bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2026–03–01
forty-five papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Opposing roles of DGAT-mediated lipid droplet biogenesis in the regulation of ferroptosis sensitivity.
  2. Selenium-Thioredoxin Axis Contributes to Ferroptosis Resistance in Pancreatic Cancer Cells.
  3. Nerve Injury-Induced Protein 2 preserves lysosomal membrane integrity to suppress ferroptosis.
  4. Hypoxia-Driven Changes in Nuclear Morphology as a Determinant of Cell Migration.
  5. Mitochondrial Permeability Transition in Skeletal Muscle Phenocopies Muscle Alterations seen in Cancer Cachexia and other Wasting Conditions.
  6. Phase I Trial of Binimetinib Plus Hydroxychloroquine in Patients with Previously Treated Metastatic Pancreatic Cancer.
  7. Chemical biology approaches for revealing interorganelle lipid transport pathways.
  8. Intratumoral lymphatics: When less is more.
  9. A disease model resource reveals core principles of tissue-specific cancer evolution.
  10. Piezo2 tension sensitivity and its modulation by alternative splicing.
  11. Quantifying interleaflet coupling of phase behavior and observing anti-registered phases in asymmetric lipid bilayers.
  12. The GENEVA platform models tumor mosaicism to reveal variations of responses to KRAS inhibitors and identify improved drug combinations.
  13. Autophagosome turnover requires Arp2/3 complex-mediated maintenance of lysosomal integrity.
  14. FGTI-2734 prevents ERK-mediated resistance and enhances MRTX1133 efficacy in KRAS G12D pancreatic cancer.
  15. Systemic hypoxia suppresses solid tumor growth.
  16. Microautophagy: current understanding of its molecular mechanisms and functions.
  17. Beta cell-derived cholecystokinin drives obesity-associated pancreatic adenocarcinoma development.
  18. High Fat Diet and Obesity Each Increase Tumor Cell Proliferation and Muscle Wasting in Experimental Cancer Cachexia.
  19. Atezolizumab and Motixafortide, Cobimetinib or Simlukafusp Alfa in Pretreated Advanced Pancreatic Cancer: Phase I/IIb MORPHEUS-PDAC Umbrella Study.
  20. Cell enlargement drives aging-associated proteome remodeling and shortens replicative lifespan.
  21. SenNet Portal: Build, Optimization and Usage.
  22. Translating ferroptosis into oncology: challenges, opportunities and future directions.
  23. Targeting mitochondrial phosphatase PGAM5 alleviates ferroptosis and acute pancreatitis by upregulating NRF2-mediated FSP1 expression.
  24. Aspartate availability drives differential engagement of the malate-aspartate shuttle.
  25. Lipid Regulation of Mechanosensitive Ion Channels.
  26. Light Microscopy-Based Organelle Quantification: A Comprehensive Protocol.
  27. pH-Dependent Microenvironmental Ionic Signaling in Pancreatic Ductal Adenocarcinoma.
  28. Acting on dormancy: the interplay between the actin cytoskeleton and tumor cell dormancy.
  29. Fatty acids promote uncoupled respiration via ATP/ADP carriers in white adipocytes.
  30. CLCC1 promotes hepatic neutral lipid flux and nuclear pore complex assembly.
  31. A translational colorectal cancer organoid biobank mirrors patients' tumor histology, molecular profiles, and treatment responses.
  32. Control of phagophore membrane expansion: Atg8-Atg1 as the master switch.
  33. miR-940 suppresses ferroptosis by controlling expression of key regulatory genes.
  34. 3D, multi-omic imaging reveals molecular biomarkers of the pre-metastatic niche in lung cancer.
  35. PRMT5 in mitochondria regulates mtDNA stability through TFAM arginine methylation.
  36. Mitochondria contact lipid droplets through the mitochondrial import complex binding to lipid metabolism enzyme Ayr1.
  37. Genetic interactions, synthetic lethality and complexity in cancer vulnerability mapping-Insights and perspectives from the 2nd EuroDepMap symposium.
  38. A Pan-Cancer Ex Vivo Drug Screen Atlas for Functional Precision Oncology.
  39. Cell jamming transition is regulated by mitochondrial pyruvate transport and endocytosis.
  40. Treating Pancreatic Ductal Adenocarcinoma: The Targeted Revolution is Here.
  41. ATP8B1-TMEM30B Flippase Activity Maintains Stereocilia Lipid Asymmetry Required for Hearing.
  42. Multiscale Analysis of PNPLA2 and PNPLA3 Membrane Targeting.
  43. Lipid scrambling: New players, new questions, new opportunities.
  44. Whole-organ and whole-body 3D atlases enable cellome-wide profiling.
  45. Peripheral immune-inducer dendritic cells drive early-life allergic inflammation.
  1. FEBS J. 2026 Feb 23.
    Opposing roles of DGAT-mediated lipid droplet biogenesis in the regulation of ferroptosis sensitivity.
    Ana Kump, Leja Perne, Špela Koren, Eva Jarc Jovičić, Nastja Feguš, Carina Pinto Kozmus, Michele Wölk, Kristyna Brejchova, Maria Fedorova, Ondrej Kuda, Toni Petan.
      Lipid droplets (LDs) are dynamic fat storage organelles involved in fatty acid metabolism, signaling, and trafficking. By storing polyunsaturated fatty acids (PUFAs) in the form of neutral lipids, LDs can either mitigate or exacerbate lipotoxic damage. However, their role in regulating cellular fatty acid distribution, membrane unsaturation, and ferroptosis susceptibility remains poorly understood. Here, we show that inhibition of diacylglycerol acyltransferase (DGAT)-mediated LD biogenesis in PUFA-supplemented triple-negative breast cancer cells triggers widespread lipidome reorganization and membrane phospholipid acyl-chain remodeling, promoting lipid peroxidation and ferroptosis sensitivity. Lipidomic analyses reveal that LDs efficiently sequester exogenous PUFAs within triacylglycerols and cholesteryl esters, significantly altering neutral lipid unsaturation profiles. When LD formation is impaired by DGAT inhibition, PUFAs are redistributed into membrane ester and ether glycerophospholipids, enhancing overall membrane unsaturation, lipid peroxidation, and increasing ferroptosis susceptibility, even in the absence of additional ferroptosis inducers. In contrast, in human lung adenocarcinoma cells, LDs exhibit a dual, context-dependent role in ferroptosis regulation, whereby exogenous PUFA levels and the extent of ferroptosis protection determine whether DGAT inhibition promotes or protects against cell death. The pro-ferroptotic function of LDs predominates in these cells and is strongly enhanced by ferroptosis suppressor protein 1 (FSP1) deficiency, which amplifies lipid peroxidation within LDs and promotes its propagation to other cellular compartments. This study highlights LDs as multifaceted regulators of ferroptosis, interlinking metabolic and redox quality control mechanisms.
    Keywords:  diacylglycerol acyltransferase; fatty acids; ferroptosis; lipid droplets; lipid peroxidation; lipidomics
    DOI:  https://doi.org/10.1111/febs.70467
  2. Int J Mol Sci. 2026 Feb 23. pii: 2062. [Epub ahead of print]27(4):
    Selenium-Thioredoxin Axis Contributes to Ferroptosis Resistance in Pancreatic Cancer Cells.
    Arslan Amer, Micah Idowu, Aqsa Ahsan, Alyssa Abbas, Tahiyat Alothaim, Xiaohu Tang.
      Pancreatic ductal adenocarcinoma (PDAC) shows substantial heterogeneity in cysteine dependence and ferroptosis sensitivity. We identify two PDAC subtypes distinguished by EMT status: mesenchymal-like cells are highly cysteine-dependent and rapidly undergo ferroptosis upon cystine deprivation or system xc- inhibition, whereas epithelial-type cells are ferroptosis-resistant. Selenium supplementation protects cells from erastin-induced ferroptosis, and this protection persists even when intracellular glutathione (GSH) is depleted, supporting an additional GPX4-independent protective mechanism. Sepp1 knockdown does not alter sensitivity, indicating that selenium's protective effect is independent of Sepp1. Instead, epithelial-type cells rely on both cytosolic and mitochondrial thioredoxin reductases (TrxR1 and TrxR2) to maintain ferroptosis resistance. Chemical inhibition of thioredoxin reductases abolishes selenium-mediated protection and sensitizes epithelial cells to ferroptosis inducers, while dual genetic suppression of TrxR1 and TrxR2 similarly restores ferroptosis sensitivity. These findings uncover a selenium-thioredoxin redox axis that functions independently of GPX4 and contributes ferroptosis resistance in epithelial-type PDAC cells. Co-targeting cysteine metabolism and thioredoxin reductases may therefore represent a rational strategy to overcome ferroptosis resistance in some PDAC subtypes.
    Keywords:  EMT; PDAC; ferroptosis; resistance; selenium; thioredoxin
    DOI:  https://doi.org/10.3390/ijms27042062
  3. bioRxiv. 2026 Feb 11. pii: 2026.02.09.704867. [Epub ahead of print]
    Nerve Injury-Induced Protein 2 preserves lysosomal membrane integrity to suppress ferroptosis.
    Jin Zhang, Miranda Bustamante, Yang Shi, Ken-Ichi Nakajima, Xinbin Chen.
      Nerve injury-induced protein 1 (NINJ1), a cell adhesion molecule, is oligomerized during lytic cell death and mediates plasma membrane rupture to release large intracellular molecules that propagate the inflammatory response. We and others previously showed that NINJ2, a close relative of NINJ1, does not promote plasma membrane rupture to spread inflammation. Here, we identify that NINJ2 is necessary for the lysosome membrane integrity to protect cells from ferroptosis. Specifically, we found that NINJ2 localizes to lysosomes and interacts with LAMP1, an anchor glycoprotein of the lysosome membranes and a sensor of stressed lysosomes. We also found that loss of NINJ2 exacerbates lysosomal membrane permeabilization (LMP), which allows for selective leakage of lysosomal contents, such as labile iron, into the cytosol. Accordingly, loss of NINJ2 elevates cellular labile iron accumulation and decreases expression of ferritins, the primary intracellular iron storage protein complexes. Mechanistically, we found that loss of NINJ2 promotes ferritin FTH degradation in lysosomes, which can be reversed by knockdown of LAMP1. Moreover, we found that loss of NINJ2 sensitizes cells to ferroptosis induced by RSL3 and Erastin, consistent with a recent study that loss of Ninj2 predisposes mice to chronic inflammation. Together, these findings uncover a previously unrecognized activity of NINJ2 from lysosome homeostasis to ferroptosis, which can be explored as a cancer therapeutic strategy especially considering that NINJ2 and ferritins are found to be overexpressed and positively associated with iron-addicted cancers.
    DOI:  https://doi.org/10.64898/2026.02.09.704867
  4. Biophys J. 2026 Feb 24. pii: S0006-3495(26)00151-7. [Epub ahead of print]
    Hypoxia-Driven Changes in Nuclear Morphology as a Determinant of Cell Migration.
    Prema Kumari Agarwala, Rohit Joshi, Abhijit Majumder, Shobhna Kapoor.
