ageing shapes immunotherapy outcomes. Together, these perspectives provide a framework for integrating age as a critical biological variable, underscore the need to consider age in both preclinical models and clinical trial design, and identify key challenges and priorities for the field moving forward.
    DOI:  https://doi.org/10.1038/s41568-025-00858-z
  34. FEBS Lett. 2025 Aug 11.
    Exploring lipid diversity and minimalism to define membrane requirements for synthetic cells.
    Sergiy Gan, Victoria Scarpelli, Marten Exterkate.
      The creation of minimal synthetic cells that mimic the essential functions of biological cells is a long-term goal in synthetic biology. Achieving this objective not only advances our understanding of the origin of life, but also unlocks the way for applications in industry, medicine, etc. A key characteristic of life is self-reproduction, which includes growth and division of the cell and its membrane. This boundary layer is formed by a lipid matrix in which proteins are anchored. The complexity of natural lipid membranes is a major challenge for the construction of a minimal system, as it directly influences membrane shape and protein function. Although simple synthetic compartmentalization systems can consist of a single lipid species, there is substantial uncertainty regarding the complexity of the lipidome required to sustain the essential functions of a self-reproducing cell. This Review highlights the contrast between bottom-up and top-down approaches toward synthetic cell construction, emphasizing the critical interplay between membrane proteins and their surrounding lipid environment. We explore the complexity and compatibility of membrane systems and discuss minimal lipidome requirements for synthetic cellular systems. Impact statement Synthetic cell research will help us to truly understand the basic principles of cellular life, in which lipid membranes are crucial. Ultimately, synthetic cells should lead to engineered specialized entities that can be applied in various fields, including medicine, bio-technology, and environmental science.
    Keywords:  JCVI‐Syn3A; bottom‐up synthetic biology; compartmentalization; lipid synthesis; synthetic cell
    DOI:  https://doi.org/10.1002/1873-3468.70131
  35. J Cell Sci. 2025 Aug 15. pii: jcs264018. [Epub ahead of print]138(16):
    Energy deprivation in youth and old age.
    Michael Stern.
      In youth, energy deprivation primarily results from fasting. Because inconsistent nutrient availability is common for most organisms, natural selection has provided mechanisms that detect nutrient-deprived states, followed by adaptive responses that increase the likelihood of survival until nutrients are restored. Organisms respond to fasting first by oxidizing the cellular cytoplasm, then by activating redox-sensitive kinases - namely the c-Jun N-terminal kinases (henceforth collectively termed JNK) and AMP-activated protein kinase (AMPK) - and Foxo transcription factors (henceforth referred to collectively as Foxo). Together, JNK, AMPK and Foxo induce autophagy. This fasting response is beneficial because autophagy supplies substrates for metabolism that replace missing nutrients and enhances removal of damaged organelles such as mitochondria, which increases lifespan and enhances survival through the fast. Although this response is adaptive in the context of acute nutrient deprivation, it can have harmful consequences when activated chronically. Here, I propose that cells from old organisms are constitutively energy deprived because of lifetime accumulation of dysfunctional mitochondria. As a result, these cells reactivate the fasting response seen in youth. Hence, old organisms constitutively oxidize the cellular cytoplasm and activate JNK, AMPK, Foxo and, finally, autophagy. However, because energy deprivation in old age is driven by mitochondrial insufficiency rather than nutrient deprivation, this response fails to restore ATP production and becomes chronic and deleterious. I suggest that many age-related pathologies, such as oxidative stress, neurodegeneration and sarcopenia, result from aberrant activation of the fasting response.
    Keywords:  Aging; Autophagy; Nutrient deprivation; Oxidative Stress; Signal transduction
    DOI:  https://doi.org/10.1242/jcs.264018
  36. bioRxiv. 2025 Aug 04. pii: 2025.08.04.668444. [Epub ahead of print]
    Genetic mechanisms of resistance to targeted KRAS inhibition.
