bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2025–04–27
forty-two papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Spatial mapping of transcriptomic plasticity in metastatic pancreatic cancer.
  2. Hepatic gluconeogenesis and PDK3 upregulation drive cancer cachexia in flies and mice.
  3. Targeting PIKfyve-driven lipid metabolism in pancreatic cancer.
  4. Multimetric MRI Captures Early Response and Acquired Resistance of Pancreatic Cancer to KRAS Inhibitor Therapy.
  5. Evolutionary paths towards metastasis.
  6. A Common CTRB misfolding variant associated with pancreatic cancer risk causes ER stress and inflammation in mice.
  7. Intrinsic properties of the lymph node render it immunologically susceptible to metastasis.
  8. DHODH modulates immune evasion of cancer cells via CDP-Choline dependent regulation of phospholipid metabolism and ferroptosis.
  9. Protocol for the establishment of murine orthotopic lung tumors and the assessment of contralateral pulmonal metastasis by flow cytometry.
  10. How cell crowding causes cancer cells to spread.
  11. Cellular Signaling at the Nano-Bio Interface: Spotlighting Membrane Curvature.
  12. Mechanistic insights and therapeutic strategies for targeting autophagy in pancreatic ductal adenocarcinoma.
  13. Softness or Stiffness What Contributes to Cancer and Cancer Metastasis?
  14. Synchronized temporal-spatial analysis via microscopy and phosphoproteomics (STAMP) of quiescence.
  15. Aberrant phase separation drives membranous organelle remodeling and tumorigenesis.
  16. Long-chain sulfatide enrichment is an actionable metabolic vulnerability in intraductal papillary mucinous neoplasm (IPMN)-associated pancreatic cancers.
  17. Structural dissection of ergosterol metabolism reveals a pathway optimized for membrane phase separation.
  18. Cell Painting PLUS: expanding the multiplexing capacity of Cell Painting-based phenotypic profiling using iterative staining-elution cycles.
  19. Localizatome: a database for stress-dependent subcellular localization changes in proteins.
  20. Local mapping of the nanoscale viscoelastic properties of fluid membranes by AFM nanorheology.
  21. Macrophages and fibroblasts as regulators of the immune response in pancreatic cancer.
  22. PANTAX: a phase Ib clinical trial of the efflux pump inhibitor SCO-101 in combination with gemcitabine and nab-paclitaxel in non-resectable or metastatic pancreatic cancer.
  23. Metabolites in tumour interstitial fluid directly suppress T cells.
  24. Non-invasive tools for analysis of plasma membrane protein topology in living cells.
  25. Boundary Flow-Induced Membrane Tubulation Under Turgor Pressures.
  26. Four rising stars at the forefront of cancer research.
  27. Distinct gene expression mechanisms in classical and basal PDAC subtypes.
  28. LC-MS and High-Throughput Data Processing Solutions for Lipid Metabolic Tracing Using Biorthogonal Click Chemistry.
  29. Cell crowding activates pro-invasive mechanotransduction pathway in high-grade DCIS via TRPV4 inhibition and cell volume reduction.
  30. Mechano-metabolism: Recent Findings on the Intersection of Cell Adhesion, Cell Migration, and Metabolism.
  31. Protecting centrosomes from fracturing enables efficient cell navigation.
  32. Cancer cachexia: exploring parallels with other paraneoplastic syndromes.
  33. A protein tunnel that shuttles lipids around the cell.
  34. Origin and evolution of mitochondrial inner membrane composition.
  35. Protocol on utilizing murine gastric cancer organoids for modeling subcutaneous, orthotopic primary, and liver metastatic disease in mice.
  36. Autophagosomes anchor an AKAP11-dependent regulatory checkpoint that shapes neuronal PKA signaling.
  37. Tumor-Infiltrating Clonal Hematopoiesis.
  38. Tumour interstitial fluid-enriched phosphoethanolamine suppresses T cell function.
  39. Mechanisms and Therapeutic Strategies for Minority Cell-Induced Paclitaxel Resistance and Tumor Progression Mediated by Mechanical Forces.
  40. Epithelial cell extrusion at a glance.
  41. Collective Vibration Decoupling of Confined Water in Membrane Channels.
  42. SVF mediates immunometabolic alterations in burn-induced hypermetabolic adipose tissue via mitochondrial transfer.
  1. Nature. 2025 Apr 23.
    Spatial mapping of transcriptomic plasticity in metastatic pancreatic cancer.
    Guangsheng Pei, Jimin Min, Kimal I Rajapakshe, Vittorio Branchi, Yunhe Liu, Benson Chellakkan Selvanesan, Fredrik Thege, Dorsay Sadeghian, Daiwei Zhang, Kyung Serk Cho, Yanshuo Chu, Enyu Dai, Guangchun Han, Mingyao Li, Cassian Yee, Kazuki Takahashi, Bharti Garg, Herve Tiriac, Vincent Bernard, Alexander Semaan, Jean L Grem, Thomas C Caffrey, Jared K Burks, Andrew M Lowy, Andrew J Aguirre, Paul M Grandgenett, Michael A Hollingsworth, Paola A Guerrero, Linghua Wang, Anirban Maitra.
      Patients with treatment-refractory pancreatic cancer often succumb to systemic metastases1-3; however, the transcriptomic heterogeneity that underlies therapeutic recalcitrance remains understudied, particularly in a spatial context. Here we construct high-resolution maps of lineage states, clonal architecture and the tumour microenvironment (TME) using spatially resolved transcriptomics from 55 samples of primary tumour and metastases (liver, lung and peritoneum) collected from rapid autopsies of 13 people. We observe discernible transcriptomic shifts in cancer-cell lineage states as tumours transition from primary sites to organ-specific metastases, with the most pronounced intra-patient distinctions between liver and lung. Phylogenetic trees constructed from inferred copy number variations in primary and metastatic loci in each patient highlight diverse patient-specific evolutionary trajectories and clonal dissemination. We show that multiple tumour lineage states co-exist in each tissue, including concurrent metastatic foci in the same organ. Agnostic to tissue site, lineage states correlate with distinct TME features, such as the spatial proximity of TGFB1-expressing myofibroblastic cancer-associated fibroblasts (myCAFs) to aggressive 'basal-like' cancer cells, but not to cells in the 'classical' or 'intermediate' states. These findings were validated through orthogonal and cross-species analyses using mouse tissues and patient-derived organoids. Notably, basal-like cancer cells aligned with myCAFs correlate with plasma-cell exclusion from the tumour milieu, and neighbouring cell analyses suggest that CXCR4-CXCL12 signalling is the underlying basis for observed immune exclusion. Collectively, our findings underscore the profound transcriptomic heterogeneity and microenvironmental dynamics that characterize treatment-refractory pancreatic cancer.