      Metastatic pancreatic cancer is marked by extreme hypoxia and resistance to current therapies, necessitating urgent need for novel treatment strategies. Here, we investigate how hypoxia-mimetic conditions induced by cobalt chloride drives pancreatic cancer cell invasion by modulating cellular and nuclear mechanics. Through microscopic imaging, atomic force microscopy and mass spectrometry, we show that hypoxia induces changes in cellular morphology by reducing cell spread area, enhancing filopodia formation, and decreasing actin anisotropy, promoting a migratory and invasive phenotype. We next demonstrated, hypoxia alters nuclear morphological and mechanical attributes, reducing nuclear size, and stiffness, accompanied by decreased lamin A expression, thereby facilitating nuclear deformability required for cell migration. Notably, we observed substantial wrinkling of the nuclear envelope in pancreatic cancer under hypoxia, highlighting it as a potentially efficient mechanical phenotype for pancreatic cancer. Finally, hypoxia triggers specific changes in the nuclear lipidome and proteome, including increased lipid saturation and acyl chain length with lower expression of LINC (linker of nucleo-skeleton and cytoskeleton) proteins, aligning with altered nuclear mechanics. Together, our findings reveal a mechanoadaptive response of hypoxia that links biophysical remodeling with metastatic potential, offering new possibilities for using mechanics-targeted treatments to limit cancer cell migration, hence reducing metastasis.
    Keywords:  Cell Mechanics; Hypoxia; Lipidomics; Metastasis; Nuclear Mechanics; Pancreatic Cancer
    DOI:  https://doi.org/10.1016/j.bpj.2026.02.030
  5. bioRxiv. 2026 Feb 13. pii: 2026.02.12.705530. [Epub ahead of print]
    Mitochondrial Permeability Transition in Skeletal Muscle Phenocopies Muscle Alterations seen in Cancer Cachexia and other Wasting Conditions.
    Maya Semel, Cole Lukasiewicz, Sarah Skinner, Mark R Viggars, Martin Picard, Abbey-Gale Mannings, Michael Cohen, Dennis Wolan, Terence E Ryan, Russell T Hepple.
       Background: Skeletal muscle in wasting conditions often exhibits a common set of phenotypes that include atrophy, mitochondrial respiratory dysfunction, and fragmentation of the acetylcholine receptor (AChR) cluster at the endplate. Mitochondria are frequently implicated in driving muscle pathology in these conditions, although which aspects of mitochondrial function are most relevant is poorly understood.
    Methods: To address this gap, we focused on mitochondrial permeability transition (mPT), a well-established pathological mechanism in ischemia-reperfusion injury and neurodegeneration but poorly studied in skeletal muscle. We performed a broad assessment of the consequences of mPT in skeletal muscle, focusing on features that are common in wasting conditions. We then tested whether tumor-host factors could promote mPT and compared differentially expressed genes (DEGs) with mPT and a mouse model of pancreatic cancer cachexia.
    Results: Inducing mPT in mouse skeletal muscle bundles in a Ca 2+ retention capacity assay progressively altered mitochondrial morphology, beginning with cristae swirling and condensation, progressing to mitochondrial cristae displacement, and culminating in breach of the outer mitochondrial membrane; features that are common in wasting conditions. Inducing mPT with Bz423 in single mouse muscle fibers increased mROS and Caspase 3 (Casp3) activity and was prevented by inhibitors of mPT, mROS or Casp3. Incubating single muscle fibers with Bz423 for 24 h reduced fiber diameter by ∼20% which was prevented by inhibiting mPT, mROS, or Casp3. Inducing mPT caused a complex I-specific mitochondrial respiratory impairment and increased co-localization of lysosomes with mitochondria. Inducing mPT also fragmented the AChR cluster at the muscle endplate and was prevented by inhibiting mPT or Casp3. The Ca 2+ threshold for mPT and mitochondrial calcein colocalization were reduced by pancreatic tumor-conditioned media in skeletal muscle or C2C12 myoblasts, respectively, and these effects were counteracted by mPT inhibition or cyclophilin D knockout. Finally, there was significant overlap between the transcriptome of mPT and that seen in diaphragm muscle in a mouse model of pancreatic cancer cachexia, particularly during the muscle wasting phase.
    Conclusions: We conclude that inducing mPT in skeletal muscle recapitulates muscle phenotypes common with muscle wasting conditions like cachexia. Furthermore, mPT is engaged by tumor-host factors and had significant overlap with DEGs seen during the muscle wasting phase in a mouse model of pancreatic cancer cachexia, warranting further investigation of mPT as a therapeutic target.
    DOI:  https://doi.org/10.64898/2026.02.12.705530
  6. Oncologist. 2026 Feb 27. pii: oyag071. [Epub ahead of print]
    Phase I Trial of Binimetinib Plus Hydroxychloroquine in Patients with Previously Treated Metastatic Pancreatic Cancer.
    S Daniel Haldar, Fen Saj, So Jung Hong, Rishi Surana, Lianchun Xiao, J Jack Lee, Brandon Smaglo, Dan Zhao, Huili Zhu, Ryan Huey, Jason Willis, M Pia Morelli, Michael Overman, Florencia McAllister, Robert Wolff, Anirban Maitra, David Fogelman, Channing Der, Shubham Pant.
       BACKGROUND: Dual mitogen-activated protein kinase (MAPK) pathway and autophagy inhibition shows synergistic antitumor activity in preclinical models of RAS-mutant cancers. We hypothesized that autophagy blockade with hydroxychloroquine (HCQ) could overcome resistance to MEK inhibition with binimetinib (BINI) and provide clinical benefit in previously treated, KRAS-mutated, metastatic pancreatic ductal adenocarcinoma (PDAC).
    METHODS: This investigator-led, single-arm, open-label, phase I dose escalation/expansion trial evaluated the safety and tolerability of BINI + HCQ in patients with previously treated, metastatic PDAC (NCT04132505). Key eligibility criteria: ECOG 0-1, adequate organ function, ≥ 1 prior line of therapy for metastatic disease, and presence of KRAS mutation. Dose escalation followed a Bayesian optimal interval (BOIN) design. The primary endpoint was the maximum tolerated dose (MTD). Secondary endpoints included safety, objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).
    RESULTS: From December 2019 to August 2024, 34 patients were enrolled in dose escalation (n = 17) and dose expansion (n = 17). Two dose-limiting toxicities occurred among the first 3 patients treated at dose level 1 (BINI 45 mg + HCQ 600 mg): grade 3 creatine phosphokinase elevation with renal impairment (BINI) and grade 3 QT prolongation (HCQ). Following dose de-escalation due to poor tolerance, the MTD was determined to be BINI 30 mg + HCQ 600 mg twice daily and used in expansion. Out of 31 response-evaluable patients, 2 patients achieved a partial response and 9 patients achieved stable disease, yielding ORR 6.5% and DCR 35.5%, respectively. Median PFS was 1.9 months, and median OS was 5.3 months.
    CONCLUSION: The combination of BINI + HCQ demonstrated a challenging toxicity profile and limited clinical activity in patients with chemorefractory metastatic PDAC.
    Keywords:  KRAS; MEK inhibition; autophagy; hydroxychloroquine; pancreatic cancer
    DOI:  https://doi.org/10.1093/oncolo/oyag071
  7. Curr Opin Cell Biol. 2026 Feb 26. pii: S0955-0674(26)00011-6. [Epub ahead of print]99 102623
    Chemical biology approaches for revealing interorganelle lipid transport pathways.
    Yuan-Ting Cho, Jeremy M Baskin.
      Membranes are dynamic, lipid-rich structures that encapsulate cells and their organelle compartments. Understanding how lipids are metabolized, organized, and exchanged within tightly packed membrane environments requires robust strategies capable of mapping organelle-specific lipid networks and their associated protein machinery. Recent progress coming from the chemical biology arena has afforded a panoply of powerful and precise tools to probe lipids at the organelle level, enabling visualization, quantification, and manipulation of lipid pools with high spatiotemporal precision. These approaches include bespoke small-molecule chemical probes as well as designer engineered protein-based tools. We summarize recent progress across this technological landscape and highlight applications toward mapping enzymes and transporters that control organelle membrane lipid homeostasis. Together, these chemical strategies are expanding our ability to dissect lipid dynamics and providing new insights into fundamental cellular lipid homeostasis and related disease mechanisms.
    DOI:  https://doi.org/10.1016/j.ceb.2026.102623
  8. Cancer Cell. 2026 Feb 26. pii: S1535-6108(26)00099-1. [Epub ahead of print]
    Intratumoral lymphatics: When less is more.
    Nathan Dangle, Andy J Minn.
      Lymphatic vessels assume two-faced roles in cancer, functioning as facilitators of both immune surveillance and metastasis. In this issue of Cancer Cell, Karakousi et al. establish IFNγ as a key phenotypic and metabolic switch in tumor-associated lymphatic vessels that reinforces antitumor immunity while simultaneously blocking regional metastasis.
    DOI:  https://doi.org/10.1016/j.ccell.2026.02.003
  9. Nature. 2026 Feb 25.
    A disease model resource reveals core principles of tissue-specific cancer evolution.
    Sebastian Mueller, Niklas de Andrade Krätzig, Markus Tschurtschenthaler, Miguel G Silva, Chiara Thordsen, Riccardo Trozzo, Perrine Simon, Frederic Saab, Thorsten Kaltenbacher, Magdalena Zukowska, Daniele Lucarelli, Rupert Öllinger, Joscha Griger, Nina Groß, Tanja Groll, Jessica Löprich, Antonio E Zaurito, Linus R Schömig, Jeroen M Bugter, Stefanie Bärthel, Chiara Falcomatà, Alexander Strong, Cordelia Brandt, Mulham Najajreh, Aristeidis Papargyriou, Roman Maresch, Katharina A N Collins, David Sailer, Christian Schneeweis, Sebastian Burger, Lisa M Fröhlich, Christine Klement, Alexander Belka, Juan J Montero, Ute Jungwirth, Maximilian Reichert, Markus Moser, Jens Neumann, George Vassiliou, Juan Cadiñanos, Ignacio Varela, Carsten Marr, Daniel F Alonso, Pier-Luigi Lollini, Jean Zhao, Louis Chesler, Clare M Isacke, Angela Riedel, Christian J Braun, Martin L Sos, Filippo Beleggia, Hans C Reinhardt, Monica Musteanu, Mariano Barbacid, Michael Quante, Marc Schmidt-Supprian, Günter Schneider, Simon Clare, Trevor D Lawley, Gordon Dougan, Katja Steiger, Nathalie Conte, Allan Bradley, Lena Rad, Dieter Saur, Roland Rad.
      Oncogenes such as KRAS display marked tissue specificity in their oncogenic potential, genetic interactions and phenotypic effects, but the underlying determinants remain largely unresolved1-5. Here, to address these questions, we developed the Mouse Cancer Cell line Atlas, a broad-utility resource of 590 comprehensively characterized models across a wide range of entities ( www.mcca.tum.de ). Comparative and functional studies using this platform, human cohorts and mice identified core principles underlying tissue-specific evolution of KRAS-initiated cancers. First, we show that mutant KRAS dosage gain through allelic imbalance exerts cell-type-specific effects, defining its timing across entities, as exemplified by dosage-sensitive developmental reprogramming during pancreatic cancer initiation. Second, we highlight how tissue- and stage-specific evolutionary requirements, such as block of differentiation in the intestine, select for KRAS-collaborating alterations. Third, we identified context-dependent epistatic KRAS-tumour suppressor interactions and show that reciprocal dosage sensitivities dictate the entity-specific patterns of cancer gene alterations, explaining their frequency, zygosity and acquisition chronology. These findings highlight how intrinsic and acquired determinants instruct cancer evolution in different tissues, with predictable molecular patterns, temporal dynamics and phenotypic outcomes. Our study provides major advances towards a mechanistic understanding of cancer genomes.