    Bianca J Diaz, Max Kops, Sara Bernardo, Henri Schmidt, Elizabeth Grankowsky, Adrian Vega, Chen Zhang, Matthew Bott, Maria Skamagki, Aidan Tomlinson, Nicole A Vita, Alyna Katti, Mark P Labrecque, Ida Aronchik, Mallika Singh, Lukas E Dow.
      KRAS mutations are among the most prevalent oncogenic drivers in non-small cell lung cancer (NSCLC), yet the mechanisms of therapeutic resistance to KRAS inhibitors in these cancers remains poorly understood. Here, we deploy high-throughput CRISPR base editing screens to systematically map resistance mutations to three mechanistically distinct KRAS-targeted therapies, including KRAS-G12C(OFF) inhibitor (adagrasib), RAS(ON) G12C-selective tri-complex inhibitor (RMC-4998), and RAS(ON) multi-selective tri-complex inhibitor (RMC-7977). Using both a saturation Kras tiling approach and cancer-associated mutation library, we identify common and compound-selective second-site resistance mutations in Kras , as well as gain-of-function and loss-of-function variants across cancer-associated genes that rewire signaling networks in a context-dependent manner. Notably, we identify a recurrent missense mutation in capicua ( Cic ), that promotes resistance to RMC-7977 in vitro and in vivo. Moreover, we show that targeting NFκB signaling in CIC-mutant cells can resensitize them to RAS pathway inhibition and overcome resistance.
    DOI:  https://doi.org/10.1101/2025.08.04.668444
  37. Br J Pharmacol. 2025 Aug 10.
    Bilirubin prevents hyperlipidaemic acute pancreatitis by inhibiting aryl hydrocarbon receptor-mediated acinar cell pyroptosis.
    Wenjie Liang, Hanxiao Lu, Bo Wu, Hongnian Shen, Li-Long Pan, Xiaoliang Dong, Jun Yang.
       BACKGROUND AND PURPOSE: Hyperlipidaemia-induced acute pancreatitis (HLAP) represents a specific subtype of acute pancreatitis (AP) characterised by elevated serum triglyceride levels. However, the precise pathophysiological mechanisms underlying HLAP remain unclear. Bilirubin, an essential haem metabolite, displays significant capabilities in neutralising oxidative stress and modulating inflammatory responses. Here, we investigate the role of bilirubin in mediating HLAP.
    EXPERIMENTAL APPROACH: We analysed the serum from 627 AP patients, including 160 HLAP patients and 467 non-HLAP patients. Using an experimental HLAP mouse model, knockout mice and an aryl hydrocarbon receptor (AHR) inhibitor, we evaluated the role and underlying mechanism of bilirubin during HLAP development.
    KEY RESULTS: Bilirubin levels were significantly down-regulated in HLAP patients, and this decrease is correlated positively with the severity of the disease. Additionally, in the HLAP mouse model, we found that bilirubin supplementation mitigates lipid dysregulation and reduces pancreatic inflammation. Moreover, the Nrf2/HO-1 pathway is an upstream activator of bilirubin accumulation. Our data showed that Nrf2-/- HLAP mice exhibited enhanced pancreatic injuries compared with control mice. Furthermore, transcriptome analysis demonstrated marked elevation of the NOD-like receptor pathway in pancreatic tissue of HLAP mice, and bilirubin supplementation notably inhibited pancreatic pyroptosis. In addition, using an aryl hydrocarbon receptor (AHR) inhibitor and a pancreatic acinar cell line, we demonstrated that bilirubin prevents HLAP by inhibiting AHR-mediated pyroptosis.
    CONCLUSIONS AND IMPLICATIONS: Our data demonstrated that bilirubin protects against HLAP by suppressing AHR-mediated pyroptosis, highlighting bilirubin modulation as a potential therapeutic target for clinical intervention.
    Keywords:  aryl hydrocarbon receptor; bilirubin; cell pyroptosis; hyperlipidaemic acute pancreatitis
    DOI:  https://doi.org/10.1111/bph.70168
  38. FEBS Open Bio. 2025 Aug 11.
    Most autophagic cell death studies lack evidence of causality.