    DOI:  https://doi.org/10.1038/s41586-025-08927-x
  2. Nat Metab. 2025 Apr;7(4): 823-841
    Hepatic gluconeogenesis and PDK3 upregulation drive cancer cachexia in flies and mice.
    Ying Liu, Ezequiel Dantas, Miriam Ferrer, Ting Miao, Mujeeb Qadiri, Yifang Liu, Aram Comjean, Emma E Davidson, Tiffany Perrier, Tanvir Ahmed, Yanhui Hu, Marcus D Goncalves, Tobias Janowitz, Norbert Perrimon.
      Cachexia, a severe wasting syndrome characterized by tumour-induced metabolic dysregulation, is a leading cause of death in people with cancer, yet its underlying mechanisms remain poorly understood. Here we show that a longitudinal full-body single-nuclei-resolution transcriptome analysis in a Drosophila model of cancer cachexia captures interorgan dysregulations. Our study reveals that the tumour-secreted interleukin-like cytokine Upd3 induces fat-body expression of Pepck1 and Pdk, key regulators of gluconeogenesis, disrupting glucose metabolism and contributing to cachexia. Similarly, in mouse cancer cachexia models, we observe IL-6-JAK-STAT-signalling-mediated induction of Pck1 and Pdk3 expression in the liver. Increased expression of these genes in fly, mouse, and human correlates with poor prognosis, and hepatic expression of Pdk3 emerges as a previously unknown mechanism contributing to metabolic dysfunction in cancer cachexia. This study highlights the conserved nature of tumour-induced metabolic disruptions and identifies potential therapeutic targets to mitigate cachexia in people with cancer.
    DOI:  https://doi.org/10.1038/s42255-025-01265-2
  3. Nature. 2025 Apr 23.
    Targeting PIKfyve-driven lipid metabolism in pancreatic cancer.
    Caleb Cheng, Jing Hu, Rahul Mannan, Tongchen He, Rupam Bhattacharyya, Brian Magnuson, Jasmine P Wisniewski, Sydney Peters, Saadia A Karim, David J MacLean, Hüseyin Karabürk, Li Zhang, Nicholas J Rossiter, Yang Zheng, Lanbo Xiao, Chungen Li, Dominik Awad, Somnath Mahapatra, Yi Bao, Yuping Zhang, Xuhong Cao, Zhen Wang, Rohit Mehra, Pietro Morlacchi, Vaibhav Sahai, Marina Pasca di Magliano, Yatrik M Shah, Lois S Weisman, Jennifer P Morton, Ke Ding, Yuanyuan Qiao, Costas A Lyssiotis, Arul M Chinnaiyan.
      Pancreatic ductal adenocarcinoma (PDAC) subsists in a nutrient-deregulated microenvironment, making it particularly susceptible to treatments that interfere with cancer metabolism1,2. For example, PDAC uses, and is dependent on, high levels of autophagy and other lysosomal processes3-5. Although targeting these pathways has shown potential in preclinical studies, progress has been hampered by the difficulty in identifying and characterizing favourable targets for drug development6. Here, we characterize PIKfyve, a lipid kinase that is integral to lysosomal functioning7, as a targetable vulnerability in PDAC. Using a genetically engineered mouse model, we established that PIKfyve is essential to PDAC progression. Furthermore, through comprehensive metabolic analyses, we found that PIKfyve inhibition forces PDAC to upregulate a distinct transcriptional and metabolic program favouring de novo lipid synthesis. In PDAC, the KRAS-MAPK signalling pathway is a primary driver of de novo lipid synthesis. Accordingly, simultaneously targeting PIKfyve and KRAS-MAPK resulted in the elimination of the tumour burden in numerous preclinical human and mouse models. Taken together, these studies indicate that disrupting lipid metabolism through PIKfyve inhibition induces synthetic lethality in conjunction with KRAS-MAPK-directed therapies for PDAC.
    DOI:  https://doi.org/10.1038/s41586-025-08917-z
  4. Clin Cancer Res. 2025 Apr 21.
    Multimetric MRI Captures Early Response and Acquired Resistance of Pancreatic Cancer to KRAS Inhibitor Therapy.
    Mamta Gupta, Hoon Choi, Samantha B Kemp, Emma E Furth, Stephen Pickup, Cynthia Clendenin, Margo Orlen, Mark Rosen, Fang Liu, Quy Cao, Ben Z Stanger, Rong Zhou.
       PURPOSE: In pancreatic ductal adenocarcinoma (PDAC), KRAS mutations drive both cancer cell growth and formation of a dense stroma. Small molecule KRAS inhibitors (KRASi) represent a promising new treatment hence clinical tools that can assess early response, detect resistance and/or predict prolonged survival are desirable to understand clinical biology of KRASi. We hypothesized that diffusion-weighted MRI (DWI) can detect cell death while dynamic contrast enhanced MRI (DCE) and magnetization transfer ratio (MTR) imaging are sensitive to tumor microenvironment changes, and these metrics shed insights into tumor size change induced by KRASi treatment.
    EXPERIMENTAL DESIGN: Multiple preclinical PDAC models including a genetically engineered mouse model (KPC) received MRTX1133, a KRASi specific for KRASG12D mutation. Quantitative imaging markers were corroborated with immunohistochemistry (IHC) analyses.
    RESULTS: Significant increase of tumor apparent diffusion coefficient (a DWI metric) was detected as early as 48h and persisted to Day7 after initiation of KRASi treatment and was strongly correlated with cell death and reduced cellularity, resulting in greatly prolonged median survival in treated mice. Capillary perfusion/permeability (a DCE metric) exhibited an inverse relationship with microvascular density. Distinct responses of KRASG12C versus KRASG12D tumors to MRTX1133 were captured by the MRI metrics corroborated with IHC. When tumors developed resistance to MRTX1133, the imaging marker values exhibited a reversal from those of responding tumors.
    CONCLUSIONS: Multiparametric MRI provides early biological insights of cancer and stromal response to KRASi treatment and sets the stage for testing the utility of these clinically ready MRI methods in patients receiving KRASi therapy.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-24-4049
  5. Nat Rev Cancer. 2025 Apr 22.
    Evolutionary paths towards metastasis.
    Kamila Naxerova.
      The evolution of metastasis in humans is considerably less well understood than the biology of early carcinogenesis. For over a century, clinicians and scientists have been debating whether metastatic potential is the intrinsic property of a cancer, pre-determined by the molecular characteristics of the tumour founder cell, or whether metastatic capacity evolves in a stepwise fashion as the tumour grows, akin to the multistage accumulation of oncogenic alterations that give rise to the first cancer cell. In this Perspective, I examine how genetic analyses of primary tumours and matched metastases can distinguish between these two competing metastasis evolution models, with particular emphasis on the utility of metastatic randomness - a quantitative measure that reflects whether metastases arise from a random selection of primary tumour subclones or whether they are enriched for descendants of privileged lineages that have acquired pro-metastatic traits. Probable metastasis evolution trajectories in tumours with high and low baseline metastatic capacity are discussed, along with the role of seeding rates and selection at different metastatic host sites. Finally, I argue that trailblazing insights into human metastasis biology are immediately possible if we make a concerted effort to apply existing experimental and theoretical tools to the right patient cohorts.