    DOI:  https://doi.org/10.1038/s41586-026-10187-2
  10. bioRxiv. 2026 Feb 17. pii: 2026.02.16.706133. [Epub ahead of print]
    Piezo2 tension sensitivity and its modulation by alternative splicing.
    Michael Sindoni, William Sharp, Jörg Grandl.
      Piezo2 is a force-gated ion channel that functions as a sensor of mechanical touch, proprioception, lung inflation, and gut transit. Human Piezo2 contains seven domains that are alternatively spliced in a tissue-specific fashion resulting in the expression of at least 22 distinct variants. Despite the relevance of Piezo2 in human physiology, its sensitivity to membrane tension, and how this fundamental biophysical property is affected by alternative splicing, are unknown. Here, we use cell-attached pressure-clamp electrophysiology combined with differential interference contrast microscopy to quantify the response of Piezo2 to membrane tension and identify the alternatively spliced exon 35 as a domain sufficient to confer high sensitivity to membrane tension and cellular indentation. We further show that physiological variants of Piezo2 sense mechanical forces with distinct sensitivities and dynamic ranges. Together, our findings rationalize how Piezo2 variants may fulfill distinct physiological functions required for somatosensation and interoception.
    DOI:  https://doi.org/10.64898/2026.02.16.706133
  11. bioRxiv. 2026 Feb 18. pii: 2026.02.17.706271. [Epub ahead of print]
    Quantifying interleaflet coupling of phase behavior and observing anti-registered phases in asymmetric lipid bilayers.
    Kristen B Kennison-Cook, Averi M Cooper, Frederick A Heberle.
      Model asymmetric lipid bilayers provide a powerful platform for probing how lateral phase behavior in one leaflet is coupled to that of the opposing leaflet. Here, we use calcium-induced hemifusion to generate asymmetric giant unilamellar vesicles (aGUVs) and investigate how lipid composition modulates interleaflet coupling of liquid-liquid phase separation. Symmetric GUVs composed of cholesterol, the high-melting lipid DPPC, and a low-melting phosphatidylcholine (either 14:1-PC or 16:1-PC) were prepared at compositions exhibiting coexisting liquid-ordered (Lo) and liquid-disordered (Ld) phases. Hemifusion with a uniformly mixed supported lipid bilayer composed of the low-melting lipid and cholesterol selectively altered the outer leaflet composition, producing aGUVs with controlled but variable asymmetry. Quantification of outer leaflet exchange using both probe-exit and probe-entry fluorescence measurements revealed substantial vesicle-to-vesicle variability within a given preparation, resulting in overlapping populations of phase-separated and uniformly mixed aGUVs. To account for this variability, we developed a population-based, coupled-distributions framework that enables robust determination of the asymmetric miscibility boundary, defined as the outer leaflet composition at which macroscopic phase separation is suppressed. Independent analyses of probe-exit and probe-entry data yielded consistent boundary locations. Comparing the two lipid systems, we find that aGUVs containing 14:1-PC require significantly greater outer leaflet exchange to abolish phase separation than those containing 16:1-PC. Only in the 14:1-PC system do we observe vesicles exhibiting coexistence of distinct anti-registered phases, a theoretically predicted but rarely observed regime consistent with large hydrophobic mismatch. By expressing both symmetric and asymmetric miscibility boundaries in a common fractional-coordinate framework, we introduce a phenomenological parameter, Δ ∗ , that quantifies the direction and strength of interleaflet coupling of phase behavior. Together, these results demonstrate that modest changes in lipid chain length can markedly alter asymmetric miscibility boundaries and provide a quantitative link between experimental observations, leaflet dominance concepts, and coupled-leaflet theories of membrane organization.
    Statement of Significance: Membrane asymmetry is a defining feature of eukaryotic cells whose influence on lateral membrane organization remains unclear. Using asymmetric giant vesicles, we find that coexisting liquid-ordered and liquid-disordered domains transition to a uniform appearance as saturated lipid in the outer leaflet is replaced with unsaturated lipid. The extent of exchange required to disrupt phase separation increased with acyl-chain length mismatch, revealing a compositional dependence of interleaflet coupling. In mixtures with greater hydrophobic mismatch, we also observe coexisting anti-registered phases predicted by theory but rarely observed experimentally, providing new constraints for models of coupled-leaflet behavior. By accounting for vesicle-to-vesicle compositional variability, these results provide a framework for measuring asymmetric miscibility boundaries and for connecting asymmetric membrane organization to lipid raft phenomena.
    DOI:  https://doi.org/10.64898/2026.02.17.706271
  12. Nat Cancer. 2026 Feb 24.
    The GENEVA platform models tumor mosaicism to reveal variations of responses to KRAS inhibitors and identify improved drug combinations.
    Johnny X Yu, Jung Min Suh, Katerina D Popova, Kristle Garcia, Tanvi Joshi, Bruce Culbertson, Jessica B Spinelli, Vishvak Subramanyam, Kevin Lou, Trey Charbonneau, Kevan M Shokat, Jonathan Weissman, Hani Goodarzi.
      The clinical success of cancer drug candidates depends on efficacy across many different individuals. Because xenografts are challenging to scale, we currently rely on a limited set of in vivo preclinical models. Here, to address this limitation, we introduce GENEVA, a scalable single-cell-resolution platform for measuring responses to drug perturbations. GENEVA models cancer genetic diversity by combining multiple patient-derived cell lines and cancer cell lines into pooled three-dimensional cultures and xenograft models, allowing us to study drug responses across a wide range of genetic backgrounds within a single experiment. We apply GENEVA to investigate KRAS-G12C inhibitors and demonstrate that mitochondrial activation is a key driver of cell death following KRAS inhibition, while epithelial-to-mesenchymal transition is a prominent resistance mechanism. These findings highlight the utility of GENEVA to identify therapeutic targets and optimize combination therapies with the potential to bridge the gap between preclinical cancer models and patient outcomes.
    DOI:  https://doi.org/10.1038/s43018-026-01130-5
  13. Mol Biol Cell. 2026 Feb 25. mbcE24030109
    Autophagosome turnover requires Arp2/3 complex-mediated maintenance of lysosomal integrity.
    Corey J Theodore, Lianna H Wagner, Kenneth G Campellone.
      Autophagy is an intracellular degradation process that maintains homeostasis, responds to stress, and plays key roles in preventing aging and disease. Autophagosome biogenesis, vesicle rocketing, and autolysosome tubulation are controlled by multiple actin cytoskeletal factors, but the impact of actin assembly on completion of the autophagic degradation pathway is not well understood. Here we studied autophagosomes and lysosomes in mouse fibroblasts harboring an inducible knockout (iKO) of the Arp2/3 complex, an essential actin nucleator. Arp2/3 complex ablation resulted in increased basal levels of autophagy receptors and lipidated membrane proteins from the LC3 and GABARAP families. Such phenotypes were accompanied by the steady-state presence of abnormally high numbers of autolysosomes and an inability of the Arp2/3 complex-deficient cells to complete autolysosome turnover due to lysosomal damage. When normal cells were treated with a lysosomal membrane-disrupting agent, the Arp2/3-activating protein WHAMM was recruited to lysosomes, and Arp2/3 complex activity was required for restoring intact lysosomal structure. Deletion of WHAMM in mouse or human fibroblasts decreased Arp2/3 localization to lysosomes and increased lysosomal damage. These results reveal the importance of the Arp2/3 complex and WHAMM for autophagic degradation and uncover a new role for the actin nucleation machinery in maintaining lysosomal integrity.
    DOI:  https://doi.org/10.1091/mbc.E24-03-0109
  14. Eur J Cancer. 2026 Feb 03. pii: S0959-8049(26)00035-3. [Epub ahead of print]236 116255
    FGTI-2734 prevents ERK-mediated resistance and enhances MRTX1133 efficacy in KRAS G12D pancreatic cancer.
    Deblina Ghosh, Aslamuzzaman Kazi, Hitesh Kumar Kantilal Vasiyani, Vignesh Vudatha, Nicolas Lecomte, Christine Iacobuzio-Donahue, Jose Trevino, Said M Sebti.
       INTRODUCTION: The KRAS G12D inhibitor MRTX1133 represents a major advance in targeting oncogenic KRAS, but adaptive resistance driven by ERK reactivation, dependent on wild-type (WT) RAS membrane localization, limits its efficacy.
    RESULTS: Here, we identify a rational strategy to overcome this resistance mechanism using FGTI-2734, a dual farnesyltransferase (FT) and geranylgeranyltransferase-1 (GGT-1) inhibitor that disrupts WT RAS membrane localization. FGTI-2734 blocks MRTX1133-induced ERK feedback reactivation and synergizes with MRTX1133 to inhibit proliferation and induce apoptosis in KRAS G12D pancreatic cancer cell lines. Across organoids derived from 12 patients with KRAS G12D pancreatic cancer, including those with primary and metastatic tumors with diverse genetic alterations (KRAS, TP53, CDKN2A, SMAD4, RTKs, PI3K/AKT, JAK/STAT, DNA repair/cell cycle, and chromatin modifiers), the MRTX1133/FGTI-2734 combination produced robust synergy regardless of tumor stage, treatment status, or MRTX1133 resistance. In vivo, FGTI-2734 enhanced MRTX1133 anti-tumor activity, driving significant tumor regression in orthotopic patient-derived xenografts from a KRAS G12D pancreatic cancer patient who relapsed after radiation and chemotherapy, as well as KRAS G12D human pancreatic tumor cell xenografts. Notably, treatment of mice with FGTI-2734 inhibited MRTX1133-induced ERK reactivation in KRAS G12D pancreatic cancer xenografts.
    CONCLUSION: These findings establish a combination strategy that overcomes a significant mechanism of resistance to MRTX1133 and offer a potential treatment option for pancreatic cancers, including those refractory to current therapies.
    Keywords:  FGTI-2734; Farnesyltransferase; Geranylgeranyltransferase-1; KRAS G12D; MRTX1133; Pancreatic cancer; Resistance
    DOI:  https://doi.org/10.1016/j.ejca.2026.116255
  15. bioRxiv. 2026 Feb 10. pii: 2026.02.09.704975. [Epub ahead of print]
    Systemic hypoxia suppresses solid tumor growth.
    Ayush D Midha, Brandon T L Chew, Benedict M H Choi, Jung Min Suh, Chris Carpenter, Alan H Baik, Tej A Joshi, Skyler Y Blume, Augustinus G Haribowo, Pedro Ruivo, Will R Flanigan, Ankur Garg, Daniel D Zhang, Vishvak Subramanyam, Rebecca Shuere, Youngho Seo, Henry VanBrocklin, Hani Goodarzi, Isha H Jain.
