bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2026–09–13
29 papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Nerve injury-induced protein 2 preserves lysosomal membrane integrity to suppress ferroptosis.
  2. Targeting cholesterol-dependent Piezo1 activation impairs amoeboid migration in melanoma cells.
  3. Lipid-driven membrane remodeling engages a lysosome-dependent adaptive repair program during retinal aging.
  4. Lipid flip-flop in biological membranes: through the lens of TMEM16F.
  5. Plasma membrane order maps functional diversity in immune cells.
  6. Baseline cellular state shapes the molecular impact of mutant KRAS alleles in reconstituted pancreatic cancer cells.
  7. An Unbiased Geometry-Resolved Membrane Platform for Proteome-Scale Discovery of Membrane Curvature Sensors.
  8. Mitochondrial ATP promotes T cell differentiation through chromatin accessibility.
  9. Cell biology of cancer dormancy.
  10. Multicellular rosette formation guides epithelial tissue assembly in pancreatic ductal adenocarcinoma cell organoids.
  11. A simple, anesthesia-free infusion technique for in vivo metabolic tracing.
  12. Dangerous liaisons: interactions between cancer cells and adipocytes as drivers of cancer progression.
  13. A serpin-myeloid axis in pancreatic cancer heterogeneity and immune evasion.
  14. MemBrain v2: an end-to-end tool for the analysis of membranes in cryo-electron tomography.
  15. Spatiotemporal Multi-Omic Mapping Reveals Liver-Muscle Metabolic Crosstalk in Cancer Cachexia.
  16. Reflecting on 25 years of cancer research: transformative advances and unmet expectations.
  17. Senescent cells: Leaving cellular waste behind.
  18. Pervasive tissue specificity of driver genes revealed by mutational analysis of 265 cancer types.
  19. Retraction Notice: STAT3 induces anoikis resistance, promotes cell invasion and metastatic potential in pancreatic cancer cells.
  20. Imaging cellular activity across all organs reveals body-wide circuits.
  21. Macrophages transfer functional proteins to their surface during live-cell uptake.
  22. Targeted Lifetime Probe Enables Quantitative FLIM Mapping of Lipid Droplet Polarity Remodeling under Copper-Induced Oxidative Stress.
  23. Activation of PP2A-B56a leads to aberrant EGFR signaling and proliferative phenotypes in PDAC.
  24. Multi-modal digital twin model outperforms conventional biomarker stratification in pancreatic cancer.
  25. Clusters, fingers, and singles: A mechanical landscape of tumor invasion.
  26. A cancer that swims between hosts.
  27. MuSpAn: a toolbox for multiscale spatial analysis.
  28. The next 25 years of cancer research: emerging perspectives and priorities.
  29. Heterotypic tumor microenvironments mirror dynamic wound-healing process.
  1. Elife. 2026 Sep 11. pii: RP110919. [Epub ahead of print]15
    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 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.
    Keywords:  Lamp1; NINJ2; cancer biology; ferritin; ferroptosis; human; lysosomal membrane permeabilities
    DOI:  https://doi.org/10.7554/eLife.110919
  2. Proc Natl Acad Sci U S A. 2026 Sep 15. 123(37): e2607369123
    Targeting cholesterol-dependent Piezo1 activation impairs amoeboid migration in melanoma cells.
    Sylvia H Kuang, Alleah G 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, suppress amoeboid migration of melanoma cells in confined environments by reducing intracellular cholesterol. This disrupts plasma membrane tension sensing by Piezo1, lowering intracellular Ca2+ 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.
    Keywords:  amoeboid; bleb; cancer; melanoma; statin
    DOI:  https://doi.org/10.1073/pnas.2607369123
  3. Mol Neurodegener. 2026 Aug 29. pii: 56. [Epub ahead of print]21(1):
    Lipid-driven membrane remodeling engages a lysosome-dependent adaptive repair program during retinal aging.
    Emily Tom, Fangyuan Gao, Carolina N Franco, Adrian Wong, Nathan Kemmerer, Zichen Wang, Amit Jairaman, Qianlan Xu, Yinyin Zhuang, Samuel W Du, Grazyna Palczewska, Krzysztof Palczewski, Itay Budin, Shivashankar Othy, Xiaoyu Shi, Vera L Bonilha, Johannes Schoeneberg, Karl J Wahlin, Lauren V Albrecht, Dorota Skowronska-Krawczyk.
      Age-associated remodeling of membrane lipid composition has been implicated in cellular dysfunction, yet the mechanisms linking lipid changes to membrane integrity and disease remain poorly defined. In the retinal pigment epithelium (RPE), lipid dysregulation is strongly associated with aging and age-related macular degeneration (AMD), a neurodegenerative disease of the central nervous system, but the causal pathways remain unclear. Here, we identify reduced activity of the lipid elongase ELOVL2 as a central driver of age-dependent membrane remodeling. Loss of ELOVL2-dependent polyunsaturated fatty acid (PUFA) elongation shifts plasma membrane lipid composition, leading to altered membrane biophysical properties and compromised membrane integrity. In response to this stress, RPE cells do not undergo apoptosis but instead activate a lysosome-dependent plasma membrane repair program that preserves barrier function under metabolic challenge. However, this adaptive response drives spatially polarized lysosomal exocytosis, promoting extracellular remodeling and accumulation of sub-RPE deposits associated with aging and AMD. Restoration of ELOVL2-derived lipid products reverses membrane abnormalities and suppresses lysosome-mediated remodeling phenotypes, demonstrating direct metabolic control of membrane homeostasis. Together, these findings define an ELOVL2-dependent lipid-lysosome axis that links PUFA elongation to plasma membrane integrity and reveals how compensatory repair mechanisms can contribute to tissue remodeling and disease progression in aging epithelia.