    Ali Burak Özkaya, Yasmin Ghaseminejad.
      Autophagy plays a critical role in maintaining cellular homeostasis and is implicated in various physiological and pathological processes, including cancer, neurodegeneration, and metabolic disorders. Although typically associated with cell survival, autophagy has also been proposed to contribute to cell death, referred to as autophagic cell death (ACD). However, the identification of ACD remains contentious due to inconsistencies in experimental methodologies and terminological misuse. In this study, we systematically evaluated 104 research articles published in 2022 that claimed to demonstrate ACD. Articles were assessed based on established criteria, including evidence for autophagy, evidence for cell death, exclusion of apoptosis, and experimental designs demonstrating causality. Our findings reveal that only 12.5% of the articles fulfilled all ACD criteria, while 37.5% provided only correlation-level evidence. Additionally, 54.81% failed to demonstrate autophagy flux, 32.7% relied on viability loss rather than direct evidence of cell death, and 45.0% of studies utilizing autophagy inhibition failed to demonstrate actual inhibition of autophagy. Inconsistent terminology was also prevalent, with "autophagy-mediated cell death" often misclassified as ACD and ACD frequently misused to describe autophagy co-occurring with cell death. These issues highlight a lack of rigor in current practices, with correlation-level evidence, inappropriate experimental designs, and terminological misuse undermining study robustness. To address these challenges, we developed a systematic workflow providing experimental and analytical guidance for classifying evidence for different modes of autophagy. Our analysis underscores the need for greater rigor, standardized approaches, and precise terminology to advance understanding of the interplay between autophagy and cell death.
    Keywords:  apoptosis; autophagic cell death; autophagy; autophagy‐associated cell death; autophagy‐mediated cell death; cell viability
    DOI:  https://doi.org/10.1002/2211-5463.70101
  39. bioRxiv. 2025 Jul 18. pii: 2025.07.13.664578. [Epub ahead of print]
    Endothelial Trauma Depends on Surface Charge and Extracellular Calcium Levels.
    Jade H Cleary, Kara J Wentzel, Abigail J Howard, Adrian M Sackheim, Sophia H Piffard, J Cory Benson, Grant Hennig, Dev Majumdar, Mohamed Trebak, Mark T Nelson, Kalev Freeman.
      We hypothesized that cationic histones bind to endothelial cell membranes through electrostatic interactions with negatively charged phospholipids, and consequently, that low Ca 2+ exacerbates toxicity by increasing binding and uptake of histones into cells. The role of the ubiquitous store-operated Ca 2+ entry (SOCE) in histone responses is also unknown. Here, studying endothelial cells in surgical preparations and in culture, we observed clinically relevant histone concentrations, produced fast plasma membrane movements including vesiculation, blebbing, ruffling, and cellular collapse. The cell membrane theatrics observed were markedly different from the uniform pattern of exocytosis and blebbing produced by calcium overload with ionomycin. Interestingly, membrane permeabilization produced by histones (and not ionomycin) was transient and a subset of cells recovered membrane integrity within 1 hour. A role for SOCE in histone responses was ruled out by genetic ablation of the ORAI1/2/3 channel trio. Removal of extracellular Ca 2+ prevented histone-induced intracellular Ca 2+ overload while surprisingly exacerbating plasma membrane deformation. Conversely, decreasing the density of the negative charge surface by adding calcium or multivalent cations gadolinium or increasing extracellular Ca 2+ levels effectively screened common membrane phospholipids from interactions with labeled histones and prevented endothelial damage in cells exposed to histones. Collectively, these results indicate that low extracellular Ca 2+ levels enhance interactions between histones and endothelial cell membrane phospholipids to increase cytotoxicity. Importantly, this supports the concept of aggressive Ca 2+ repletion during resuscitation to prevent hypocalcemia, stabilize the endothelial cell membranes and improve cardiovascular recovery from shock.