      Local hypoxia is a hallmark of solid tumors and a negative prognostic factor in the progression and treatment of cancer. Here, we showed that systemic hypoxia, in contrast to localized tumor hypoxia, decreases tumor growth in vivo across multiple cancer types and preclinical models. The reduced tumor growth in systemic hypoxia was not explained by hypoglycemia, hypoinsulinemia, or HIF activation. Instead, metabolite profiling in tumors and tumor interstitial fluid revealed extensive perturbations in purine-related metabolites. Stable isotope tracing demonstrated that systemic hypoxia caused tumors to suppress de novo purine synthesis. Furthermore, tumors did not develop resistance to systemic hypoxia therapy, and when used in combination with chemotherapy or immunotherapy, systemic hypoxia dramatically suppressed tumor growth. Finally, we showed that systemic hypoxia can be achieved pharmacologically with the small molecule HypoxyStat. These findings challenge the long-held paradigm of hypoxia as a negative prognostic factor in cancer progression, and they suggest a potential therapeutic role for systemic hypoxia in suppressing solid tumor growth.
    DOI:  https://doi.org/10.64898/2026.02.09.704975
  16. Autophagy Rep. 2026 ;5(1): 2626661
    Microautophagy: current understanding of its molecular mechanisms and functions.
    Yasuyoshi Sakai, Christian Behrends, Jayanta Debnath, Masanori Izumi, Andreas Jenny, Maurizio Molinari, Shuhei Nakamura, Masahide Oku, Marisa S Otegui, Laura Santambrogio, Han-Ming Shen, Tomohiko Taguchi, Michael Thumm, Takashi Ushimaru, Zhiping Xie, Ana Maria Cuervo, Fulvio Reggiori.
      Microautophagy (MI-autophagy) is an umbrella term for intracellular degradative pathways that entail the invagination or protrusion of the limiting membranes of endolysosomal compartments, that is, late endosomes and mammalian lysosomes or yeast and plant vacuoles, followed by pinching-off of the membrane into the lumen of the organelle. During these processes, the material specifically and nonspecifically targeted for degradation is sequestered within the invaginating or protuberating membrane. In contrast to macroautophagy, the molecular mechanisms underlying MI-autophagy are largely unknown due to their diversity and complexity in location, regulation and molecular machinery requirements. Here, we review recent progress in the field of MI-autophagy, describing the molecular basis and functions of the MI-autophagic pathways reported to date in eukaryotic cells, from yeast to mammalian and plant cells.
    Keywords:  Endosomes; lysosomes; multivesicular bodies; organelle turnover; proteolysis; vacuole
    DOI:  https://doi.org/10.1080/27694127.2026.2626661
  17. Nat Commun. 2026 Feb 27.
    Beta cell-derived cholecystokinin drives obesity-associated pancreatic adenocarcinoma development.
    Cathy C Garcia, Aarthi Venkat, Daniel C McQuaid, Sherry S Agabiti, Alexander Tong, Boby Mathew, Rebecca L Cardone, Rebecca Starble, Christian F Ruiz, Christy Zheng, Akin Sogunro, Jeremy B Jacox, Ken H Loh, Richard G Kibbey, Smita Krishnaswamy, Mandar Deepak Muzumdar.
      Pancreatic endocrine-exocrine crosstalk plays a key role in normal physiology and disease and can be altered by host metabolic states, such as obesity. Classically, endocrine islet beta (β) cell secretion of insulin is thought to promote the development of obesity-associated pancreatic adenocarcinoma (PDAC), an exocrine cell-derived tumor. Here, we show that β cell expression of the peptide hormone cholecystokinin (CCK) is necessary and sufficient for obesity-associated PDAC progression in mice and that CCK expression - rather than insulin - correlates strongly with enhanced tumorigenesis. Single-cell RNA-sequencing, in silico latent-space archetypal and trajectory analysis, and experimental lineage tracing in vivo reveal that obesity induces the expansion of postnatal immature β cells, which adapt to express CCK via stress-responsive JNK/cJun signaling. Finally, obesity perturbs CCK-dependent peri-islet exocrine cell transcriptional states and enhances islet-proximal tumor formation. These results define endocrine-exocrine CCK signaling as a bona fide driver of obesity-associated PDAC development and uncover avenues to target the endocrine pancreas to subvert exocrine tumorigenesis.
    DOI:  https://doi.org/10.1038/s41467-026-69821-2
  18. Am J Physiol Cell Physiol. 2026 Feb 21.
    High Fat Diet and Obesity Each Increase Tumor Cell Proliferation and Muscle Wasting in Experimental Cancer Cachexia.
    Brittany R Counts, Andrea Bonetto, Ho Lam Chan, Ernie D Au, Yanlin Jiang, Marion E Couch, Denis C Guttridge, Michael C Ostrowski, Leonidas G Koniaris, Teresa A Zimmers.
      High fat diet (HFD) and associated obesity are suggested to predispose to cancer development, complicate cancer treatment, and accelerate mortality. Paradoxically, obese patients with lung cancer are reported to live longer, suggesting that high body mass is protective. Given that cachexia-tumor-induced weight loss with adipose and muscle wasting-is prevalent in lung cancer, we speculated that obese patients might survive longer due to the protective effect of larger tissue reservoirs, slowing time to fatal wasting. Thus, we modeled this condition using lean and high fat diet (HFD)-induced obese mice with Lewis lung carcinoma (LLC) tumors versus non-tumor bearing controls. We also assessed the effects of feeding HFD to lean mice with and without LLC tumors. HFD and obese-HFD without tumors gained weight over the study, with obese HFD mice exhibiting low muscle mass with obesity at endpoint. Low fat diet (LFD)-fed lean mice with LLC tumors (LFD-LLC) showed no change in total body weight, but exhibited reduced skeletal muscle, heart, and fat pad mass along with hepatosplenomegaly at endpoint. HFD and pre-existing obesity both modified the response to Lewis lung carcinoma (LLC) tumors. HFD did not affect tumor-induced weight loss, fat loss, or tumor burden, but worsened loss of gastrocnemius, tibialis anterior, and heart muscle, prevented hepatosplenomegaly, and enhanced tumor cell proliferation and expression of the cachexia-inducing cytokine, Interleukin-6 (IL-6). Obese-HFD mice showed greater tumor burden versus LFD and the worst cachexia phenotypes, including greater weight loss and muscle loss than HFD or LFD. This worsened cachexia was associated with increased blood-born inflammatory cytokines, increased phosphorylated STAT3 in muscle, and increased IL-6 expression in muscle, spleen, and tumor. Obese-HFD was associated with the highest rate of tumor cell proliferation in vivo and serum from obese HFD mice increased LLC cell proliferation in vitro. Thus, HFD and pre-existing obesity each separately enhance inflammation, cachexia, and tumor growth. These distinct contributions of HFD and chronic adiposity are potential therapeutic targets to slow cachexia and tumor growth in cancer.
    Keywords:  Interleukin-6; cancer cachexia; high fat diet; obesity; skeletal muscle
    DOI:  https://doi.org/10.1152/ajpcell.00545.2025
  19. Oncologist. 2026 Feb 25. pii: oyag023. [Epub ahead of print]
    Atezolizumab and Motixafortide, Cobimetinib or Simlukafusp Alfa in Pretreated Advanced Pancreatic Cancer: Phase I/IIb MORPHEUS-PDAC Umbrella Study.
    Gulam A Manji, Vincent Chung, Do-Youn Oh, Jill Lacy, Charles D Lopez, Mariano Ponz-Sarvisé, Teresa Macarulla, Roby Thomas, Ben George, Angela Alistar, Jens T Siveke, Yun Xu, Janet Lau, Edward Cha, Kyu-Pyo Kim, Eileen M O'Reilly.
       BACKGROUND: The MORPHEUS platform comprised multiple open-label, randomized, phase Ib/II trials to identify early signals with different treatment combinations across multiple cancers. MORPHEUS-PDAC (NCT03193190) evaluated atezolizumab combinations in pancreatic ductal adenocarcinoma (PDAC). We describe outcomes with atezolizumab plus either motixafortide, cobimetinib, or two simlukafusp alfa regimens.
    METHODS: Eligible patients with advanced, pretreated PDAC were randomized to receive second-line (2 L) atezolizumab plus either motixafortide (BL8040; n = 15), cobimetinib (n = 14), simlukafusp alfa every 2 weeks (q2w; n = 15), or simlukafusp alfa every 3 weeks (q3w; n = 16); or control (mFOLFOX6 [n = 25] or gemcitabine plus nab-paclitaxel [n = 25]). Patients experiencing disease progression or toxicity who met eligibility criteria were enrolled to receive third-line (3 L) atezolizumab plus cobimetinib (n = 14), or atezolizumab plus simlukafusp alfa q2w (n = 1) or q3w (n = 6). Primary endpoints were objective response rates (ORRs) per RECIST 1.1 and safety.
    RESULTS: ORRs were 7.1% with atezolizumab-simlukafusp alfa q2w, 8.7% with mFOLFOX6 (both 2 L; 0% in other arms), 14.3% with atezolizumab-cobimetinib, and 16.7% with atezolizumab-simlukafusp alfa q3w (both 3 L). Grade 3-5 adverse event rates were 53.3% (2 L atezolizumab-motixafortide), 64.3% (2 L atezolizumab-cobimetinib), 57.1% (2 L atezolizumab-simlukafusp alfa q2w), 53.3% (2 L atezolizumab-simlukafusp alfa q3w), 63.0% (2 L mFOLFOX6 or gemcitabine-nab-paclitaxel), 50.0% (3 L atezolizumab-cobimetinib), and 100% (3 L atezolizumab-simlukafusp alfa q3w).
    CONCLUSIONS: The overall safety of atezolizumab combinations was manageable and consistent with each agent's known safety profile. This novel trial design enabled rapid evaluations of three atezolizumab combinations; all had limited efficacy as 2 L or 3 L treatment for metastatic PDAC. New treatments are needed to improve outcomes in previously treated PDAC.
    Keywords:  CXCR4 inhibitor; FAP-IL2v; MAP/ERK kinase inhibitor; atezolizumab combination; immunotherapy; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.1093/oncolo/oyag023
  20. bioRxiv. 2026 Feb 16. pii: 2026.02.15.706013. [Epub ahead of print]
    Cell enlargement drives aging-associated proteome remodeling and shortens replicative lifespan.
    Michael C Lanz, Manuel Hotz, Rachel Kroll-Ling, Eileen Wang, Jabob Kim, Joshua E Elias, Daniel E Gottschling, Jan M Skotheim.
      The molecular and cellular basis of aging and its associated functional decline remains poorly understood. Even free-living microorganisms age and, in yeast, replicative aging shares key hallmarks with human cellular senescence, including progressive cell enlargement. Recent work has shown that chemical and genetic manipulations that increase cell size promote the onset of senescence in both yeast and human cells, suggesting that cell enlargement can drive some of the physiological changes associated with aging. Here, we quantitatively determined how cell enlargement contributes to age-associated physiology in yeast by combining automated aging technologies with quantitative proteomics. We find that the majority of aging-associated proteome remodeling can be recapitulated by genetically enlarging young proliferating cells. These enlarged cells exhibit accelerated proteome aging and shortened replicative lifespans, while smaller cells are longer-lived. While cell enlargement is the predominant factor driving proteome remodeling during aging, we also identified a minority of aging-specific molecular markers whose expression influences lifespan. Together, our results demonstrate that cell enlargement is a major driver of aging-associated proteome remodeling and influences lifespan independently of established aging factors such as extrachromosomal rDNA circles.