    Keywords:  Age-related macular degeneration (AMD); Aging; Lysosomal exocytosis; Membrane remodeling; Neurodegeneration
    DOI:  https://doi.org/10.1186/s13024-026-00990-w
  4. Physiol Rev. 2026 Sep 10.
    Lipid flip-flop in biological membranes: through the lens of TMEM16F.
    Ke Z Shan, Augustus J Lowry, Maria A González Torres, Megha S Seri, Huanghe Yang.
      The asymmetric distribution of phospholipids between membrane leaflets is a hallmark of all known cells, yet many fundamental questions about membrane lipid asymmetry remain unanswered. Why do cells invest energy to establish and maintain this thermodynamically unstable state? How do cells exploit lipid asymmetry to support essential functions? What are the consequences for health and disease when this organization breaks down? Recent identification of bona fide lipid scramblases, which catalyze rapid phospholipid translocation across the hydrophobic membrane core (lipid flip-flop), has shed new light on these longstanding questions. In particular, studies of the Ca²⁺-activated phospholipid scramblase TMEM16F have revealed how regulated lipid scrambling can couple Ca²⁺ signaling to membrane remodeling, phosphatidylserine (PS) exposure, cellular communication, and disease pathogenesis. In this review, we examine the biology of regulated transmembrane phospholipid flip-flop mediated by lipid scramblases, using TMEM16F as a prototypical model to illustrate core molecular mechanisms, physiological functions, pathological implications, and emerging pharmacological opportunities. By placing TMEM16F within the broader landscape of lipid scramblases and scramblase-like proteins, we highlight how regulated membrane lipid scrambling shapes cell physiology and disease. We also discuss critical knowledge gaps and future directions for understanding this rapidly evolving field.
    Keywords:  Cell signaling; Lipid asymmetry; Phosphatidylserine; Scramablases; TMEM16F
    DOI:  https://doi.org/10.1152/physrev.00046.2025
  5. Nat Chem Biol. 2026 Sep 09.
    Plasma membrane order maps functional diversity in immune cells.
    Luca A Andronico, Cenk O Gurdap, Abishek Arora, Franziska Ragaller, Patrick A Sandoz, Yidan Jiang, Sarantis Giatrellis, Leonard L de Boer, Valentina Carannante, Sofiia Iskrak, Jaromir Mikes, Marcus Buggert, Anders Österborg, Björn Önfelt, Andrey S Klymchenko, Petter Brodin, Erdinc Sezgin.
      Cell membranes undergo biophysical remodeling as an adaptation to the surroundings and to perform specific biological functions. However, the extent and relevance of such changes in human immune cells remain unknown, largely because of the lack of single-cell and multidimensional methodologies. Here we apply a cytometry-based method to fill this gap by combining biophysical profiling with simultaneous analysis of immune cell markers. This platform reveals notable cell-type-dependent plasma membrane order heterogeneity in immune cells. By sorting immune cells according to their membrane order and performing transcriptome and spatial surface proteome analyses together with functional tests, we show that plasma membrane order can be used to identify subsets of immune cells with distinct phenotypes and functional behaviors. Our findings demonstrate a broad heterogeneity of plasma membrane order in immune cells that will provide a more precise definition of immune cell states on the basis of their biophysical properties in health and disease.
    DOI:  https://doi.org/10.1038/s41589-026-02322-x
  6. Mol Omics. 2026 Sep 10. pii: aaiag022. [Epub ahead of print]
    Baseline cellular state shapes the molecular impact of mutant KRAS alleles in reconstituted pancreatic cancer cells.
    Yanixa Quiñones-Avilés, Barbora Salovska, Cassandra S Markham, Yi Di, Benjamin E Turk, Yansheng Liu, Mandar Deepak Muzumdar.
      KRAS is mutated in over 90% of pancreatic ductal adenocarcinomas (PDAC), where hotspot alterations in codons 12, 13, and 61 drive tumor initiation and progression. Although distinct biochemical properties have been described for individual KRAS mutants, whether they generate unique allele-specific signaling programs in PDAC cells remains unresolved. Here, we systematically interrogated the molecular consequences of seven common KRAS mutant variants in reconstituted isogenic, KRAS-deficient PDAC cell lines by integrated transcriptomic, proteomic, and phosphoproteomic profiling. We found that baseline cellular state, rather than allele identity, was the predominant driver of molecular variation. Comparisons with established KRAS reference signatures revealed significant but moderate overlap at the mRNA level and less so at the proteome level. Pathway analyses highlighted interferon response and mitochondrial translation-related proteins as recurrently altered across mutant alleles, while phosphoproteomic data confirmed robust ERK1/2 activity and suppression of DYRK kinase substrates by mutant KRAS expression. Importantly, no robust mutant allele-specific molecular programs were identified in our KRAS-reconstituted cell lines. Together, our study establishes a comprehensive multi-omics resource for KRAS signaling in PDAC and demonstrates that cellular context exerts a stronger influence than allele identity in shaping molecular profiles, with implications for interpreting putative allele-specific signaling dependencies.