    DOI:  https://doi.org/10.1038/s41568-025-00814-x
  6. Gut. 2025 Apr 19. pii: gutjnl-2024-333406. [Epub ahead of print]
    A Common CTRB misfolding variant associated with pancreatic cancer risk causes ER stress and inflammation in mice.
    Cristina Bodas, Irene Felipe, Brice Chanez, Miguel Lafarga, Evangelina Lopez de Maturana, Jaime Martinez de Villarreal, Natalia Del Pozo, Marina Malumbres, Pierfrancesco Vargiu, Ana Cayuela, Isabel Peset, Katelyn Connelly, Jason Hoskins, Raúl Méndez, Laufey Amundadottir, Núria Malats, Sagrario Ortega, Francisco X Real.
       BACKGROUND: Genome-wide association studies have identified an exon 6 CTRB2 deletion variant proposed to increase pancreatic cancer risk.
    OBJECTIVE: To acquire evidence on its causal role, we developed and analysed a new mouse strain carrying an equivalent variant in Ctrb1, the mouse CTRB2 orthologue.
    DESIGN: We used CRISPR/Cas9 to introduce a 707 bp deletion encompassing Ctrb1 exon 6 (Ctrb1Δexon6 ). This mutation closely mimics the human variant. Mice carrying the mutant allele were profiled at 3 months to assess their phenotype.
    RESULTS: Ctrb1Δexon6 mutant mice express a truncated CTRB1 that accumulates in the endoplasmic reticulum (ER). The pancreas of homozygous mutant mice displays reduced chymotrypsin activity, total protein synthesis and amylase secretion. The histological aspect of the pancreas is inconspicuous but ultrastructural analysis shows evidence of dramatic ER stress and cytoplasmic and nuclear inclusions. Transcriptomic studies of the mutant pancreas reveal downregulation of the acinar programme and increased activity of ER stress-related and inflammatory pathways. Agr2 is one of the most upregulated genes in mutant pancreata. Heterozygous mice have an intermediate phenotype. Ctrb1Δexon6 mutant mice exhibit impaired recovery from acute caerulein-induced pancreatitis. Administration of tauroursodeoxycholic acid or sulindac partially alleviates the phenotype. A transcriptomic signature derived from the mutant pancreata is significantly enriched in normal human pancreas of CTRB2 exon 6 deletion variant carriers from the GTEx cohort.
    CONCLUSIONS: This mouse strain provides evidence that the exon 6 deletion causes ER stress and inflammation and is an excellent model to understand its contribution to pancreatic cancer and identify preventive strategies.
    Keywords:  CANCER GENETICS; EXPERIMENTAL PANCREATITIS; INFLAMMATION; PANCREATIC CANCER
    DOI:  https://doi.org/10.1136/gutjnl-2024-333406
  7. Cancer Discov. 2025 Apr 24.
    Intrinsic properties of the lymph node render it immunologically susceptible to metastasis.
    Benjamin M Kahn, Raymond W S Ng, Il-Kyu Kim, Cody Eskandarian, Chelsey O Chen, Bing Huang, Alfredo Lucas, Lequn Li, Ivan Maillard, Ben Z Stanger.
      Lymph nodes (LNs) are the staging grounds for anti-tumor immunity, therefore their high susceptibility to metastatic colonization is a paradox. Previous studies have suggested that extrinsic tumor-derived factors precondition the draining LN to enable tumor cell survival by promoting a state of immune suppression. Here, we investigate whether properties of the LN itself may impede its ability to clear metastasizing tumor cells. Using multiple immunocompetent transplant models, we show that LNs possess intrinsic features, independent of preconditioning, which make them an advantageous site for tumor cells to evade T cell control. Tumor growth in the LN is facilitated by regulatory T cells, which locally suppress the cytolytic capacity of tumor-specific CD8 T cells by restricting IL-2. These findings identify an intrinsic mechanism that contributes to the high rate of LN metastasis in solid tumors.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-1847
  8. Nat Commun. 2025 Apr 24. 16(1): 3867
    DHODH modulates immune evasion of cancer cells via CDP-Choline dependent regulation of phospholipid metabolism and ferroptosis.
    Da Teng, Kenneth D Swanson, Ruiheng Wang, Aojia Zhuang, Haofeng Wu, Zhixin Niu, Li Cai, Faith R Avritt, Lei Gu, John M Asara, Yaqing Zhang, Bin Zheng.
      The ability of cancer cells to evade immune destruction is governed by various intrinsic factors including their metabolic state. Here we demonstrate that inactivation of dihydroorotate dehydrogenase (DHODH), a pyrimidine synthesis enzyme, increases cancer cell sensitivity to T cell cytotoxicity through induction of ferroptosis. Lipidomic and metabolomic analyses reveal that DHODH inhibition reduces CDP-choline level and attenuates the synthesis of phosphatidylcholine (PC) via the CDP-choline-dependent Kennedy pathway. To compensate this loss, there is increased synthesis from phosphatidylethanolamine via the phospholipid methylation pathway resulting in increased generation of very long chain polyunsaturated fatty acid-containing PCs. Importantly, inactivation of Dhodh in cancer cells promotes the infiltration of interferon γ-secreting CD8+ T cells and enhances the anti-tumor activity of PD-1 blockade in female mouse models. Our findings reveal the importance of DHODH in regulating immune evasion through a CDP-choline dependent mechanism and implicate DHODH as a promising target to improve the efficacy of cancer immunotherapies.
    DOI:  https://doi.org/10.1038/s41467-025-59307-y
  9. STAR Protoc. 2025 Apr 23. pii: S2666-1667(25)00199-6. [Epub ahead of print]6(2): 103793
    Protocol for the establishment of murine orthotopic lung tumors and the assessment of contralateral pulmonal metastasis by flow cytometry.
    Gregor Zaun, Siyang Liu, Maximilian Webendörfer, Abubakar Wani, Diego Rodriguez, Douglas R Green, Halime Kalkavan.
      Murine orthotopic tumor models can accurately resemble cancer biology characteristics including metastasis, drug sensitivity, and remodeling of the tumor microenvironment. Here, we present a protocol for establishing murine orthotopic lung tumors and assessing contralateral pulmonary metastasis by flow cytometry. We describe steps for marking tumor cells with label retention dyes, preparing cell mixtures in Matrigel, and performing intrapulmonary injection. We then detail procedures for ex vivo processing of lungs followed by fluorescence-activated cell sorting (FACS) data analysis and quantification of metastatic capacity. For complete details on the use and execution of this protocol, please refer to Kalkavan et al.1.