    DOI:  https://doi.org/10.64898/2026.02.15.706013
  21. bioRxiv. 2026 Feb 09. pii: 2026.02.06.704469. [Epub ahead of print]
    SenNet Portal: Build, Optimization and Usage.
    SenNet Team
      Cellular senescence is a hallmark of aging and a driver of functional decline across tissues, yet its heterogeneity and context dependence have limited systematic study. The Common Fund's Cellular Senescence Network (SenNet) Program addresses this challenge by generating multimodal, multi-tissue datasets that profile senescent cells across the human lifespan and complementary mouse models. The SenNet Data Portal ( https://data.sennetconsortium.org ) serves as the public gateway to these resources, providing open access to harmonized single-cell, spatial, imaging, transcriptomic, and proteomic data; senescence biomarker catalogs; and standardized protocols that can be used to comprehensively identify and characterize senescent cells in mouse and human tissue. As of January 2026, the portal hosts 1,753 publicly available human and mouse datasets across 15 organs using 6 general assay types. Experts from 13 Tissue Mapping Centers (TMCs) and 12 Technology Development and Application (TDAs) components contribute tissue data, analyze data, identify senescent biomarkers, and agree on panels for cross-tissue antibody harmonization. They also register human tissue data into the Human Reference Atlas (HRA) and develop user interfaces for the multiscale and multimodal exploration of this data. Built on a scalable hybrid cloud microservices architecture by the Consortium Organization and Data Coordinating Center (CODCC), the Portal enables data submission, management, integrated analysis, spatial context mapping, and cross-species senescence mapping critical for aging research. This paper presents user needs, the Portal's architecture, data processing workflows, and senescence-focused analytical tools. The paper also presents usage scenarios illustrating applications in biomarker discovery, quality benchmarking, hypothesis generation, spatial analysis, cost-efficient profiling, and cell distance distribution analysis. Current limitations and planned extensions-including expanded spatial-omics releases and improved tools for senotype characterization-are discussed. SenNet protocols, code, and user interfaces are freely available on https://docs.sennetconsortium.org/apis .
    DOI:  https://doi.org/10.64898/2026.02.06.704469
  22. Nat Rev Clin Oncol. 2026 Feb 24.
    Translating ferroptosis into oncology: challenges, opportunities and future directions.
    Rui Kang, Jiao Liu, Jiayi Wang, Guido Kroemer, Daolin Tang.
      Ferroptosis is an oxidative, lipid peroxidation-driven form of regulated cell death that occurs when antioxidant and organelle-protective systems are compromised. Increasing evidence implicates ferroptosis as a process that can exert both tumour-suppressive and tumour-promoting effects depending on cellular context at multiple stages of cancer evolution (from tumour initiation to metastatic colonization), sparking substantial interest in therapeutically exploiting this mechanism of cell death. Yet, despite rapid preclinical progress, clinical translation of ferroptosis-based strategies remains nascent. In this Review, we examine the major barriers to translation, including pharmacological limitations, tumour-intrinsic heterogeneity, microenvironmental and immune constraints, and gaps in current preclinical modelling. We also highlight emerging opportunities such as new ferroptosis-inducing agents, biomarker-guided patient selection and rational combinations with chemotherapy, radiotherapy, targeted agents or immunotherapies. Finally, we outline a translational roadmap for integrating ferroptosis-based therapies into oncology practice. By defining key challenges and future directions, this Review aims to position ferroptosis as a viable therapeutic paradigm and to accelerate progress towards clinical application.
    DOI:  https://doi.org/10.1038/s41571-026-01128-z
  23. Cell Death Dis. 2026 Feb 21.
    Targeting mitochondrial phosphatase PGAM5 alleviates ferroptosis and acute pancreatitis by upregulating NRF2-mediated FSP1 expression.
    Shuang Ma, Jianhua Qin, Jing Luan, Guoyan Hou, Jiyuan He, Minghui Gao.
      Ferroptosis is a regulated necrosis that is driven by iron-dependent lipid peroxidation. Phosphoglycerate mutase 5 (PGAM5), as a mitochondrial signaling hub, modulates mitochondrial dynamics, senses mitochondrial stress, and regulates the anti-oxidative response. However, the function of PGAM5 in ferroptosis remains elusive. Here, we discovered that PGAM5 emerges as a critical regulator of ferroptosis, with both genetic deletion and overexpression conferring protection against ferroptosis by upregulating nuclear factor erythroid 2-related factor 2 (NRF2) mediated ferroptosis suppressor protein 1 (FSP1) expression. On the one hand, dyregulation of PGAM5 upregulates NRF2 expression transcriptionally and inhibits its polyubiquitination. On the other hand, modulating the expression of PGAM5 results in energy stress ([AMP + ADP]/[ATP] ratio increase) and AMP-activated protein kinase (AMPK) activation. AMPK-dependent phosphorylation of NRF2 drives its nuclear accumulation, where it transcriptionally upregulates FSP1 to promote cell survival. Furthermore, pharmacological inhibition of PGAM5 attenuates arginine-induced acute pancreatitis, highlighting its therapeutic potential. Our findings establish PGAM5 as a central node in ferroptosis regulation and implicate its pathogenic role in acute pancreatitis.The molecular mechanism of alleviation of ferroptosis by dysregulation of PGAM5.
    DOI:  https://doi.org/10.1038/s41419-026-08484-9
  24. Mol Cell. 2026 Feb 26. pii: S1097-2765(26)00099-7. [Epub ahead of print]
    Aspartate availability drives differential engagement of the malate-aspartate shuttle.
    Julia S Brunner, Anna E Bridgeman, Benjamin T Jackson, Sangita Chakraborty, Maider Fagoaga-Eugui, Katrina I Paras, Abigail Xie, Paige K Arnold, Julia Losner, Lydia W S Finley.
      The malate-aspartate shuttle is a major electron shuttle that transfers reducing equivalents from the cytosol to the mitochondria, where they can be safely deposited onto the electron transport chain. Nevertheless, many proliferating cells discard reducing equivalents in the form of lactate, raising the question of what factors limit electron shuttle use. Here, we show that aspartate availability determines engagement of the malate-aspartate shuttle. In proliferating cells, increasing aspartate availability enhances use of the malate-aspartate shuttle and increases metabolism of glucose-derived pyruvate in mitochondria, a process that requires regeneration of oxidized electron carriers in the cytosol. During differentiation, elevated flux through the malate-aspartate shuttle cells enables cells to fuel mitochondrial networks from glucose-derived carbon. Engineering aspartate demand reverses this metabolic signature of differentiated cells. Together, these results demonstrate that cell-state-specific demand for aspartate is sufficient to determine use of the malate-aspartate shuttle and drives changing mitochondrial substrate preferences during differentiation.
    Keywords:  GOT1; GOT2; TCA cycle; Warburg effect; aspartate; differentiation; electron shuttles; malate-aspartate shuttle; metabolism; proliferation
    DOI:  https://doi.org/10.1016/j.molcel.2026.02.004
  25. Int J Mol Sci. 2026 Feb 19. pii: 1984. [Epub ahead of print]27(4):
    Lipid Regulation of Mechanosensitive Ion Channels.
    Yurou Cai, Claudia Bauer, Jian Shi.
      Mechanosensitive ion channels (MSCs) are fundamental transducers that convert mechanical forces into electrochemical signals, enabling cells to regulate processes such as Ca2+ homeostasis, migration, proliferation, and adhesion. Located in both plasma and organellar membranes, MSCs, including Piezos, TRPs, K2Ps, MscL, and MscS families exhibit diverse ion selectivity, gating mechanisms and physiological roles. Emerging evidence demonstrates that lipids are dynamic regulators of MSC activation, sensitivity, and kinetics. Endogenous membrane lipids such as cholesterol, phospholipids, sphingolipids and fatty acids modulate MSC behavior by altering bilayer tension, curvature, stiffness and protein-lipid interactions. Exogenous lipids, including dietary fatty acids and lipid-derived metabolites, influence MSCs by modifying membrane physical properties or engaging specific lipid-binding sites on channel proteins. These interactions shape fundamental biological processes and contribute to disease mechanisms in cardiovascular dysfunction, neurological disorders, metabolic disease, and cancer. Despite significant progress, the molecular principles by which lipids regulate MSC conformational transitions and force sensing remain incompletely defined. This review synthesizes current knowledge on endogenous and exogenous lipid modulation of MSCs, integrating structural, computational and electrophysiological insights to highlight emerging therapeutic opportunities targeting lipid-mechanotransduction interfaces.
    Keywords:  K2P channel; Msc channel; TRP channel; fatty acids; lipids; mechanosensitive ion channels; piezo channel; regulation
    DOI:  https://doi.org/10.3390/ijms27041984
  26. Curr Protoc. 2026 Mar;6(3): e70324
    Light Microscopy-Based Organelle Quantification: A Comprehensive Protocol.
    Suraj Thapliyal, Hari Kalpana Namdar, Ronald McMillan, Jermiah Afolabi, Andrea Marshall, Prasanna Venkhatesh, Ravi Kumar Pujala, Antentor Hinton, Hailey A Parry, Brian Glancy, Prasanna Katti.
      Cellular organelles are not just static structures; they are highly dynamic and directly linked to cellular functions. Changes in their morphology can be early indicators of diseases. Recent advancements in light microscopy techniques have transformed organelle research from qualitative descriptions to precise, quantitative measurements, enabling nanoscale resolution, high-throughput image analysis, and live-cell compatibility. This enables accurate measurement of organelle morphology, dynamics, and spatial organization using modern imaging and analysis techniques. By quantifying organelles, we go beyond simply visualizing to measuring and statistically comparing cellular features across different samples. This article addresses a wide range of cellular organelles across all major experimental systems, specifically mentioning mitochondria, myofibers, actin filaments, endoplasmic reticulum, and Golgi apparatus, by integrating experimental design, optimized sample preparation, high-resolution imaging, and validated Fiji/ImageJ-based analysis workflows. For each organelle, step-by-step protocols specify reagents, equipment, acquisition parameters, and expected results. Although recent advances, such as expansion microscopy, correlative light-electron microscopy, and AI-powered segmentation, offer gains in throughput and resolution, this workflow demonstrates that Fiji-based analysis remains fully capable of delivering high-precision organelle quantification. The entire workflow can be completed within 2-4 weeks, from initial design through validation and the production of measurements suitable for cross-study comparisons. Overall, these protocols establish a flexible approach to standardizing organelle quantification so as to understand multiple organelles simultaneously in their cellular contexts. © 2026 Wiley Periodicals LLC. Basic Protocol 1: Mitochondrial quantification Basic Protocol 2: Lipid droplet identification and image processing Basic Protocol 3: Myofibril quantification Basic Protocol 4: Golgi apparatus morphometry Basic Protocol 5: Endoplasmic reticulum network analysis Alternate Protocol: Super-resolution imaging protocol.