    DOI:  https://doi.org/10.1093/molecular-omics/aaiag022
  7. Adv Sci (Weinh). 2026 Sep 08. e77654
    An Unbiased Geometry-Resolved Membrane Platform for Proteome-Scale Discovery of Membrane Curvature Sensors.
    Takumi Komikawa, Rikuto Kawakami, Kunanon Chattrairat, Tatsuya Niwa, Taiga Ajiri, Takao Yasui, Masayoshi Tanaka.
      Membrane curvature organizes protein-driven biochemistry on cellular membranes. Conventional membrane curvature assays are inherently limited by both candidate-based experimental designs and restricted membrane geometries, preventing proteome-scale discovery of curvature-sensing proteins. Here, we present a geometry-resolved membrane platform that enables hypothesis-agnostic identification of curvature-sensing proteins. A supported lipid bilayer on a hemispherical microwell array simultaneously presents convex rims, concave well interiors, and flat planar regions, while providing sufficient membrane surface area for shotgun proteomics. Following validation using canonical BAR domain proteins, we applied the platform to proteomic screening of a cell-derived peripheral membrane protein fraction. This analysis identified 671 proteins, including 71 curvature-responsive candidates spanning preferences for positively curved, negatively curved, and flat membranes. Subsequent candidate prioritization using a protein-protein interaction-guided workflow, followed by validation with purified proteins, demonstrated that the platform provides a comprehensive pipeline linking proteomics-based discovery to imaging-based evaluation. By interrogating membranes of positive, negative, and zero curvature in parallel, this platform eliminates geometric bias, expands the experimentally accessible landscape of membrane curvature sensing, and enables the discovery of previously overlooked modes of membrane curvature recognition.
    Keywords:  geometry‐resolved platform; membrane curvature sensor; proteome analysis; supported lipid bilayer
    DOI:  https://doi.org/10.1002/advs.77654
  8. Cell. 2026 Sep 11. pii: S0092-8674(26)00996-7. [Epub ahead of print]
    Mitochondrial ATP promotes T cell differentiation through chromatin accessibility.
    Charles Ng, Tak Shun Fung, Dayi Li, Korbinian N Kropp, Luis F Somarribas Patterson, Alexandria Markovitz, Daniel N Weinberg, Olivia Jones, Ji-Young Kim, Guoan Zhang, Richard Koche, Mara Monetti, Huayuan Tang, Yun He, Zhengshuang Xu, Xin Cai, Ziqi Yu, Geetha Bhagavatula, Sean P Colgan, Ya-Hui Lin, Zhuoning Li, Elizabeth M Steinert, Christopher A Klebanoff, Santosha A Vardhana, Navdeep S Chandel, Lin Wu, Craig B Thompson.
      Immune elimination of chronic infection or cancer requires cytotoxic CD8+ T cells that adopt and maintain an effector phenotype. Cytotoxic T cell function is a bioenergetically demanding process. Here, we report the ability of D-α-hydroxybutyrate (DAHB) to act as a signaling molecule that increases mitochondrial ATP production and drives the conversion of proliferating T cells into cytotoxic effector cells. DAHB signaling switches ATP production from glycolysis to oxidative phosphorylation supported by fatty acid oxidation. This conversion elevates the level of a phosphagen, phosphocreatine (PCr). Both the PCr bioenergetic reserve and oxidative phosphorylation were required for T cell effector differentiation. DAHB-induced CD8 effector gene transcription was coupled to bioenergetics by BAF-complex-dependent remodeling of chromatin at effector loci. DAHB-enhanced CD8+ T cell antitumor activity both in vitro and in vivo. Together, these findings link cellular bioenergetics to the regulation of chromatin accessibility and gene expression required to support effector function.
    Keywords:  BAF; CD8 T cell effector function; D-alpha-hydroxybutyrate; OXPHOS; chromatin remodeling; creatine; phosphocreatine; tumor immunology
    DOI:  https://doi.org/10.1016/j.cell.2026.08.023
  9. J Cell Sci. 2026 Sep 01. pii: jcs264936. [Epub ahead of print]139(17):
    Cell biology of cancer dormancy.
    Ishani Sharma, Partha Roy.
      Cancer dormancy is a dynamic state in which residual disseminated tumor cells persist without overt expansion yet retain the capacity to reawaken and drive metastatic relapses. In this Review, we discuss major conceptual and mechanistic advances in the cell biology of cancer dormancy. Firstly, we summarize the recognized principal forms and constraints of dormancy, including cellular and tumor mass dormancy, metabolic and extracellular matrix-dependent growth restriction, immune-mediated equilibrium, angiogenic limitation and drug-tolerant persistence states. Next, we examine organ-specific dormancy switches in major clinical sites of metastasis (bone, liver, lung and brain), focusing on how local stromal, vascular, epithelial, immune and neural cues govern the balance between long-term dormancy or quiescence and metastatic outgrowth. Finally, we review the evolution of dormancy-focused therapeutic strategies, from the early attempts to eliminate minimal residual disease to newer approaches targeting dormant-cell survival pathways and the metastatic niche. We conclude by discussing the major unresolved questions in this field, including dormant-state heterogeneity, organ-specific regulation of dormancy and the timing of reactivation, all of which will be central to designing future strategies that prevent metastatic recurrence.