    Keywords:  Cancer; Cell Biology; Flow Cytometry; Model Organisms; Single Cell
    DOI:  https://doi.org/10.1016/j.xpro.2025.103793
  10. Elife. 2025 Apr 21. pii: e106768. [Epub ahead of print]14
    How cell crowding causes cancer cells to spread.
    Rui Hua, Jean X Jiang.
      Cell crowding causes high-grade breast cancer cells to become more invasive by activating a molecular switch that causes the cells to shrink and spread.
    Keywords:  DCIS; TRPV4; calcium homeostasis; cancer biology; cell biology; cell volume; human; mechanotransduction; trafficking
    DOI:  https://doi.org/10.7554/eLife.106768
  11. Annu Rev Phys Chem. 2025 Apr;76(1): 251-277
    Cellular Signaling at the Nano-Bio Interface: Spotlighting Membrane Curvature.
    Chih-Hao Lu, Christina E Lee, Melissa L Nakamoto, Bianxiao Cui.
      No longer viewed as a passive consequence of cellular activities, membrane curvature-the physical shape of the cell membrane-is now recognized as an active constituent of biological processes. Nanoscale topographies on extracellular matrices or substrate surfaces impart well-defined membrane curvatures on the plasma membrane. This review examines biological events occurring at the nano-bio interface, the physical interface between the cell membrane and surface nanotopography, which activates intracellular signaling by recruiting curvature-sensing proteins. We encompass a wide range of biological processes at the nano-bio interface, including cell adhesion, endocytosis, glycocalyx redistribution, regulation of mechanosensitive ion channels, cell migration, and differentiation. Despite the diversity of processes, we call attention to the critical role of membrane curvature in each process. We particularly highlight studies that elucidate molecular mechanisms involving curvature-sensing proteins with the hope of providing comprehensive insights into this rapidly advancing area of research.
    Keywords:  membrane curvature; nano-bio interface; surface nanotopography
    DOI:  https://doi.org/10.1146/annurev-physchem-090722-021151
  12. Discov Oncol. 2025 Apr 23. 16(1): 592
    Mechanistic insights and therapeutic strategies for targeting autophagy in pancreatic ductal adenocarcinoma.
    Federica Michetti, Mara Cirone, Raffaele Strippoli, Gabriella D'Orazi, Marco Cordani.
      Pancreatic ductal adenocarcinoma (PDAC) is characterised by early metastasis and resistance to anti-cancer therapy, leading to an overall poor prognosis. Macroautophagy (hereinafter referred to as autophagy) is a conserved cellular homeostasis mechanism that degrades various cargoes (e.g., proteins, organelles, and pathogens) mainly playing a role in promoting survival under environmental stress. Autophagy is an essential defense mechanism against PDAC initiation, acting on multiple levels to maintain cellular and tissue homeostasis. However, autophagy is also intimately involved in the molecular mechanisms driving PDAC progression, facilitating the adaptation of cancer cells to the tumor microenvironment's harsh conditions. In this review, we examine the complex role of autophagy in PDAC and assess the potential of modulating autophagy as a therapeutic strategy. By reviewing current research and clinical trials, we seek to elucidate how targeting autophagy can disrupt PDAC tumor survival mechanisms, enhance the efficacy of existing treatments, and ultimately improve patient outcomes.
    Keywords:  Autophagy; Cancer treatment; Immune response; PDAC; Pancreatic cancer; Tumor microenvironment (TME)
    DOI:  https://doi.org/10.1007/s12672-025-02400-x
  13. Cells. 2025 Apr 12. pii: 584. [Epub ahead of print]14(8):
    Softness or Stiffness What Contributes to Cancer and Cancer Metastasis?
    Claudia Tanja Mierke.
      Beyond the genomic and proteomic analysis of bulk and single cancer cells, a new focus of cancer research is emerging that is based on the mechanical analysis of cancer cells. Therefore, several biophysical techniques have been developed and adapted. The characterization of cancer cells, like human cancer cell lines, started with their mechanical characterization at mostly a single timepoint. A universal hypothesis has been proposed that cancer cells need to be softer to migrate and invade tissues and subsequently metastasize in targeted organs. Thus, the softness of cancer cells has been suggested to serve as a universal physical marker for the malignancy of cancer types. However, it has turned out that there exists the opposite phenomenon, namely that stiffer cancer cells are more migratory and invasive and therefore lead to more metastases. These contradictory results question the universality of the role of softness of cancer cells in the malignant progression of cancers. Another problem is that the various biophysical techniques used can affect the mechanical properties of cancer cells, making it even more difficult to compare the results of different studies. Apart from the instrumentation, the culture and measurement conditions of the cancer cells can influence the mechanical measurements. The review highlights the main advances of the mechanical characterization of cancer cells, discusses the strength and weaknesses of the approaches, and questions whether the passive mechanical characterization of cancer cells is still state-of-the art. Besides the cell models, conditions and biophysical setups, the role of the microenvironment on the mechanical characteristics of cancer cells is presented and debated. Finally, combinatorial approaches to determine the malignant potential of tumors, such as the involvement of the ECM, the cells in a homogeneous or heterogeneous association, or biological multi-omics analyses, together with the dynamic-mechanical analysis of cancer cells, are highlighted as new frontiers of research.
    Keywords:  atomic force microscopy; cell mechanics; deformability; matrix confinement; mechanobiology; optical cell stretcher; physics of cancer; softness and stiffness; tissue patchiness; viscoelasticity
    DOI:  https://doi.org/10.3390/cells14080584
  14. Sci Adv. 2025 Apr 25. 11(17): eadt9712
    Synchronized temporal-spatial analysis via microscopy and phosphoproteomics (STAMP) of quiescence.
    Mohammad Ovais Azizzanjani, Rachel E Turn, Anushweta Asthana, Karen Y Linde-Garelli, Lucy Artemis Xu, Leilani E Labrie, Mohammadamin Mobedi, Peter K Jackson.
      Coordinated cell cycle regulation is essential for homeostasis, with most cells in the body residing in quiescence (G0). Many pathologies arise due to disruptions in tissue-specific G0, yet little is known about the temporal-spatial mechanisms that establish G0 and its signaling hub, primary cilia. Mechanistic insight is limited by asynchronous model systems and failure to connect context-specific, transient mechanisms to function. To address this gap, we developed STAMP (synchronized temporal-spatial analysis via microscopy and phosphoproteomics) to track changes in cellular landscape occurring throughout G0 transition and ciliogenesis. We synchronized ciliogenesis and G0 transition in two cell models and combined microscopy with phosphoproteomics to order signals for further targeted analyses. We propose that STAMP is broadly applicable for studying temporal-spatial signaling in many biological contexts. The findings revealed through STAMP provide critical insight into healthy cellular functions often disrupted in pathologies, paving the way for targeted therapeutics.