    Keywords:  Fiji/ImageJ; confocal microscopy; image analysis; morphometric analysis; organelle quantification
    DOI:  https://doi.org/10.1002/cpz1.70324
  27. Acta Physiol (Oxf). 2026 Apr;242(4): e70183
    pH-Dependent Microenvironmental Ionic Signaling in Pancreatic Ductal Adenocarcinoma.
    Albrecht Schwab, Micol Rugi, Pawel Swietach, Wiktoria Błaszczak, Ivana Novak, Ganga Deshar, Stine Falsig Pedersen, Renata Ialchina, Albin Sandelin, Jiayi Yao, Stephan J Reshkin, Rosa A Cardone, Tiago M A Carvalho, Annarosa Arcangeli, Rayhana Bouazzi, Franco N D'Alessandro, Natalia Prevarskaya, Madelaine M Audero, Halima Ouadid-Ahidouch, Julie Schnipper, Luis A Pardo, Xiaoyi Shi, Frauke Alves, Jakub Mitręga, Anna Trauzold, Sofie E Hagelund, György Panyi, Marco Cozzolino, Clemens M W G Löwik, Laura Mezzanotte, Roisin McMorrow, Andreas Pahl, Torsten Hechler, Elena Papacharisi, Alessandra Fiorio Pla, Ildiko Szabo, Verena Hofschröer, Zoltán Pethő.
       AIM: Pancreatic ductal adenocarcinoma (PDAC) develops within a uniquely dynamic pH landscape shaped by substantial acid-base fluxes produced by the exocrine pancreas. Secretion of alkaline pancreatic juice, normally linked to digestion, produces intermittent acidifications of the pancreatic interstitium, which challenges epithelial and stromal cells. It was postulated that these unique pancreatic pH dynamics can facilitate PDAC initiation and progression through selection of a more aggressive phenotype emerging with PDAC driver mutations.
    METHODS: Here, we summarize evidence that pH-regulatory transport proteins have an important role in shaping the PDAC microenvironment.
    RESULTS: pH-regulatory transport proteins generate and sense their microenvironment and act as signaling hubs to regulate proliferation, migration, and metabolism, and immune evasion. In this way, transport proteins that are crucial for the normal physiology of the exocrine pancreas are misused and become coerced into playing a pro-cancer role in pancreatic tumor cells, pancreatic stellate cells, or infiltrating immune cells. Experiments with PDAC mouse models revealed a therapeutic potential of targeting pH dynamics, notably by inhibition or genetic ablation of pH-regulatory proteins. It is a consistent finding that these maneuvers have a marked impact on the tumor immune defense and the communication between cancer and immune cells.
    CONCLUSION: Collectively, we present a case for considering pH-regulating proteins as a therapeutic avenue.
    DOI:  https://doi.org/10.1111/apha.70183
  28. Cancer Res. 2026 Feb 24.
    Acting on dormancy: the interplay between the actin cytoskeleton and tumor cell dormancy.
    Hayley M Sabol, Jose Javier Bravo-Cordero, Lucia Borriello.
      Dormant disseminated tumor cells (DTCs) can survive long term and drive metastatic relapse years to decades after primary tumor treatment, which remains a major clinical problem. EMT allows these dormant cells to evade immune surveillance, highlighting a potential therapeutic target to prevent metastatic recurrence. In a recent study, Wang ad colleagues demonstrated that a transforming growth factor-β (TGF-β) driven atypical or hybrid EMT state allows lung adenocarcinoma cells to evade the immune system and persist in a dormant state. This atypical EMT state relies on the upregulation of the cytoskeletal protein gelsolin, which mediates the conversion to round, softer cells, that are resistant to immune surveillance and promote dormant cell survival. The inhibition of TGF-B or gelsolin prevents the change in cell morphology, and the cells remain stiff and become susceptible to immune clearance in vivo. This study identifies a novel vulnerability of dormant tumor cells that could be exploited to eliminate dormant DTCs and prevent metastatic relapse.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-0793
  29. Nat Metab. 2026 Feb 23.
    Fatty acids promote uncoupled respiration via ATP/ADP carriers in white adipocytes.
    Maryam Ahmadian, A Melisa Aksu, Preetveer Dhillon, Zane J Zerbel, Yosip Kelemen, Oluwafemi Gbayisomore, Nicolás Gómez-Banoy, Serena J Chen, Shannon M Reilly.
      Energy stored in adipocytes as triglycerides is mobilized via lipolysis, releasing fatty acids and glycerol into the circulation. Re-esterification of fatty acids that remain within the adipose tissue is the primary driver of adipocyte ATP consumption. Paradoxically, re-esterification suppresses respiration in lipolytic adipocytes. We previously found that STAT3 drives respiration by inhibiting re-esterification via GPAT3. Here we show that free fatty acids drive uncoupled respiration in complex with the ATP/ADP carriers. The impacts of lipolysis and re-esterification on uncoupled respiration correspond with fatty acids, not fatty acyl-CoAs or beta-oxidation. Under standard housing conditions, brown adipocyte uncoupling via uncoupling protein 1 is the dominant thermogenic pathway. However, in obese thermoneutral-adapted mice, uncoupled respiration in white adipocytes contributes to thermogenesis and cold tolerance, independent of brown adipose tissue or muscle activity. Our results suggest that uncoupled respiration in white adipocytes contributes to whole-body energy expenditure and could be a promising target for obesity treatment.
    DOI:  https://doi.org/10.1038/s42255-026-01467-2
  30. Nature. 2026 Feb 25.
    CLCC1 promotes hepatic neutral lipid flux and nuclear pore complex assembly.
    Alyssa J Mathiowetz, Emily S Meymand, Güneş Parlakgül, Niek van Hilten, Emily F Torres, Leonardo L Artico, Kirandeep K Deol, Mike Lange, Stephany P Pang, Cody E Doubravsky, Melissa A Roberts, Danielle M Jorgens, Reena Zalpuri, Misun Kang, Casadora Boone, Brian W Parks, Yaohuan Zhang, David W Morgens, Emily Tso Newman, Yingjiang Zhou, Saswata Talukdar, Michael Grabe, Gregory Ku, Tim P Levine, Ana Paula Arruda, James A Olzmann.
      Imbalances in lipid storage and secretion lead to hepatic steatosis, the accumulation of lipid droplets in hepatocytes1,2. Our understanding of the mechanisms that govern the channelling of neutral lipids in hepatocytes towards cytosolic lipid droplets or secreted lipoproteins remains incomplete3,4. Here we performed a series of CRISPR-Cas9 screens under different metabolic states that led to the identification of CLCC1 as a critical regulator of neutral lipid storage and secretion in hepatocytes. Loss of CLCC1 resulted in the buildup of large lipid droplets in hepatoma cells and Clcc1 knockout in mice caused liver steatosis. Lipid droplets were present in the lumen of the endoplasmic reticulum of the Clcc1-knockout hepatocytes and exhibited properties of lipoproteins, indicating a profound shift in neutral lipid flux. The loss of CLCC1 also led to the accumulation of nuclear membrane herniations accompanied by a reduction in nuclear pores. Remote homology searches identified a domain in CLCC1 that is homologous to yeast Brl1 and Brr6, factors that promote nuclear envelope fusion during nuclear pore complex assembly. Molecular dynamics simulations and mutagenesis studies support a model in which CLCC1 mediates membrane bending and fusion. We propose that CLCC1 mediates membrane fusion to promote hepatic neutral lipid flux and nuclear pore complex assembly.
    DOI:  https://doi.org/10.1038/s41586-025-10064-4
  31. J Exp Clin Cancer Res. 2026 Feb 25.
    A translational colorectal cancer organoid biobank mirrors patients' tumor histology, molecular profiles, and treatment responses.
    Moritz Jesinghaus, Miguel Gomes Silva, Antonio Enrico Zaurito, Valentina Brunner, Frederic Saab, Anantharamanan Rajamani, Niklas de Andrade Krätzig, Nicholas Bodenstein, Rémi Guillemant, Junika Pohl, Maxime Schmitt, Rupert Öllinger, Federico Fusco, Julius Shakhtour, Peter Klare, Klaus-Peter Janssen, Sebastian Foersch, Katja Steiger, Roland Rad, Nicole Pfarr, Dieter Saur, Markus Tschurtschenthaler.
       BACKGROUND: Colorectal cancer (CRC) exhibits pronounced inter- and intratumoral heterogeneity, emphasizing the need for preclinical models that accurately capture its molecular and histological diversity. Patient-derived organoids (PDOs) represent valuable ex vivo systems to model CRC, yet whether they can preserve subtype-specific features and maintain fidelity upon in vivo transplantation remains unclear.
    METHODS: We established a biobank of PDOs from both treatment-naïve and neoadjuvant-treated CRC patients, encompassing the major histological subtypes - micropapillary, medullary, serrated, mucinous, and adenocarcinoma not otherwise specified (NOS). PDOs were comprehensively characterized by histomorphological, genomic, and transcriptomic analyses. To assess in vivo fidelity, PDOs were orthotopically transplanted into immunodeficient mice to generate patient-derived organoid xenografts (PDOXs). PDOX-derived tumors and organoids were analyzed to evaluate the preservation of histological and molecular traits, as well as therapy responses.
    RESULTS: PDOs displayed distinct, subtype-specific morphologies and growth patterns that closely paralleled their respective patient tumor histologies. Orthotopic PDOXs recapitulated the histological architecture, gene expression profiles, and signaling pathway activation of the original tumors. PDOX-derived organoids retained these subtype-specific morphologies, molecular features, and exhibited similar responses to FOLFOX treatment as their corresponding PDOs, confirming both molecular and functional stability of the organoid-xenograft cycle.
    CONCLUSION: This study establishes orthotopic transplantation of CRC PDOs as a robust and predictive preclinical model that captures the full spectrum of CRC heterogeneity. The model preserves histological and molecular subtype fidelity across in vitro and in vivo contexts and enables functional assessment of therapy response. By bridging patient-derived tumor biology with translational modeling, this platform provides a valuable resource for dissecting CRC pathogenesis and advancing patient-tailored precision oncology.
    Keywords:  Colorectal cancer; Histological subtypes; PDOX models; Patient-derived organoids (PDOs); Tumor heterogeneity
    DOI:  https://doi.org/10.1186/s13046-026-03666-x
  32. Autophagy. 2026 Feb 25. 1-3
    Control of phagophore membrane expansion: Atg8-Atg1 as the master switch.
    Yi-He Feng, Jing Zhu, Yu Ding, Fan Yan, Zhiping Xie.
      Autophagosome formation is catalyzed by multiple branches of Atg protein machineries, calling for the existence of a master regulator to coordinate their distinct activities. A prime candidate of such a regulator is Atg8. This protein has a well-established role in controlling phagophore expansion. But the signaling mechanism has been unclear. Our recent work demonstrates that Atg8 recruits activated Atg1 to the phagophore, together forming such a master switch. Our data indicate that different branches of Atg proteins localize to spatially separated zones. The physical distances among the zones, at times exceeding 250 nm, would limit signal transduction efficiency if a signaling molecule were exclusively localized to a single zone. By covering the phagophore surface, Atg8 maintains physical proximity to different Atg machineries, and transmits a permissive signal by recruiting activated Atg1. Compromising Atg8-mediated Atg1 recruitment leads to confinement of Atg1 to the initiation protein condensate and failure of phagophore expansion. Conversely, the Atg8-Atg1 switch can be manually augmented to substantially increase autophagosome size and autophagic flux. Our work thus reveals a critical regulatory circuit of macroautophagy/autophagy that is built on the spatial organization of Atg protein machineries.