    Keywords:  Angiogenesis; Cancer; Disseminated tumor cells; Dormancy; Immune equilibrium; Minimal residual disease; Therapy
    DOI:  https://doi.org/10.1242/jcs.264936
  10. Proc Natl Acad Sci U S A. 2026 Sep 15. 123(37): e2512284123
    Multicellular rosette formation guides epithelial tissue assembly in pancreatic ductal adenocarcinoma cell organoids.
    Marion K Raich, Fridtjof Brauns, Tamara Müller, Maximilian Reichert, Andreas R Bausch.
      Mesenchymal-to-epithelial transitions are essential for epithelial tissue formation and thus the development of functional organs. Here, we demonstrate that the transition from a disordered mesenchymal state to a columnar epithelial structure in branched pancreatic ductal adenocarcinoma organoids is associated with rosette formation. We show that fluctuations in acto-myosin contractions on the emerging apical side of branches with high cell density create a tug-of-war mechanism, leading to regular spacing of rosettes. The distance between adjacent rosettes depends on the branch diameter, which we validate with a minimal theoretical model based on apical constriction. The resulting lumen formation occurs through the apoptosis of an inner cell mass, leaving an epithelial layer lining the cavity. In summary, our findings show that rosette architecture is set by geometrical confinement of the cell nuclei in combination with acto-myosin driven contractions. This underscores the critical role of mechanical processes in self-organized assembly of epithelial tissue.
    Keywords:  PDAC organoids; acto-myosin fluctuations; mesenchymal-to-epithelial transition; nuclear packing; rosette formation
    DOI:  https://doi.org/10.1073/pnas.2512284123
  11. Sci Adv. 2026 Sep 11. 12(37): eaeg1157
    A simple, anesthesia-free infusion technique for in vivo metabolic tracing.
    Yumi Kim, Samantha Caldwell, Meredith Long, Dominique Abrahams, Margi Baldwin, Gina M DeNicola.
      Accurate metabolic flux analysis requires tracer delivery that preserves physiological metabolism. Current methods may distort metabolism through isoflurane anesthesia, surgical stress, or complex procedures. We demonstrate that isoflurane anesthesia profoundly alters serum and tissue metabolism across multiple pathways. In serum, acylcarnitines and fatty acids were broadly decreased, whereas amino acid metabolites and select nucleotide species were increased. Across multiple organs, isoflurane induced coordinated metabolic remodeling and distinct tissue-specific responses, including glycolytic remodeling in the brain and amino acid accumulation in the pancreas. To address these metabolic disturbances, we established a nonsurgical tail vein catheterization method completed in minutes under brief isoflurane anesthesia that enables multihour tracer infusion in awake, freely moving mice. Using U-13C6-cystine infusion, this method achieved robust cysteine labeling and downstream labeling comparable to jugular infusion while maintaining circulating cystine pools closer to physiological levels. This platform provides a practical approach for in vivo stable isotope tracing under more physiological conditions.
    DOI:  https://doi.org/10.1126/sciadv.aeg1157
  12. Genes Dev. 2026 Sep 09.
    Dangerous liaisons: interactions between cancer cells and adipocytes as drivers of cancer progression.
    Carolina Dehesa Caballero, Almut Schulze.
      Metabolic plasticity and flexibility are key characteristics that allow cancer cells to adapt and thrive in different environments. Specifically, cancer cells can dynamically change the routing of metabolic pathways in response to environmental changes and adapt their metabolic activity depending on local nutrient availability. The tumor microenvironment (TME) plays crucial roles in cancer development and progression. It is now widely accepted that different stromal cells, as well as soluble factors, including metabolites, derived from the TME support cancer cell proliferation and survival and drive migration, invasion, and the formation of metastases. Some cancer types grow in the proximity of adipose tissue (AT), which is mostly composed of mature adipocytes, a specialized cell type responsible for the storage and controlled release of lipids. In response to specific stimuli released by cancer cells, adipocytes can transform into cancer-associated adipocytes (CAAs). CAAs release signaling molecules, and provide fatty acids to cancer cells and other cell types in the TME, which can then utilize these fatty acids as fuel. The interaction between cancer cells and adipocytes creates a dynamic cross-talk that promotes disease progression through multiple mechanisms. In this review, we aim to provide an overview of the main factors in the CAA-cancer cell cross-talk, with a focus on the metabolic consequences of this interaction.
    Keywords:  EMT; cancer-associated adipocytes; fatty acid transport; lipid droplets; metabolic flexibility and plasticity; metastasis; oxidative stress
    DOI:  https://doi.org/10.1101/gad.353813.126
  13. Nature. 2026 Sep 09.
    A serpin-myeloid axis in pancreatic cancer heterogeneity and immune evasion.
    Chiara Falcomatà, Maximilian M Schaefer, Bhavya Singh, Divya Chhamalwan, Alexander Tepper, Sebastian R Nielsen, Hunter T Potak, Maxime Dhainaut, Gurkan Mollaoglu, Matthew D Park, Miriam Merad, Alessia Baccarini, Brian D Brown.