    DOI:  https://doi.org/10.1126/sciadv.adt9712
  15. Mol Cell. 2025 Apr 18. pii: S1097-2765(25)00304-1. [Epub ahead of print]
    Aberrant phase separation drives membranous organelle remodeling and tumorigenesis.
    Xinyu Wang, Amin Jiang, Quan Meng, Tao Jiang, Huaide Lu, Xiaohan Geng, Zikuo Song, Xinyao Hu, Zhu Yu, Wencong Xu, Chao Ning, Yajing Lin, Dong Li.
      Membrane remodeling is essential for numerous cellular functions. Although liquid-liquid phase separation (LLPS) of intrinsically disordered region (IDR)-rich proteins could drive dramatic membrane remodeling of artificial giant unilamellar vesicles, it remains elusive whether LLPS-mediated membrane-remodeling functions in live cells and what role it plays in specific bioprocesses. Here, we show that three IDR-rich integral transmembrane fusion proteins (MFPs), generated by chromosomal translocations, can lead to de novo remodeling of their located membranous organelles. Taking FUS-CREB3L2, prevalent in low-grade fibromyxoid sarcoma (LGFMS), as a proof of concept, we recorded super-resolution long-time imaging of endoplasmic reticulum (ER) remodeling dynamics as accumulating FUS-CREB3L2, meanwhile causing spontaneous ER stress to hijack the X-box-binding protein 1 (XBP1) pathway. We further reveal the underlying mechanisms of how FUS-CREB3L2 transduces its tumorigenic signals and aberrant LLPS effects from the ER membrane into the nucleus autonomously, which activates hundreds of LGFMS-specific genes de novo compared with CREB3L2, thus sufficiently reprogramming the cells into an LGFMS-like status.
    Keywords:  ER stress; FUS-CREB3L2; fusion proteins; membrane remodeling; phase separation; spontaneous regulated intramembrane proteolysis
    DOI:  https://doi.org/10.1016/j.molcel.2025.04.001
  16. Gut. 2025 Apr 23. pii: gutjnl-2025-335220. [Epub ahead of print]
    Long-chain sulfatide enrichment is an actionable metabolic vulnerability in intraductal papillary mucinous neoplasm (IPMN)-associated pancreatic cancers.
    Yihui Chen, Riccardo Ballarò, Marta Sans, Fredrik Ivar Thege, Mingxin Zuo, Rongzhang Dou, Jimin Min, Michele Yip-Schneider, J Zhang, Ranran Wu, Ehsan Irajizad, Yuki Makino, Kimal I Rajapakshe, Hamid K Rudsari, Mark W Hurd, Ricardo A León-Letelier, Hiroyuki Katayama, Edwin Ostrin, Jody Vykoukal, Jennifer B Dennison, Kim-Anh Do, Samir M Hanash, Robert A Wolff, Paolo A Guerrero, Michael Kim, C Max Schmidt, Anirban Maitra, Johannes F Fahrmann.
       BACKGROUND: We conducted an integrated cross-species spatial assessment of transcriptomic and metabolomic alterations associated with progression of intraductal papillary mucinous neoplasms (IPMNs), which are bona fide cystic precursors of pancreatic ductal adenocarcinoma (PDAC).
    OBJECTIVE: We aimed to uncover biochemical and molecular drivers that underlie malignant progression of IPMNs to PDAC.
    DESIGN: Matrix-assisted laser desorption/ionisation (MALDI) mass spectrometry (MS)-based spatial imaging and Visium spatial transcriptomics (ST) was performed on human resected IPMN/PDAC tissues (n=23) as well as pancreata from a mutant Kras;Gnas mouse model of IPMN/PDAC. Functional studies in murine IPMN/PDAC-derived Kras;Gnas cells were performed using CRISPR/cas9 technology, small interfering RNAs, and pharmacological inhibition.
    RESULTS: MALDI-MS analyses of patient tissues revealed long-chain hydroxylated sulfatides to be selectively enriched in the neoplastic epithelium of IPMN/PDAC. Integrated ST analyses showed cognate transcripts involved in sulfatide biosynthesis, including UGT8, Gal3St1, and FA2H, to co-localise with areas of sulfatide enrichment. Genetic knockout or pharmacological inhibition of UGT8 in Kras;Gnas IPMN/PDAC cells decreased protein expression of FA2H and Gal3ST1 with consequent alterations in mitochondrial morphology and reduced mitochondrial respiration. Small molecule inhibition of UGT8 elicited anticancer effects via ceramide-mediated compensatory mitophagy and activation of intrinsic apoptosis pathways. In vivo, UGT8 inhibition suppressed tumour growth in allograft models of murine IPMN/PDAC cells derived from Kras;Gnas and Kras;Tp53;Gnas mice.
    CONCLUSION: Our work identifies enhanced sulfatide metabolism as an early metabolic alteration in cystic precancerous lesions of the pancreas that persists through invasive neoplasia and a potential actionable vulnerability in IPMN-derived PDAC.
    Keywords:  METABOLOMICS; PANCREATIC CANCER
    DOI:  https://doi.org/10.1136/gutjnl-2025-335220
  17. Sci Adv. 2025 Apr 25. 11(17): eadu7190
    Structural dissection of ergosterol metabolism reveals a pathway optimized for membrane phase separation.
    Israel Juarez-Contreras, Laura J S Lopes, Jamie Holt, Lorena Yu-Liao, Katherine O'Shea, Jose Ruiz-Ruiz, Alexander Sodt, Itay Budin.
      Sterols are among the most abundant lipids in eukaryotic cells yet are synthesized through notoriously long metabolic pathways. It has been proposed that the molecular evolution of such pathways must have required each step to increase the capacity of its product to condense and order phospholipids. Here, we carry out a systematic analysis of the ergosterol pathway that leverages the yeast vacuole's capacity to phase separate into ordered membrane domains. In the post-synthetic steps specific to ergosterol biosynthesis, we find that successive modifications act to oscillate ordering capacity, settling on a level that supports phase separation while retaining fluidity of the resulting domains. Simulations carried out with each intermediate showed how conformers in the sterol's alkyl tail are capable of modulating long-range ordering of phospholipids, which could underlie changes in phase behavior. Our results indicate that the complexity of sterol metabolism could have resulted from the need to balance lipid interactions required for membrane organization.
    DOI:  https://doi.org/10.1126/sciadv.adu7190
  18. Nat Commun. 2025 Apr 24. 16(1): 3857
    Cell Painting PLUS: expanding the multiplexing capacity of Cell Painting-based phenotypic profiling using iterative staining-elution cycles.
    Elena von Coburg, Marlene Wedler, Jose M Muino, Christopher Wolff, Nils Körber, Sebastian Dunst, Shu Liu.