    Significance: In acute critical illness, the rapid collapse of vascular endothelial functions drives aberrant blood clotting and organ failure through mechanisms that are not understood. The recent breakthrough in transfusion medicine showing that administration of donor plasma improves survival of trauma patients has transformed the massive transfusion protocols used in surgical settings, but the sodium citrate used to prevent coagulation often produces significant and severe hypocalcemia. Here, we demonstrate that cytotoxic trauma factors that are elevated in the blood during resuscitation bind endothelial cell phospholipids, and that low Ca 2+ exacerbates toxicity by increasing this interaction. These experiments lead to our surprising discovery of unexpected endothelial cell membrane theatrics that occur in response to injury, with direct visualization of fast plasma membrane movements and the release and reuptake of extracellular vesicles. These findings provide important insights into the nature of shock-induced endotheliopathy and highlight the potential cardiovascular risk associated with chelation-induced hypocalcemia during resuscitation.
    DOI:  https://doi.org/10.1101/2025.07.13.664578
  40. Curr Opin Cell Biol. 2025 Aug 09. pii: S0955-0674(25)00109-7. [Epub ahead of print]96 102571
    Mechanisms of cellular fitness and cell competition: Towards an integrated view.
    Jules Lavalou, Karyna Kulakova, Yogaspoorthi J Subramaniam, Eugenia Piddini.
      Cell competition is a fundamental mechanism of tissue quality control that enables the selective elimination of less fit, mis-specified, diseased or aged cells. By shaping tissue composition, it plays a critical role in development, organismal health and a wide range of physiological and pathological contexts, including cancer. As its biological significance continues to grow, elucidating the molecular mechanisms underlying cell competition is essential for advancing our understanding of tissue biology, disease progression and future therapeutic strategies. In this review, we highlight recently identified, evolutionarily conserved pathways that govern cell competition through metabolites and systemic signals, proteostasis and mechanical exchange. By integrating findings across species and pathways, we reveal how these distinct mechanisms may intersect and coordinate to determine competitive outcomes, providing a conceptual framework to inform and guide future research.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102571
  41. Chem Commun (Camb). 2025 Aug 13.
    PFOA induces fission of phase-separated phospholipid vesicles.
    Seungsu Han, Emad Pirhadi, Xin Yong, Sangwoo Shin.
      Per- and polyfluoroalkyl substances (PFAS) are known for their strong surface activity, making it easy for them to disrupt cellular membranes. Here, we examine how perfluorooctanoic acid (PFOA), one of the most widespread PFAS species in the environment, interacts with phase-separated ternary vesicles as a model system for cellular membranes. We show experimentally that PFOA induces rapid fission of the vesicles along the phase boundary. All-atom molecular dynamics simulations suggest that the mechanism behind the fission process is attributed to a drastic change in the spontaneous curvature of the vesicle upon interacting with PFOA. Our findings reveal the significance of PFAS on the dynamics of phase-separated vesicles, implying a potential disruptive impact of PFAS exposure on cellular membranes.
    DOI:  https://doi.org/10.1039/d5cc03353e
  42. Cancer Res Commun. 2025 Aug 15.
    HuR-regulated extracellular vesicles promote endothelial cell remodeling in pancreatic cancer.
    Jennifer M Finan, Yifei Guo, Alexandra Q Bartlett, Kevin Hawthorne, Matthew Reyer, Margaret Haerr, Olayinka Lamikanra, Hen Halamish, Valerie Calvert, Canping Chen, Zheng Xia, Emanuel F Petricoin, Rosalie C Sears, Katelyn T Byrne, Jonathan R Brody.