      Pancreatic ductal carcinoma (PDAC) is characterized by a highly immunosuppressive, extracellular matrix-rich microenvironment, yet tumours display marked heterogeneity1-4. This raises the question of whether immune resistance is a global tumour property or is organized within spatially restricted niches. Here, using Perturb-map spatial functional genomics, we determine how different genes shape the growth and cellular environments of PDAC clones across space and time. This analysis revealed early gene-driven remodelling of local immune neighbourhoods preceding late-stage spatial clonal dominance. We identify SERPINE1 (encoding plasminogen activator inhibitor 1 (PAI1)) and SERPINB2 (encoding PAI2) as dominant regulators of tumour microenvironment control and immune evasion. These serpins promote stabilization of fibrin-rich extracellular matrix niches that spatially retain and programme macrophages towards immunosuppressive states while excluding cytotoxic T cells. Loss of Serpine1 or Serpinb2, or pharmacological inhibition of PAI1 or CD18, improves tumour control in mice and synergizes with anti-PD-1. Multimodal spatial analysis of patient tumours revealed that immunosuppressive niches form around rare SERPINB2- and SERPINE1-expressing PDAC subpopulations, dominated by SPP1+/MARCO+ macrophages. These findings identify cancer-derived SERPINE1 and SERPINB2 as local spatial organizers of immune suppression, linking tumour-intrinsic heterogeneity to local microenvironmental control and immunotherapy resistance in PDAC.
    DOI:  https://doi.org/10.1038/s41586-026-11002-8
  14. Nat Methods. 2026 Sep 08.
    MemBrain v2: an end-to-end tool for the analysis of membranes in cryo-electron tomography.
    Lorenz Lamm, Simon Zufferey, Hanyi Zhang, Ricardo D Righetto, Florent Waltz, Wojciech Wietrzynski, Kevin A Yamauchi, Alister Burt, Ye Liu, Antonio Martinez-Sanchez, Sebastian Ziegler, Fabian Isensee, Julia A Schnabel, Benjamin D Engel, Tingying Peng.
      Cryo-electron tomography provides unique insights into macromolecular complexes in their native environments, yet membrane analysis remains a major bottleneck due to low signal-to-noise ratios, missing wedge artifacts and the complexity of membrane-associated particles. Existing tools often require extensive manual annotation, struggle with generalization across datasets and lack integrated solutions for segmentation, particle localization and quantitative analysis. We introduce MemBrain v2, a deep-learning-enabled framework that unifies these tasks into a streamlined pipeline. MemBrain-seg leverages a diverse, collaboratively generated training dataset and specialized model training strategies to achieve generalizable membrane segmentation across variable tomographic conditions. MemBrain-pick enables data-efficient localization of membrane-bound particles by integrating geometric constraints with deep learning, reducing the need for extensive manual annotation. MemBrain-stats provides quantitative insights into particle distributions, computing spatial metrics to analyze intramembrane particle organization. MemBrain v2 integrates seamlessly into cryo-electron tomography workflows, providing an accessible and structured approach to membrane analysis.
    DOI:  https://doi.org/10.1038/s41592-026-03178-8
  15. Adv Sci (Weinh). 2026 Sep 08. e77489
    Spatiotemporal Multi-Omic Mapping Reveals Liver-Muscle Metabolic Crosstalk in Cancer Cachexia.
    Zihan Tian, Qianyu Wang, Wenyan Gao, Xianfeng Li, Jiawen Fan, Xiaoliang Wu, Siqi Liu, Xiangdong Ming, Danna Yeerken, Mutian Shen, Qingjie Min, Qimin Zhan, Yan Wang.
      Tumor and host interaction contributes to cancer cachexia, a systemic wasting syndrome characterized by tissue loss (adipose and skeletal muscle), anorexia, fatigue, and metabolic reprogramming. Nevertheless, the spatio-temporal molecular dynamics of multiple tissues during cancer cachexia development remain elusive. Here, we present a comprehensive overview of the biological alterations and metabolic reprogramming of cancer cachexia across two species, 25 organs, and 3230 samples, by integrating transcriptomic, proteomic, and metabolomic profiles spanning different cachectic stages and sexual dimorphism. Using this cancer cachexia atlas (CCAtlas), we identified dysregulated tissues of cancer cachexia, including skeletal muscle, liver, and blood. We revealed coordinated metabolic reprogramming across tissues, including dysregulated amino acid metabolism and one-carbon metabolism. Temporal profiling illustrated dynamic molecular signatures during cancer cachexia progression. The exacerbated inflammatory status in males potentially contributed to a more severe whole-body wasting phenotype. The liver-muscle crosstalk potentiated skeletal muscle atrophy through creatine deficiency via hepatic Gamt downregulation in the LLC model. Creatine supplementation and hepatic Gamt overexpression in the LLC model attenuated skeletal muscle wasting. Together, CCAtlas provides fundamental and systemic insights into multi-omic molecular dynamics and metabolic rewiring of cancer cachexia from the perspective of tumor and/or inter-organ crosstalk across species.
    Keywords:  Gamt; cancer cachexia; creatine; inter‐organ crosstalk; metabolism reprogramming; spatiotemporal dynamics
    DOI:  https://doi.org/10.1002/advs.77489
  16. Nat Rev Cancer. 2026 Sep 08.
    Reflecting on 25 years of cancer research: transformative advances and unmet expectations.
    Allan Balmain, René Bernards, Hans Clevers, Karen H Vousden, Paul Workman, Marinka Zitnik.
      
    DOI:  https://doi.org/10.1038/s41568-026-00974-4
  17. Dev Cell. 2026 Sep 09. pii: S1534-5807(26)00315-1. [Epub ahead of print]61(9): 1747-1748
    Senescent cells: Leaving cellular waste behind.
    Hélène Martini, João F Passos.