    Keywords:  Autophagy; kinase; membrane biogenesis; membrane expansion; protein trafficking; ubiquitin-like protein
    DOI:  https://doi.org/10.1080/15548627.2026.2636092
  33. bioRxiv. 2026 Feb 11. pii: 2026.02.09.704912. [Epub ahead of print]
    miR-940 suppresses ferroptosis by controlling expression of key regulatory genes.
    Andrea Kolak, Juliane Tschuck, Stefanie A I Weiß, Daniel Kaemena, Karolin Klimm, Ana Galhoz, Larissa Ringelstetter, Myles Fennell, Juliane Merl-Pham, Anna Artati, Stefanie Strasser, Ralph Garippa, Michael Witting, Hans Zischka, Joel A Schick, Stefanie M Hauck, Michael P Menden, Michelle Vincendeau, Brent R Stockwell, Kamyar Hadian.
      Ferroptosis is a form of regulated cell death that is characterized by iron-dependent lipid peroxidation. This process is regulated by specific metabolites, the lipid composition of the cells, redox-active iron, and antioxidant mechanisms. Although numerous regulators have been identified over the past decade, exploring other mechanisms, particularly from non-coding genomic regions, can build a thorough understanding of the multifaceted regulatory processes underlying ferroptosis. MicroRNAs (miRNAs) play a crucial role in gene regulation and cellular functions. Through a CRISPR KO screen, we identified miR-940 as a negative regulator of ferroptosis. Overexpression of miR-940 in several cell lines consistently suppressed ferroptosis induced by system x c - inhibition. Notably, multiple cancer patient cohorts with elevated miR-940 levels exhibit reduced survival. Integrated bioinformatic, transcriptomic, and proteomic analyses revealed that miR-940 decreases the expression of ACSL4, LPCAT3, DMT1, and NCOA4, and simultaneously increases levels of GPX4. Pharmacological inhibition of GPX4 attenuated the protective effect of miR-940, indicating that its primary anti-ferroptotic activity is mediated through GPX4. Overall, this gene rewiring is associated with reduced levels of redox-active iron and diminished lipid peroxidation, consistent with ferroptosis suppression. These findings suggest that miR-940 coordinates ferroptosis inhibition, which presents a novel regulatory layer for therapeutic exploration in susceptible cancers.
    DOI:  https://doi.org/10.64898/2026.02.09.704912
  34. bioRxiv. 2026 Feb 18. pii: 2026.02.18.706515. [Epub ahead of print]
    3D, multi-omic imaging reveals molecular biomarkers of the pre-metastatic niche in lung cancer.
    John Michel, André Forjaz, Vasco Queiroga, Kelly Casella, Kaitlin Stivers, Helen Nguyen, Maria Browne, Feiyu Chen, Ada Tam, Omkar Dhaygude, Hongni Fan, Hitoaki Maehira, Cheng Ting Lin, Elise Gray-Gaillard, Talia L Benducci, Suguru Yamauchi, Ife Shoyombo, Ziying Xu, Eugene Shenderov, Peng Huang, Denis Wirtz, Jennifer H Elisseeff, Yun Chen, Malcolm V Brock, Ashley L Kiemen, Franck Housseau.
      The recurrence rate following complete surgical resection of primary non-small cell lung cancer is as high as 55%, yet no approach currently exists to evaluate the risk of local recurrence. The premetastatic paradigm is the recognition that metastasis is preceded by reprogramming naïve tissues to prime a microenvironment for tumor cell survival and subsequent reactivation. Identification of biomarkers of the pre-metastatic niche would allow us to evaluate a patient's risk of local relapse in the normal lung parenchyma surrounding the resected tumor. We designed a workflow incorporating in vivo modelling, radiology, and deep learning-guided three-dimensional (3D) imaging, spatial proteomics, and transcriptomics to identify previously unreported signals associated with the early transformation of the lung parenchyma announcing regional metastasis. We curated biorepository spanning timepoints before and after resection of primary Lewis Lung Carcinoma (LLC) tumors. Using radiology and cellular resolution 3D histology, we calculated the number and distribution of metastases in mouse lungs and developed an algorithm to guide placement of spatial proteomics and transcriptomics to regions containing early micro-metastases and the pre-metastatic microenvironment. Molecular and tissue features associated with presence, size, and location of metastases guided the identification of both myeloid (F4/80) and senescent (p16/p21) cell signatures in the premetastatic and metastatic environments. Finally, multiparametric flow cytometry of metastatic lungs in a senescence reporter GEMM (tdTomato-p16 INKA mice) resolved senescent cells including alveolar macrophages as the cellular phenotypes associated with these early premetastatic signatures. Altogether, this work highlights a novel AI-assisted approach for detection of biomarkers of tissue remodeling during lung cancer invasion.
    DOI:  https://doi.org/10.64898/2026.02.18.706515
  35. Nat Commun. 2026 Feb 23.
    PRMT5 in mitochondria regulates mtDNA stability through TFAM arginine methylation.
    Sangheeta Bhattacharjee, Sayan Das, Banhi Chowdhury, Benu Brata Das.
      Protein arginine methyltransferase 5 (PRMT5) catalyzes arginine methylation and regulates cellular functions such as proliferation, RNA splicing, and nuclear DNA damage response. This study uncovers that a fraction of nuclear-encoded PRMT5 localizes to the mitochondria, which is critical for maintaining mitochondrial DNA (mtDNA) homeostasis. PRMT5 knockout (PRMT5-/-) cells had reduced nucleoid counts, diminished mtDNA copy numbers, disrupted the balance of the mitochondrial fission-fusion cycle, impaired mitochondrial plasticity, and nucleoid trafficking. PRMT5-/- cells are hypersensitive to mtDNA-damaging agents, exhibit reduced mitochondrial transcripts, oxidative phosphorylation, and respiratory capacity that triggers cell death. We identify TFAM as a previously unrecognized interacting partner of PRMT5, which catalyzes symmetric dimethylation of TFAM at R82 residue, which is crucial for mtDNA binding and protection. Defective R82-methylation destabilizes TFAM, which is then degraded by LonP1. Together, we establish that PRMT5 is a mitochondrial enzyme and a key regulator of TFAM in mtDNA maintenance.
    DOI:  https://doi.org/10.1038/s41467-026-69676-7
  36. Nat Cell Biol. 2026 Feb 26.
    Mitochondria contact lipid droplets through the mitochondrial import complex binding to lipid metabolism enzyme Ayr1.
    Sandra Heinen, Vitasta Tiku, Alexander Grevel, Marie Hugenroth, Lars Ellenrieder, Isabelle Steymans, Mariya Licheva, Sara Bonini, Silke Oeljeklaus, Nicole Okon, Jessica Lambertz, Sylvia Poppe, Jiyao Song, Lars Fester, Chris Meisinger, Bettina Warscheid, Matthias Eckhardt, Nils Wiedemann, Dominic Winter, Claudine Kraft, Fabian den Brave, Maria Bohnert, Nikolaus Pfanner, Thomas Becker.
      Mitochondria play central roles in the energetics and metabolism of eukaryotic cells. Their outer membrane is essential for protein transport, membrane dynamics, signalling and metabolic exchange with other cellular compartments. The mitochondrial import (MIM) complex functions as main translocase for importing the precursors of more than 90% of integral outer-membrane proteins. Here we report that the MIM complex performs a second major function in lipid-droplet homeostasis. Lipid droplets are crucial in cellular lipid metabolism and as storage organelles for neutral lipids. The lipid metabolism enzyme Ayr1 captures the MIM complex, promoting the formation of mitochondria-lipid droplet contact sites. MIM and Ayr1 enhance the lipid droplet number in cells. Ayr1 binds to MIM via its single hydrophobic segment in a substrate-mimicry mechanism but remains bound and is not released into the outer membrane. The functional diversity is mediated by different MIM complexes: MIM-Ayr1 for recruiting lipid droplets and MIM-preprotein for protein insertion into the outer membrane. Our work uncovers translocase capture as a mechanism for functional conversion of a membrane protein complex from protein insertion to lipid metabolism.
    DOI:  https://doi.org/10.1038/s41556-026-01890-3
  37. FEBS Lett. 2026 Feb 22.
    Genetic interactions, synthetic lethality and complexity in cancer vulnerability mapping-Insights and perspectives from the 2nd EuroDepMap symposium.
    Ludovica Proietti, Pedro Beltrao, Alejandra Bruna, Isidro Cortés-Ciriano, Mathew J Garnett, Emanuel Gonçalves, Carmen Herranz-Ors, Manuel Kaulich, Christopher J Lord, Evangelia Petsalaki, Roland Rad, Colm J Ryan, Aurora Savino, Debora Sesia, Lodewyk Wessels, Francesco Iorio.
      Large-scale perturbational approaches have transformed cancer research, enabling systematic identification of tumour-specific dependencies and therapeutic vulnerabilities. However, many clinically relevant vulnerabilities arise from genetic interactions, including synthetic lethal and buffering relationships, and are shaped by cellular state, lineage and treatment history. Interpreting complex dependency landscapes increasingly relies on advanced computational and AI-based approaches integrating molecular, phenotypic and contextual information. In this rapidly evolving setting, dedicated forums are needed to connect experimental and computational perspectives. Following the success of the inaugural European Cancer Dependency Map Symposium, the 2nd EuroDepMap was held on 20 November 2025 at Human Technopole in Milan, bringing together leading scientists in functional genomics, genome-editing screens, disease models and AI-driven analysis, marking a pivotal moment for the field.
    Keywords:   AI ; CRISPR; cancer; cancer vulnerabilities; computational biology; dependency map; large‐scale screenings; symposium
    DOI:  https://doi.org/10.1002/1873-3468.70306
  38. bioRxiv. 2026 Feb 17. pii: 2026.02.14.705918. [Epub ahead of print]
    A Pan-Cancer Ex Vivo Drug Screen Atlas for Functional Precision Oncology.
    Karl Pichotta, Jessica B White, Jeffrey F Quinn, Anneliese Markus, Christopher Tosh, Antoine De Mathelin, Erin Coyne, Feiyang Huang, Wesley Tansey.
      Compared to immortalized cell lines, patient-derived organoids and other ex vivo models have been shown to better recapitulate patient responses to therapy. High cost and technical complexity have prevented the creation of pan-cancer ex vivo datasets, limiting comprehensive analyses and predictive modeling for ex vivo drug response. We present the Pan-PreClinical (PPC) project: a drug screen atlas of 2.1M experiments across 1,982 ex vivo samples and 3,100 drugs spanning 134 cancer indications tested across 26 studies. We develop a contrastive Bayesian model to harmonize across studies, identifying 303 tissue-specific drug sensitivities and demonstrating drug sensitivities are predictive of clinically-relevant molecular profiles. Integrating established cell line databases reveals systematic biases across 55 cancer subtypes, with cell line screens favoring drugs targeting highly proliferative cells and undervaluing cell-cell communication targets. We leverage PPC to establish an ex vivo foundation model and computational platform for scalable ex vivo cancer biology and predictive oncology.