      Phenotypic changes in the morphology and internal organization of cells can indicate perturbations in cell functions. Therefore, imaging-based high-throughput phenotypic profiling (HTPP) applications such as Cell Painting (CP) play an important role in basic and translational research, drug discovery, and regulatory toxicology. Here we present the Cell Painting PLUS (CPP) assay, an efficient, robust and broadly applicable approach that further expands the versatility of available HTPP methods and offers additional options for addressing mode-of-action specific research questions. An iterative staining-elution cycle allows multiplexing of at least seven fluorescent dyes that label nine different subcellular compartments and organelles including the plasma membrane, actin cytoskeleton, cytoplasmic RNA, nucleoli, lysosomes, nuclear DNA, endoplasmic reticulum, mitochondria, and Golgi apparatus. In this way, CPP significantly expands the flexibility, customizability, and multiplexing capacity of the original CP method and, importantly, also improves the organelle-specificity and diversity of the phenotypic profiles due to the separate imaging and analysis of single dyes in individual channels.
    DOI:  https://doi.org/10.1038/s41467-025-58765-8
  19. Database (Oxford). 2025 Apr 21. pii: baaf028. [Epub ahead of print]2025
    Localizatome: a database for stress-dependent subcellular localization changes in proteins.
    Takahide Matsushima, Yuki Naito, Tomoki Chiba, Ryota Kurimoto, Keiko Itano, Koji Ochiai, Koichi Takahashi, Naoki Goshima, Hiroshi Asahara.
      Understanding protein subcellular localization and its dynamic changes is crucial for elucidating cellular function and disease mechanisms, particularly under stress conditions, where protein localization changes can modulate cellular responses. Currently available databases provide insights into protein localization under steady-state conditions; however, stress-related dynamic localization changes remain poorly understood. Here, we present the Localizatome, a comprehensive database that captures stress-induced protein localization dynamics in living cells. Using an original high-throughput microscopy system and machine learning algorithms, we analysed the localization patterns of 10 287 fluorescent protein-fused human proteins in HeLa cells before and after exposure to oxidative stress. Our analysis revealed that 1910 proteins exhibited oxidative stress-dependent localization changes, particularly forming distinct foci. Among them, there were stress granule assembly factors and autophagy-related proteins, as well as components of various signalling pathways. Subsequent characterization identified some specific amino acid motifs and intrinsically disordered regions associated with stress-induced protein redistribution. The Localizatome provides open access to these data through a web-based interface, supporting a wide range of studies on cellular stress response and disease mechanisms. Database URL https://localizatome.embrys.jp/.
    DOI:  https://doi.org/10.1093/database/baaf028
  20. Nat Commun. 2025 Apr 24. 16(1): 3842
    Local mapping of the nanoscale viscoelastic properties of fluid membranes by AFM nanorheology.
    William Trewby, Mahdi Tavakol, Kislon Voïtchovsky.
      Biological membranes are intrinsically dynamic entities that continually adapt their biophysical properties and molecular organisation to support cellular function. Current microscopy techniques can derive high-resolution structural information of labelled molecules but quantifying the associated viscoelastic behaviour with nanometre precision remains challenging. Here, we develop an approach based on atomic force microscopy in conjunction with fast nano-actuators to map the viscoelastic response of unlabelled supported membranes with nanometre spatial resolution. On fluid membranes, we show that the method can quantify local variations in the molecular mobility of the lipids and derive a diffusion coefficient. We confirm our experimental approach with molecular dynamics simulations, also highlighting the role played by the water at the interface with the membrane on the measurement. Probing ternary model bilayers reveals spatial correlations in the local diffusion over distances of ≈20 nm within liquid disordered domains. This lateral correlation is enhanced in native bovine lens membranes, where the inclusion of protein-rich domains induces four-fold variations in the diffusion coefficient across < 100 nm of the fluid regions, consistent with biological function. Our findings suggest that diffusion is highly localised in fluid biomembranes.
    DOI:  https://doi.org/10.1038/s41467-025-59260-w
  21. Nat Immunol. 2025 Apr 22.
    Macrophages and fibroblasts as regulators of the immune response in pancreatic cancer.
    Mojdeh Shakiba, David A Tuveson.
      Pancreatic ductal adenocarcinoma (PDAC) is one of the few cancers that has yet to benefit from immunotherapies. This is primarily a result of its characteristic 'cold' tumor microenvironment composed of cancer-associated fibroblasts (CAFs), a dense network of extracellular matrix and several immune cell types, the most abundant of which are the tumor-associated macrophages (TAMs). Advances in single-cell and spatial technologies have elucidated the vast functional heterogeneity of CAFs and TAMs, their symbiotic relationship and their cooperative role in the tumor microenvironment. In this Review, we provide an overview of the heterogeneity of CAFs and TAMs, how they establish an immunosuppressive microenvironment and their collaboration in the remodeling of the extracellular matrix. Finally, we examine why the impact of immunotherapy in PDAC has been limited and how a detailed molecular and spatial understanding of the combined role of CAFs and TAMs is paramount to the design of effective therapies.
    DOI:  https://doi.org/10.1038/s41590-025-02134-6
  22. Invest New Drugs. 2025 Apr 24.
    PANTAX: a phase Ib clinical trial of the efflux pump inhibitor SCO-101 in combination with gemcitabine and nab-paclitaxel in non-resectable or metastatic pancreatic cancer.
    Susy Shim, Anke Reinacher-Schick, Anna-Lena Kraeft, Per Pfeiffer, Line Schmidt Tarpgaard, Thomas Jens Ettrich, Angelika Kestler, Signe Christensen, Haatisha Jandu, Mubeen Nawabi, Nicklas Lindland Roest, Lars Damstrup, Peter Michael Vestlev, Nils Brünner, Jan Stenvang, Morten Ladekarl.
      De novo or acquired resistance to chemotherapy is ubiquitous in pancreatic ductal adenocarcinoma (PDAC). SCO-101 is an oral compound that may counteract chemo-resistance by interacting with SRPK1, ABCG2 drug transporter, and liver enzyme UGT1A1. We first conducted preclinical experiments in paclitaxel-resistant PDAC cells to access the tumoricidal effects of SCO-101 or SRPK1-inhibitor alone or in combination with paclitaxel. Second, we enrolled 22 patients with non-resectable PDAC in a phase Ib trial to investigate safety and pharmaco-kinetics, and to establish maximum tolerated dose (MTD) by evaluation of dose-limiting toxicities (DLTs) during the first cycle of 80% dose gemcitabine (Gem) and nab-paclitaxel (Nab) together with increasing doses of SCO-101. In paclitaxel-resistant PDAC cells in vitro, a synergistic effect between SCO-101 and paclitaxel was demonstrated. In patients, daily doses for 6 days of SCO-101 resulted in a two- to threefold drug accumulation, and drug exposure was dose proportional. Treatment was well tolerated. Transiently increased blood bilirubin attributable to SCO-101 was observed in 12 cases (55%) and associated with jaundice in three patients. One and two DLTs, respectively, were observed at 150 and 250mg dosing-levels of SCO-101, and the MTD was determined to be 200 mg of SCO-101 daily for 6 days on a bi-weekly schedule together with 80% dose of Gem and Nab. Median progression-free and overall survival was 3.3 and 9.5 months, respectively. In PDAC, SCO-101 can be added to Gem and Nab with little and manageable toxicity. However, no clear added efficacy signal was observed of the combination. Trial registration number: NCT04652205 (Nov 29, 2020).