      Cellular senescence is one of the best-studied biological programs, yet it continues to reveal unexpected aspects. In this issue of Developmental Cell, Durik et al.1 describe how senescent cells shed large cytoplasmic fragments that promote their survival and may represent a mechanism of communication with neighboring cells.
    DOI:  https://doi.org/10.1016/j.devcel.2026.08.004
  18. iScience. 2026 Sep 18. 29(9): 117272
    Pervasive tissue specificity of driver genes revealed by mutational analysis of 265 cancer types.
    Jiayi Chen, Ryan L Collins, Kevin M Haigis.
      Defining genes that are somatically mutated in different cancer types is a central goal of cancer genetics. Nevertheless, traditional definitions of "driver" genes are biased toward common cancer types and tend to overlook genes that might be specific to rarer subtypes. We developed a statistical framework that defines genes enriched for functional somatic mutations in primary cancers to quantify incidence and tissue specificity for each gene. By applying this framework to the AACR GENIE v18.0 dataset, we identified 165 genes significantly mutated in at least one subtype. We mined this dataset to derive tissue specificity scores for all 165 genes, demonstrating that tissue specificity is the norm, not the exception. We also found that oncogenes with restricted expression across normal tissues tend to exhibit higher tissue-specific mutation patterns in cancer. We anticipate that the resources developed in this study will be useful for cancer research and clinical oncology.
    Keywords:  cancer genetics; oncogenes; somatic genetics; tissue specificity; tumor suppressor genes
    DOI:  https://doi.org/10.1016/j.isci.2026.117272
  19. Carcinogenesis. 2026 Sep 09. pii: bgag064. [Epub ahead of print]
    Retraction Notice: STAT3 induces anoikis resistance, promotes cell invasion and metastatic potential in pancreatic cancer cells.
      
    DOI:  https://doi.org/10.1093/carcin/bgag064
  20. Nature. 2026 Sep 09.
    Imaging cellular activity across all organs reveals body-wide circuits.
    Virginie M S Ruetten, Wei Zheng, Igor Siwanowicz, Brett D Mensh, Mark Eddison, Amy Hu, Yunfeng Chi, Andrew L Lemire, Caiying Guo, Mykola Kadobianskyi, Marc Renz, Sara Lelek-Greskovic, Yisheng He, Kari Close, Gudrun Ihrke, Aparna Dev, Alyson Petruncio, Yinan Wan, Rongwei Zhang, Mark C Fishman, Florian Engert, Benjamin Judkewitz, Mikail Rubinov, Philipp J Keller, Chie Satou, Guoqiang Yu, Paul W Tillberg, Maneesh Sahani, Misha B Ahrens.
      An animal's ability to survive and thrive-whether fleeing from danger, eating a meal, or fighting an infection-arises from the collective moment-to-moment activity of many interacting cell types throughout the body. Physiology seeks to elucidate these cellular interactions that span organs, cell types and timescales, but has been limited by the inability to record this time-varying cellular activity simultaneously throughout the entire body. Here we develop WHOLISTIC (WHole-Organism Live-Imaging System for recording Tissue and IntraCellular activity), a method to image second-timescale activity of cells across the entire vertebrate body at cellular resolution. WHOLISTIC advances and integrates volumetric fluorescence microscopy, machine learning, and pancellular transgenic expression of calcium sensors1, demonstrated in larval zebrafish, with proof of concept in adult Danionella cerebrum. To access information about the molecular and ultrastructural substrates for the measured dynamics, we advanced whole-body expansion microscopy2. At the cellular scale, body-wide screening revealed unexpected responses, including chondrocyte reactions to cold and meningeal responses to ketamine. At the organ scale, WHOLISTIC identified rhythmic travelling waves along the renal nephron. At the multi-organ scale, it revealed unknown muscle synergies and muscle-organ interactions. At the whole-organism scale, the method captured brainstem-controlled redistribution of body-wide blood flow. Combining optogenetics with WHOLISTIC enabled all-optical causal dissection of brain-body interactions. These advances establish a paradigm for systems biology that bridges cellular and organismal physiology, enabling comprehensive discovery across scales-from fundamental mechanisms to therapeutic targets.
    DOI:  https://doi.org/10.1038/s41586-026-10979-6
  21. Nat Chem Biol. 2026 Sep 08.
    Macrophages transfer functional proteins to their surface during live-cell uptake.
    Regan F Volk, Amy C Fan, Sara W Casebeer, Vishnu R Tejus, Andrew C Condon, Bahar Zirak, Nayelis A Manon, Iryna Irkliyenko, Danielle M Torralba, Shao Tao, Tommaso Pollini, Vijay Ramani, Ajay V Maker, Matthew F Krummel, Hani Goodarzi, Balyn W Zaro.
      A cell's proteome is assumed to reflect its transcriptional and translational activity. Macrophages regularly acquire xenobiotic material from neighboring cells, which is thought to result in degradation of the material. However, increasing lines of evidence suggest that not all taken up material is degraded and other transfer-like processes also occur. Field standard technologies are unable to rigorously report on precisely how and by whom the macrophage protein repertoire is altered during these interactions, leaving unresolved the extent to which nondegradative processes contribute to altered phenotypes. Here, we leveraged chemical tools and proteomics to show that intact target cancer cell surface proteins are transferred to the macrophage cell surface at functionally impactful levels in a manner associated with live-cell uptake. Widespread acquisition of proteins during cell uptake reengineers the macrophage cell surface proteome and is a transcriptionally silent, cell-nonautonomous process with the potential to alter metabolic uptake.