      Pancreatic ductal adenocarcinoma (PDAC) tumors are hypovascular with collapsed and dysfunctional vessels that limit immune surveillance and contribute to early metastatic events. However, current anti-angiogenic therapies have failed in PDAC, highlighting the need to uncover the mechanisms by which cancer cells signal to endothelial cells to increase angiogenesis. Our lab has shown that the tumor-intrinsic RNA-binding protein HuR (ELAVL1) plays an important role in reshaping the tumor microenvironment (TME) by regulating the stability and translation of cell communication-encoding transcripts. We demonstrate that PDAC-intrinsic HuR influences endothelial cell function in the TME via extracellular vesicle (EV) signaling, an underexplored signaling axis in tumor progression. PDAC EVs contain HuR-dependent mRNA and protein cargo related to endothelial cell function and angiogenesis. Treating endothelial cells with HuR wildtype (WT) EVs increased the expression of genes involved in barrier function and endothelial cell development, and increased their migratory and tube-forming functions. In an immunocompetent mouse model of PDAC, we showed that HuR increased endothelial cell presence and sprouting, while decreasing ICAM-1 expression. Using a genetic EV reporter, we found that ICAM-1 suppression in WT tumors occurred specifically in endothelial cells that had internalized WT EVs, suggesting that this signaling axis modulates endothelial cell behavior in vivo. Furthermore, administration of WT EVs rescued impaired HuR knockout tumor growth, increased endothelial cell abundance, and decreased endothelial cell ICAM-1 expression. Collectively, our data reveal a novel role for HuR as a key mediator of EV signaling to endothelial cells, promoting angiogenesis while restricting endothelial cell leukocyte trafficking behavior.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-25-0355
  43. J Mater Chem B. 2025 Aug 12.
    Nanosecond pulsed electric field-empowered physical-chemical cascade ferroptosis therapy for triple-negative breast cancer.
    Wei Zheng, Yan Zhu, Qian Chen, Shuhan Shi, Qi Huang, Xinhua Chen, Xiawei Li, Pu Cheng, Haibin Wu, Shen Hu.
      Bis-allylic hydrogen atoms of polyunsaturated fatty acids (PUFAs) in biological membranes are major initiation sites of ferroptosis. However, the location of PUFAs in the hydrophobic interior of the lipid bilayer makes it challenging for most ferroptosis-inducing drugs to interact with the PUFAs to promote lipid peroxidation (LPO), potentially limiting the occurrence of ferroptosis. Herein, we propose a new generalized method named physical-chemical cascade ferroptosis (PCCF) for triggering ferroptosis by disrupting the integrity of the cell membrane to expose bis-allylic hydrogen atoms that react with nanozyme MnFI under nanosecond pulsed electric field (nsPEF) assistance. In vitro, PCCF continuously depletes GSH and produces LPO, inducing catalytic efficiency improvement, and collaboratively ferroptosis occurs through the GSH-mediated GPX4 pathway during triple-negative breast cancer (TNBC) treatment. In vivo, PCCF exhibit a significant tumor growth inhibitory potential through ferroptosis and increases CD8+ T cell and CD4+ T cell infiltration and DC cell maturation in tumor tissues. At the same time, the PCCF platform inhibits TNBC lung metastasis in mice. This work provides a novel TNBC therapeutic strategy that exposes PUFAs to react with nanozymes to directly trigger LPO production with nsPEF assistance and stimulate ferroptosis-mediated anti-tumour immune efficacy.
    DOI:  https://doi.org/10.1039/d5tb00711a
  44. Cell. 2025 Aug 11. pii: S0092-8674(25)00853-0. [Epub ahead of print]
    Prevalent mesenchymal drift in aging and disease is reversed by partial reprogramming.
    Jinlong Y Lu, William B Tu, Ronghui Li, Mingxi Weng, Bhargav D Sanketi, Baolei Yuan, Pradeep Reddy, Concepcion Rodriguez Esteban, Juan Carlos Izpisua Belmonte.
      The loss of cellular and tissue identity is a hallmark of aging and numerous diseases, but the underlying mechanisms are not well understood. Our analysis of gene expression data from over 40 human tissues and 20 diseases reveals a pervasive upregulation of mesenchymal genes across multiple cell types, along with an altered composition of stromal cell populations, denoting a "mesenchymal drift" (MD). Increased MD correlates with disease progression, reduced patient survival, and an elevated mortality risk, whereas suppression of key MD transcription factors leads to epigenetic rejuvenation. Notably, Yamanaka factor-induced partial reprogramming can markedly reduce MD before dedifferentiation and gain of pluripotency, rejuvenating the aging transcriptome at the cellular and tissue levels. These findings provide mechanistic insight into the underlying beneficial effects of partial reprogramming and offer a framework for developing interventions to reverse age-related diseases using the partial reprogramming approach.