    Keywords:  Chemotherapy resistance mechanisms; Cytotoxicity assay; Gemcitabine; Nab-paclitaxel; Pancreas cancer
    DOI:  https://doi.org/10.1007/s10637-025-01526-7
  23. Nat Cell Biol. 2025 Apr 21.
    Metabolites in tumour interstitial fluid directly suppress T cells.
      
    DOI:  https://doi.org/10.1038/s41556-025-01652-7
  24. Methods. 2025 Apr 20. pii: S1046-2023(25)00102-1. [Epub ahead of print]
    Non-invasive tools for analysis of plasma membrane protein topology in living cells.
    Daria Savenkova, Leysan Bulatova, Vera Skripova, Ramziya Kiyamova, Mikhail Bogdanov.
      Membrane protein topology studies offer guidance to membrane protein structure, folding, and function, serving as a credible scaffold for designing site-directed mutagenesis and biochemical experiments, helping to identify functionally significant extracellular and intracellular regions, modeling three-dimensional structures, and building reliable mechanistic models. Membrane protein structure as a function of given lipid composition and physiological state of the cell is best probed in whole intact cells. A described simple and advanced immunofluorescence protocol applied to the transmembrane orientation of extramembrane domains permits a topology analysis of plasma membrane proteins in their native state in living unperturbed eucaryotic cells. The accessibility of native epitopes to corresponding antibodies is determined in intact and permeabilized cells to establish their extra- or intracellular or localization respectively. The ability of the given antibody to bind the epitope in intact live and permeabilized cells is then assessed routinely by intact and permeabilized cell immunofluorescent confocal microscopy or fluorescence flow cytometry parametric analyses in several hours. To ensure that the observed immunofluorescence is entirely a result of the binding of antibodies, cells are alive and the plasma membrane is intact, plasma membrane integrity is routinely monitored by co-incubating the cells with a cell membrane-impermeable probe, propidium iodide. Accordingly, plasma membrane side-specific immunostaining analysis was restricted to the propidium iodide-negative, non-permeabilized cell population. The strength of this technique is its simplicity since each native epitope is unique and there is no need to mutate any endogenous sites, introduce new epitopes, or engineer single, dual, or split colorimetric enzymatic reporters. Aside from its simplicity, the advantage of this approach is that the topology is documented in the context of full-length and fully biologically active membrane protein molecules, and topology mapping is carried out using whole live cells, thereby avoiding problems related to cell fixation or the conversion of cells into membrane vesicles with a uniform orientation. The protocol can be universally adapted to any cellular system to systematically map a uniform topology of target membrane protein.
    Keywords:  Antibodies; Confocal microscopy; Flow cytometry; Fluorescence; Membrane protein; Plasma membrane; Propidium iodide; Topology
    DOI:  https://doi.org/10.1016/j.ymeth.2025.04.007
  25. Membranes (Basel). 2025 Apr 01. pii: 106. [Epub ahead of print]15(4):
    Boundary Flow-Induced Membrane Tubulation Under Turgor Pressures.
    Hao Xue, Rui Ma.
      During clathrin-mediated endocytosis in yeast cells, a small patch of flat membrane is deformed into a tubular shape. It is generally believed that the tubulation is powered by actin polymerization. However, studies based on quantitative measurement of the actin molecules suggest that they are not sufficient to produce the forces to overcome the high turgor pressure inside of the cell. In this paper, we model the membrane as a viscous 2D fluid with elasticity and study the dynamic membrane deformation powered by a boundary lipid flow under osmotic pressure. We find that in the absence pressure, the lipid flow drives the membrane into a spherical shape or a parachute shape. The shapes over time exhibit self-similarity. The presence of pressure transforms the membrane into a tubular shape that elongates almost linearly with time and the self-similarity between shapes at different times is lost. Furthermore, the width of the tube is found to scale inversely to the cubic root of the pressure, and the tension across the membrane is negative and scales to the cubic root squared of the pressure. Our results demonstrate that boundary flow powered by myosin motors, as a new way to deform the membrane, could be a supplementary mechanism to actin polymerization to drive endocytosis in yeast cells.
    Keywords:  boundary flow; endocytosis; membrane dynamics
    DOI:  https://doi.org/10.3390/membranes15040106
  26. Nature. 2025 Apr;640(8060): S68-S71
    Four rising stars at the forefront of cancer research.
    Felicity Nelson, Sandy Ong.
      
    Keywords:  Cancer; Cell biology; Computational biology and bioinformatics; Drug discovery; Medical research
    DOI:  https://doi.org/10.1038/d41586-025-01155-3
  27. Gut. 2025 Apr 19. pii: gutjnl-2024-334691. [Epub ahead of print]
    Distinct gene expression mechanisms in classical and basal PDAC subtypes.
    Irene Felipe, Mark Kalisz.
      
    Keywords:  GENE EXPRESSION; PANCREATIC CANCER
    DOI:  https://doi.org/10.1136/gutjnl-2024-334691
  28. Angew Chem Int Ed Engl. 2025 Apr 24. e202501884
    LC-MS and High-Throughput Data Processing Solutions for Lipid Metabolic Tracing Using Biorthogonal Click Chemistry.
    Palina Nepachalovich, Stefano Bonciarelli, Gabriele Lombardi Bendoula, Jenny Desantis, Michela Eleuteri, Christoph Thiele, Laura Goracci, Maria Fedorova.
      Tracing lipid metabolism in mammalian cells presents a significant technological challenge due to the vast structural diversity of lipids involved in multiple metabolic routes. Biorthogonal approaches based on click chemistry have revolutionized analytical performance in lipid tracing. When adapted for mass spectrometry (MS), it enables highly specific and sensitive analyses of lipid transformations at the lipidome scale. Here, we advance this approach by integrating liquid chromatography (LC) prior to MS detection and developing a software-assisted workflow for high-throughput data processing. LC separation resolved labelled and unmodified lipids, enabling qualitative and quantitative analysis of both lipidome fractions, as well as isomeric lipid species. Using synthetic standards and endogenously produced alkyne lipids, we characterized LC-MS behaviour, including preferential adduct formation and extent of in-source fragmentation. Specific fragmentation rules derived from tandem MS experiments for 23 lipid subclasses, were implemented in Lipostar2 software for high-throughput annotation and quantification of labelled lipids. Applying this platform, we traced metabolic pathways of palmitic and oleic acid alkynes, revealing distinct lipid incorporation patterns and metabolic bottlenecks. Altogether, here we provide integrated analytical and bioinformatics platform for high-throughput tracing of lipid metabolism using LC-MS workflow.