    DOI:  https://doi.org/10.64898/2026.02.14.705918
  39. bioRxiv. 2026 Feb 10. pii: 2026.02.09.704880. [Epub ahead of print]
    Cell jamming transition is regulated by mitochondrial pyruvate transport and endocytosis.
    Alexandra Bermudez, Zoe Latham, Johnny Diaz, Weihong Yan, Jerry Chen, Dapeng Bi, Andrew Goldstein, Jimmy K Hu, Neil Y C Lin.
      Epithelial tissues undergo dynamic transitions between fluid-like collective motion and mechanically jammed states during development, injury repair, and disease progression. However, the cellular programs that drive these transitions and regulate collective behavior remain unclear. Using a controlled crowding model integrated with live-cell imaging and time-resolved multi-omics, we demonstrate that epithelial crowding triggers early metabolic changes characterized by increased mitochondrial pyruvate anaplerosis that precedes the jamming transition. Functional inhibition of mitochondrial pyruvate import is sufficient to sustain collective cell motility, impeding jamming transition in crowded cells. This unjammed state is driven by enhanced cytoskeletal remodeling and requires RhoA-myosin II activity. Mechanistically, we show that elevated cytoskeletal signaling promotes macropinocytic uptake, which serves as a required feedback loop to maintain motility. These findings identify mitochondrial pyruvate utilization as a key regulator that links metabolic remodeling to the endocytic control of epithelial fluidity.
    DOI:  https://doi.org/10.64898/2026.02.09.704880
  40. Drugs. 2026 Feb 23.
    Treating Pancreatic Ductal Adenocarcinoma: The Targeted Revolution is Here.
    Michael S May, Wungki Park, Eileen M O'Reilly.
      Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and is a rising cause of morbidity and mortality. An immunosuppressive, hostile tumor microenvironment, and KRAS-driven biology have contributed to poor outcomes in PDAC. Recent breakthroughs in targeting tumors with homologous repair deficiency, KRASG12C mutations, rare gene fusions, and other molecular abnormalities have improved outcomes in subsets of patients. KRAS inhibitors, both allele specific and pan(K)RAS, claudin-targeting biologics, and PRMT5 inhibitors have demonstrated single agent activity in pretreated, biomarker selected PDAC. An improved understanding of the tumor immune microenvironment has facilitated the development of promising cancer vaccines and immunomodulating agents. This review summarizes the current state of PDAC therapeutics and describes drug development targets that will transform outcomes in PDAC in the proximate future.
    DOI:  https://doi.org/10.1007/s40265-026-02295-0
  41. bioRxiv. 2026 Feb 13. pii: 2026.02.12.705475. [Epub ahead of print]
    ATP8B1-TMEM30B Flippase Activity Maintains Stereocilia Lipid Asymmetry Required for Hearing.
    Henry N De Hoyos, Sihan Li, Jun-Sub Im, Alyssa Luz-Ricca, Betsy Szeto, Rachel Jonas, Emma Kim, Nikhil Amin, Jung-Bum Shin.
      Sensory hair cells convert sound-induced vibrations into electrical signals through a process called mechano-electrical transduction (MET). While the protein components of the MET complex are well studied, increasing evidence indicates that MET channel properties are significantly modulated by the surrounding lipid bilayer. The asymmetric distribution of membrane lipids between the inner and outer membrane leaflets is well established to shape membrane mechanics. The recent discovery that the core MET components TMC1 and TMC2 also act as lipid scramblases suggests a direct role for membrane lipid asymmetry in the dynamic shaping of auditory transduction. Because scramblase activity of TMC1/2 disrupts lipid asymmetry, we hypothesized that an opposing flippase may be required to restore and maintain lipid asymmetry. Here, we identify the P4-ATPase ATP8B1 and its chaperone TMEM30B as selectively expressed in outer hair cells (OHCs), enriched in stereocilia, and upregulated following the onset of MET and hearing. Loss of either protein results in elevated auditory brainstem response (ABR) thresholds, phosphatidylserine (PS) externalization, and rapid hair-cell degeneration, demonstrating that lipid homeostasis is crucial for OHC survival. Together, these findings establish ATP8B1 and TMEM30B as key regulators of membrane lipid asymmetry in sensory hair cells and establish TMEM30B as a novel deafness gene.
    DOI:  https://doi.org/10.64898/2026.02.12.705475
  42. bioRxiv. 2026 Feb 14. pii: 2026.02.12.705593. [Epub ahead of print]
    Multiscale Analysis of PNPLA2 and PNPLA3 Membrane Targeting.
    Amit Kumar, Grace Teskey, Emilio Mottillo, Yu-Ming M Huang.
      Lipid droplets (LDs) are dynamic organelles that regulate cellular lipid storage and mobilization through the coordinated action of LD-associated proteins. Patatin-like phospholipase domain-containing proteins PNPLA2 (ATGL) and PNPLA3 are central regulators of lipid metabolism, yet the molecular mechanisms underlying their membrane targeting and distinct enzymatic activities remain poorly understood. Here, we combine coarse-grained and all-atom molecular dynamics simulations with enhanced sampling to investigate how PNPLA2 and PNPLA3 associate with endoplasmic reticulum (ER) and LD membranes. Despite sharing a conserved N-terminal patatin domain, the two proteins exhibit distinct membrane-binding modes driven by divergent C-terminal amphipathic helices. In both proteins, membrane association is mediated primarily by deep insertion of C-terminal helices, while the patatin domain provides surface contact. PNPLA2 forms a deeply embedded U-shaped helical bundle on LDs that induce pronounced membrane curvature and promote opening of the catalytic dyad, consistent with its high triglyceride lipase activity. In contrast, PNPLA3 engages membranes through a more flexible helical arrangement that maintains a compact catalytic geometry and limits substrate accessibility. Membrane composition further modulates these interactions and leads to protein-specific lipid redistribution and curvature remodeling. Fluorescence microscopy experiments validate the computational predictions and demonstrate that mutation of a single arginine residue within the C-terminal region is sufficient to reduce LD targeting of both proteins. These results establish a mechanistic connection between membrane binding, conformational plasticity, and catalytic regulation in PNPLA2 and PNPLA3. Our work provides molecular insights into how lipid environments tune the function of LD-associated enzymes.
    DOI:  https://doi.org/10.64898/2026.02.12.705593
  43. Curr Opin Struct Biol. 2026 Feb 24. pii: S0959-440X(26)00009-6. [Epub ahead of print]97 103227
    Lipid scrambling: New players, new questions, new opportunities.
    Cristian Rocha-Roa, Stefano Vanni.
      Nearly a quarter of the proteins encoded in most organisms are transmembrane proteins. Contrary to textbook description, many feature a hydrophilic groove which is laterally exposed to the hydrophobic region of the lipid membrane. This cavity is stabilized by neighboring lipid headgroups that sink deep into the membrane and consequently move bidirectionally from one leaflet to the other, in a process nicknamed lipid 'scrambling.' These proteins, called scramblases, have been reported to serve in many cellular functions, ranging from lipid redistribution during organelle growth to cellular apoptosis. Despite their importance, the identity of most scramblases has remained a mystery for many years. In the last few years, in silico techniques have accelerated the discovery of dozens of new scramblases. Nonetheless, together with these discoveries, key questions have emerged. In this review, we highlight some open questions in this emerging field and showcase how modern computational techniques can help addressing them.
    DOI:  https://doi.org/10.1016/j.sbi.2026.103227
  44. Cell. 2026 Feb 25. pii: S0092-8674(25)01507-7. [Epub ahead of print]
    Whole-organ and whole-body 3D atlases enable cellome-wide profiling.
    Shota Y Yoshida, Katsuhiko Matsumoto, Satoshi Takagi, Fukuaki L Kinoshita, Katsunari Yamashita, Daichi Shigeta, Yoshichika Yoshioka, Tetsuo Ushiku, Eiichi Morii, Etsuo A Susaki, Hiroki R Ueda.
      Recent advancements in tissue clearing and light-sheet fluorescence microscopy have enabled whole-organ/body-scale analysis at single-cell resolution. However, comprehensive bioinformatics resources like digitized whole-cellome maps, analogous to whole-genome sequencing, remain limited. Here, we present the CUBIC Organ/Body Atlas, a set of three-dimensional single-cell-resolution references for eleven adult mouse organs and a neonatal whole-mouse body. To generate this atlas, we optimized tissue clearing protocols and developed exMOVIE, an imaging system achieving sufficient working distance and axial resolution for organ-/body-wide three-dimensional imaging and subsequent cell nuclei detection. The atlas facilitates comparative analysis among multiple samples at single-cell resolution, allowing for applications in organ development studies, disease state analysis, and whole-body immune cell profiling with three-dimensional immunostaining. Thus, the CUBIC Organ/Body Atlas contributes to establishing a common cellomics workflow, advancing our systems-level understanding of organisms in physiological, developmental, and pathological processes.
    Keywords:  3D imaging; CUBIC; atlas; cellome-wide profiling; cellomics; immune system; light-sheet fluorescence microscopy; tissue clearing; whole body; whole organ
    DOI:  https://doi.org/10.1016/j.cell.2025.12.057
  45. Nature. 2026 Feb 25.
    Peripheral immune-inducer dendritic cells drive early-life allergic inflammation.
    Yue Xing, Ilana Reznikov, Abonti Nur Ahmed, Ikjot Sidhu, Jill Wisnewski, Asma Farhat, Aleksandr Prystupa, Piotr Konieczny, Kody Mansfield, Melissa L Cooper, Stephen T Yeung, Madeline Kim, Sophia Adeghe, Katherine D Gaines, Meredith Manson, Ji Hyun Sim, Qingrong Huang, Ata S Moshiri, Kamal M Khanna, Theresa T Lu, Emma Guttman-Yassky, Amanda W Lund, Niroshana Anandasabapathy, Shruti Naik.
      Atopic diseases associated with allergens, as well as allergic diseases, frequently arise early in life; however, the age-dependent mechanisms governing immune responses to allergens remain poorly understood1. Here we find that in early life, exposure to common allergens triggers a distinct bifurcated immune response, simultaneously triggering type 17 inflammation in the skin and initiating canonical T helper 2 sensitization in the lymph nodes. This early-life γδ type 17-mediated dermatitis primes the exaggerated allergic lung inflammation upon secondary allergen exposure. Mechanistically, we find dendritic cell (DC)-mediated type 17 activation directly in the skin without requiring migration to lymph nodes; we term this state 'peripheral immune inducer' (pii) DC. CD301b+ conventional type 2 DCs acquire allergen, adopt the pii-DC state, produce IL-23 and activate local γδ type 17 cells independently of lymph-node engagement. The pii-DC state is enabled by the immature hypothalamic-pituitary-adrenal axis and physiologically low systemic glucocorticoids characteristic of early life2,3; DC-specific deletion of the glucocorticoid receptor recapitulates the pii-DC phenotype. These findings define a developmental checkpoint, set by neuroendocrine maturation, that enables in situ DC activation and immune induction, thereby shaping age-dependent responses to allergens.
    DOI:  https://doi.org/10.1038/s41586-026-10162-x
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