    Keywords:  Yamanaka factors; aging; chronic kidney disease; epithelial-mesenchymal transition; fibrosis; heart failure; idiopathic pulmonary fibrosis; metabolic dysfunction-associated steatohepatitis; partial reprogramming; rejuvenation
    DOI:  https://doi.org/10.1016/j.cell.2025.07.031
  45. Anal Chem. 2025 Aug 10.
    Reversible NIR Ratiometric Probe for Monitoring Redox Homeostasis in Lipid Droplets during Ferroptosis-Driven Liver Injury.
    Songjiao Li, Min Deng, Ying Liu, Yufeng Luo, Hailin Zhang, Peipei Wang, Zibo Zhai, Dan Cheng, Longwei He.
      Accurate diagnosis and timely treatment of drug-induced liver injury (DILI) are crucial to preventing progression to other liver diseases or failure. Cellular redox balance may be linked to DILI. Hypochlorous acid (HClO) and glutathione (GSH) are key redox pairs reflecting cellular status. Ferroptosis is critical for understanding liver injury mechanisms. Studies show that DILI is associated with lipid droplet (LD) dysfunction. LDs, essential for lipid metabolism and storage, are linked to ferroptosis and fatty liver. Developing fluorescent probes for LD imaging is vital for studying dynamic physiological processes. Currently, no reversible probes exist to monitor the HClO/GSH redox balance, especially in LDs. To address this, we developed the NIR ratio-fluorescent probe PSeZ-ZD to dynamically monitor the HClO/GSH balance in LDs during ferroptosis and DILI. PSeZ-ZD enables NIR ratio imaging, targets LDs, and detects oxidants and antioxidants. It has detection limits of 51.1 nM for HClO and 1.575 μM for GSH. At the cellular level, PSeZ-ZD successfully images HClO fluctuations with excellent reversibility and LD targeting. It also monitors in situ HClO/GSH in APAP- or INH-induced DILI and evaluates NAC, silybin, and their combination. This probe provides a valuable tool for early DILI diagnosis and treatment, offering new insights into ferroptosis in DILI.
    DOI:  https://doi.org/10.1021/acs.analchem.5c03499
  46. Nat Commun. 2025 Aug 11. 16(1): 7277
    Computationally unmasking each fatty acyl C=C position in complex lipids by routine LC-MS/MS lipidomics.
    Leonida M Lamp, Gosia M Murawska, Joseph P Argus, Aaron M Armando, Radu A Talmazan, Marlene Pühringer, Evelyn Rampler, Oswald Quehenberger, Edward A Dennis, Jürgen Hartler.
      Identifying carbon-carbon double bond (C=C) positions in complex lipids is essential for elucidating physiological and pathological processes. Currently, this is impossible in high-throughput analyses of native lipids without specialized instrumentation that compromises ion yields. Here, we demonstrate automated, chain-specific identification of C=C positions in complex lipids based on the retention time derived from routine reverse-phase chromatography tandem mass spectrometry (RPLC-MS/MS). We introduce LC=CL, a computational solution that utilizes a comprehensive database capturing the elution profile of more than 2400 complex lipid species identified in RAW264.7 macrophages, including 1145 newly reported compounds. Using machine learning, LC=CL provides precise and automated C=C position assignments, adaptable to any suitable chromatographic condition. To illustrate the power of LC=CL, we re-evaluated previously published data and discovered new C=C position-dependent specificity of cytosolic phospholipase A2 (cPLA2). Accordingly, C=C position information is now readily accessible for large-scale high-throughput studies with any MS/MS instrumentation and ion activation method.
    DOI:  https://doi.org/10.1038/s41467-025-61911-x
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