    DOI:  https://doi.org/10.1038/s41589-026-02292-0
  22. Anal Chem. 2026 09 08. 98(35): 26012-26021
    Targeted Lifetime Probe Enables Quantitative FLIM Mapping of Lipid Droplet Polarity Remodeling under Copper-Induced Oxidative Stress.
    Yiqiang Wang, Zhenlong Huang, Xiangcong Xu, Yuan Li, Fangrui Lin, Junle Qu, Puxiang Lai.
      Lipid droplet (LD) microenvironmental remodeling accompanies oxidative stress, mitochondrial dysfunction, and metal-induced metabolic perturbation, yet remains difficult to quantify in living systems. Here, we report LDP-Pol, a BODIPY-derived, LD-targeted fluorescence lifetime imaging microscopy (FLIM) probe for mapping LD polarity heterogeneity. LDP-Pol combines an ICT-active triphenylamine-BODIPY scaffold with a C12 methyl ester-containing chain inspired by endogenous lipid components, improving compatibility with neutral lipid-rich environments and promoting selective LD partitioning for polarity-dependent lifetime readout. Solvent and lipid-mimetic studies established a calibrated lifetime response to polarity. In living cells, LDP-Pol resolved LD polarity-associated microenvironmental changes during H2O2-induced oxidative stress and CuCl2/elesclomol-induced copper stress, while dual-color super-resolution imaging confirmed its compatibility with live-cell organelle tracking and LD-mitochondria contact analysis. In tumor models, LDP-Pol enabled tissue-level FLIM visualization of heterogeneous lipid polarity landscapes under copper-induced stress. These results establish a lifetime-based strategy for probing LD microenvironmental remodeling associated with oxidative and metal-induced cellular perturbation.
    DOI:  https://doi.org/10.1021/acs.analchem.6c03779
  23. Mol Cancer Ther. 2026 Sep 04.
    Activation of PP2A-B56a leads to aberrant EGFR signaling and proliferative phenotypes in PDAC.
    Claire M Pfeffer, Sydney J Clifford, Saadia A Karim, Ella Rose D Chianis, Brittany N Heil, Lauren E Gartenhaus, Emma F Kay, Garima Baral, Elizabeth G Hoffman, Sagar M Utturkar, Harish Kothandaraman, Whitney Smith-Kinnaman, Kasi Hansen, Emily G Smith, Elisabeth Porter, Fu-Ping Zhang, Nadia A Lanman, Jukka Westermarck, Emma H Doud, Amber L Mosley, Jennifer P Morton, Brittany L Allen-Petersen.
      Pancreatic ductal adenocarcinoma (PDAC) stands to become the second most deadly cancer by 2030. Mutations in the small GTPase, KRAS, occur in over 90% of PDAC patients and drive signaling plasticity through phosphorylation cascades. Protein phosphatases are master regulators of signal transduction, yet the contribution of phosphatase dysregulation to mutant KRAS phenotypes is poorly understood. Protein phosphatase 2A (PP2A) inhibits KRAS effectors, placing this family of enzymes as key regulators of PDAC signaling. However, we previously demonstrated that pharmacological activation of PP2A elicits heterogeneous responses in PDAC cells, with some cell lines displaying augmented oncogenic signaling despite increased phosphatase activity. Here, we determined the impact of the specific PP2A subunit, B56a, on PDAC phenotypes using both genetic and pharmacological activation strategies in human PDAC cell lines and genetic mouse models. We demonstrate that B56a knockout reduces PDAC proliferation while exogenous expression exacerbates proliferative phenotypes. This increase in proliferation predominately occurs through epidermal growth factor receptor (EGFR), a critical signaling node associated with poor patient outcome. The activation of EGFR by PP2A-B56a is mediated through increased expression and processing of EGFR ligands, such as amphiregulin. In vivo, the genetic loss of Cip2a, an endogenous PP2A inhibitor, significantly increases EGFR activation and decreases overall survival. Finally, pharmacological activation of PP2A leads to increased EGFR signaling in tumors; however, EGFR inhibition mitigates this signaling and significantly decreases tumor growth compared to single-agent treatment alone. Together, these studies implicate a previously undescribed non-canonical role for PP2A-B56a in EGFR signaling that contributes to PDAC progression.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-25-0970
  24. Front Artif Intell. 2026 ;9 1873681
    Multi-modal digital twin model outperforms conventional biomarker stratification in pancreatic cancer.
    Matthew Griffiths, Jennifer J Knox, Grainne M O'Kane, Trevor J Pugh, Julie M Wilson, Anna Dodd, Sandra E Fischer, Robert C Grant, Faiyaz Notta, Steven Gallinger, Irina Babina, Andrew V Biankin.
      Better patient selection for treatment is critical to improving both cancer care and therapeutic development in oncology. The ability to predict individual patient responses to cancer treatment ahead of time would transform cancer care with substantial impact on outcomes, quality of life and cost. We generated molecular digital twins of individual participants using a Bayesian foundation model of cancer (FarrSight®) in the COMPASS clinical trial (a non-randomized study of mFOLFIRINOX and gemcitabine + nab-paclitaxel in first-line advanced pancreatic cancer). We compared these individual digital twin predictions to the existing Moffitt classification of pancreatic ductal adenocarcinoma. Individual digital twin predictions of response to mFOLFIRINOX outperformed the Moffitt classification in the basal-like subtype with an AUC of 72.3% compared to the conventional biomarker AUC of 44.8%; overall accuracy of 65.8% vs. 47.4%; PPV of 60% vs. 40%; and NPV of 72.2% vs. 52.2%. Individual patient response predictions using models such as FarrSight® have the potential to better select patients for treatment with established therapeutics and in therapeutic development compared to biomarkers based on population averages.
    Keywords:  Bayesian; biomarker; digital twin; foundation model; pancreatic cancer; stratification
    DOI:  https://doi.org/10.3389/frai.2026.1873681
  25. PLoS Comput Biol. 2026 Sep;22(9): e1014747
    Clusters, fingers, and singles: A mechanical landscape of tumor invasion.
    Sheriff Akeeb, Adam I Marcus, Yi Jiang.
      Collective invasion is a key mechanism by which tumors disseminate and metastasize, involving coordinated migration of heterogeneous cell populations. Experimental studies in spheroid-based assays have identified specialized leader and follower cells that work together during this process, but the biophysical rules governing their interaction remain unclear. We present a mechanistic, cell-based computational model using the Cellular Potts framework to investigate how heterotypic adhesion, leader motility, and follower proliferation jointly shape invasion. Leader-follower tumors were simulated across 13 310 parameter sets, and invasion was quantified by invasive and infiltrative areas, finger-like protrusions, solitary defectors, and detached clusters. From these simulations, we identified four distinct invasion phenotypes: non-invasive, bulk collective, single-cell, and multimodal. Multimodal invasion-the coexistence of cohesive strands, solitary cells, and small clusters-emerged as the most prevalent phenotype, particularly under moderate adhesion and high motility. Proliferation increased tumor bulk rather than determining invasion mode, which was governed primarily by adhesion and leader motility. Mapping outcomes across the parameter space revealed sharp transitions between invasion modes, underscoring trade-offs between adhesion and motility in shaping invasion complexity. Our results show that hybrid invasion behaviors, previously considered rare, arise robustly from simple mechanical rules and are favored in a broad region of the parameter space. This framework reconciles binary models of invasion with experimental observations of heterogeneity, providing predictive insights into how modulating adhesion and motility may modify invasive behavior.
    DOI:  https://doi.org/10.1371/journal.pcbi.1014747
  26. Nat Genet. 2026 Sep;58(9): 2078
    A cancer that swims between hosts.
    Hui Hua.
      
    DOI:  https://doi.org/10.1038/s41588-026-02760-2
  27. Nat Commun. 2026 Aug 13. pii: 9737. [Epub ahead of print]17(1):
    MuSpAn: a toolbox for multiscale spatial analysis.
    Joshua A Bull, Joshua W Moore, Shania M Corry, Muyang Lin, Hayley L Belnoue-Davis, Eoghan J Mulholland-Illingworth, Simon J Leedham, Helen M Byrne.
      Advances in multiplex imaging and spatial omics have revolutionised spatial data generation in biology, revealing complex tissue organisation across multiple scales. However, methods for analysing these data have lagged behind, with fragmented, study-specific pipelines and limited guidance for tool selection. To address this, we introduce MuSpAn, a Multiscale Spatial Analysis package offering intuitive, flexible access to a wide range of mathematical tools - including spatial statistics, topological data analysis, geometry, and networks - within a unified framework. MuSpAn supports efficient data querying, is agnostic to imaging modality, and provides extensive documentation and community support. It enables users to create custom pipelines or conduct unbiased exploratory analyses. We demonstrate MuSpAn's capacity to interrogate cross-compartmental cell interactions at multiple length scales in both normal and neoplastic tissue using mouse intestinal spatial transcriptomic datasets. Applied to a CMS4-like murine intestinal cancer model, MuSpAn identifies a continuum of fibroblastic functional phenotypes associated with discrete and coordinated fibroblast-immune interactions, highlighting its utility as a discovery tool across diverse biological contexts.
    DOI:  https://doi.org/10.1038/s41467-026-75649-7
  28. Nat Rev Cancer. 2026 Sep 07.
    The next 25 years of cancer research: emerging perspectives and priorities.
    Myriam Chalabi, Tim H H Coorens, Leanne Li, James L Reading, Shensi Shen, Ewa Szczurek.
      
    DOI:  https://doi.org/10.1038/s41568-026-00975-3
  29. Trends Cancer. 2026 Sep 09. pii: S2405-8033(26)00203-7. [Epub ahead of print]
    Heterotypic tumor microenvironments mirror dynamic wound-healing process.
    Liqun Yu, Xiang H-F Zhang.
      Tumors co-opt normal wound-healing programs to shape their immune microenvironment, yet how distinct immune states arise and influence therapy remains unclear. Here, we synthesize emerging evidence that tumors become locked in either proinflammatory or pro-resolution phases, defined by neutrophil- or macrophage-dominated ecosystems. These states not only remodel local tissues but also systemically reprogram hematopoiesis, creating self-reinforcing immune circuits that drive progression, metastasis, and treatment resistance. We highlight recent advances linking epithelial-mesenchymal plasticity, lipid metabolism, and myeloid dynamics into an integrated 'wound-healing clock' model. This framework provides a conceptual basis for patient stratification and suggests that therapeutically redirecting immune states may unlock new strategies to overcome resistance across cancer types.
    Keywords:  myeloid plasticity; therapy resistance; tumor microenvironment; wound healing
    DOI:  https://doi.org/10.1016/j.trecan.2026.08.007
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