    Keywords:  click chemistry * LC-MS * Lipostar2 * sphingolipids * tracing lipid metabolism
    DOI:  https://doi.org/10.1002/anie.202501884
  29. Elife. 2025 Apr 21. pii: RP100490. [Epub ahead of print]13
    Cell crowding activates pro-invasive mechanotransduction pathway in high-grade DCIS via TRPV4 inhibition and cell volume reduction.
    Xiangning Bu, Nathanael Ashby, Teresa Vitali, Sulgi Lee, Ananya Gottumukkala, Kangsun Yun, Sana Tabbara, Patricia Latham, Christine Teal, Inhee Chung.
      Cell crowding is a common microenvironmental factor influencing various disease processes, but its role in promoting cell invasiveness remains unclear. This study investigates the biomechanical changes induced by cell crowding, focusing on pro-invasive cell volume reduction in ductal carcinoma in situ (DCIS). Crowding specifically enhanced invasiveness in high-grade DCIS cells through significant volume reduction compared to hyperplasia-mimicking or normal cells. Mass spectrometry revealed that crowding selectively relocated ion channels, including TRPV4, to the plasma membrane in high-grade DCIS cells. TRPV4 inhibition triggered by crowding decreased intracellular calcium levels, reduced cell volume, and increased invasion and motility. During this process, TRPV4 membrane relocation primed the channel for later activation, compensating for calcium loss. Analyses of patient-derived breast cancer tissues confirmed that plasma membrane-associated TRPV4 is specific to high-grade DCIS and indicates the presence of a pro-invasive cell volume reduction mechanotransduction pathway. Hyperosmotic conditions and pharmacologic TRPV4 inhibition mimicked crowding-induced effects, while TRPV4 activation reversed them. Silencing TRPV4 diminished mechanotransduction in high-grade DCIS cells, reducing calcium depletion, volume reduction, and motility. This study uncovers a novel pro-invasive mechanotransduction pathway driven by cell crowding and identifies TRPV4 as a potential biomarker for predicting invasion risk in DCIS patients.
    Keywords:  DCIS; TRPV4; calcium homeostasis; cancer biology; cell biology; cell volume; human; mechanotransduction; trafficking
    DOI:  https://doi.org/10.7554/eLife.100490
  30. Am J Physiol Cell Physiol. 2025 Apr 24.
    Mechano-metabolism: Recent Findings on the Intersection of Cell Adhesion, Cell Migration, and Metabolism.
    Emily D Fabiano, Jenna M Poole, Cynthia A Reinhart-King.
      Chemical and mechanical cues within the extracellular matrix (ECM) can initiate intracellular signaling that changes an array of fundamental cell functions. In recent work, studies of cell-ECM adhesion have deepened to include the influence of the physical ECM on cell metabolism. Since many biological processes involve metabolic programs, changes to cellular metabolism in response to cues in the ECM can have marked effects on cell health. In this review, we describe molecular mechanisms associated with cell-ECM adhesion that are key players in metabolism-induced changes to cell behaviors, including migration. We first review how changes to metabolite availability in the extracellular environment or manipulation of metabolic machinery in cells impact focal adhesions. We then connect this work to recent findings regarding the reverse relationship, namely how the manipulation of focal adhesion proteins or integrins feeds back to alter cell metabolism. Finally, we consider the latest findings from studies that describe how the mechanical properties of the ECM, primarily stiffness and confinement, alter cellular metabolism. We identify key areas of future investigation that may elucidate the molecular drivers that permit cells to respond to mechanical and chemical ECM cues by reprogramming their metabolism to better inform future diagnostics and therapeutics for disease states.
    Keywords:  Extracellular Matrix; Focal Adhesions; Integrins; Metabolism; Migration
    DOI:  https://doi.org/10.1152/ajpcell.00892.2024
  31. Sci Adv. 2025 Apr 25. 11(17): eadx4047
    Protecting centrosomes from fracturing enables efficient cell navigation.
    Madeleine T Schmitt, Janina Kroll, Mauricio J A Ruiz-Fernandez, Robert Hauschild, Shaunak Ghosh, Petra Kameritsch, Jack Merrin, Johanna Schmid, Kasia Stefanowski, Andreas W Thomae, Jingyuan Cheng, Gamze Naz Öztan, Peter Konopka, Germán Camargo Ortega, Thomas Penz, Luisa Bach, Dirk Baumjohann, Christoph Bock, Tobias Straub, Felix Meissner, Eva Kiermaier, Jörg Renkawitz.
      The centrosome is a microtubule orchestrator, nucleating and anchoring microtubules that grow radially and exert forces on cargos. At the same time, mechanical stresses from the microenvironment and cellular shape changes compress and bend microtubules. Yet, centrosomes are membraneless organelles, raising the question of how centrosomes withstand mechanical forces. Here, we discover that centrosomes can deform and even fracture. We reveal that centrosomes experience deformations during navigational pathfinding within motile cells. Coherence of the centrosome is maintained by Dyrk3 and cNAP1, preventing fracturing by forces. While cells can compensate for the depletion of centriolar-based centrosomes, the fracturing of centrosomes impedes cellular function by generating coexisting microtubule organizing centers that compete during path navigation and thereby cause cellular entanglement in the microenvironment. Our findings show that cells actively maintain the integrity of the centrosome to withstand mechanical forces. These results suggest that centrosome stability preservation is fundamental, given that almost all cells in multicellular organisms experience forces.
    DOI:  https://doi.org/10.1126/sciadv.adx4047
  32. Curr Opin Support Palliat Care. 2025 Apr 24.
    Cancer cachexia: exploring parallels with other paraneoplastic syndromes.
    Michael S Yule, Amy Ireland, Barry J A Laird, Richard J E Skipworth.
       PURPOSE OF REVIEW: Cancer cachexia (CC) is a paraneoplastic syndrome (PNS) that is characterised by anorexia, weight loss, fatigue and reduced function. This review explores the molecular drivers of CC and other PNS, identifying shared pathways and highlighting unexplored gaps in research.
    RECENT FINDINGS: Recent studies have provided further evidence of pro-inflammatory cytokines, such as interleukin-6 and tumour necrosis factor-α, as central players in both CC and PNS, emphasising their role in systemic effects like muscle wasting, lipolysis and pyrexia. Despite these overlaps between syndromes, cytokine profiles vary across different cancer types with one study highlighting that the interplay between multiple cytokines likely plays a more significant role in cancer phenotypes than individual cytokines. Mediators, such as parathyroid hormone related peptide and vascular endothelial growth factor, which are typically associated with malignant hyperkalaemia and hypertrophic osteoarthropathy respectively, have also been linked to cachexia, suggesting a shared role.
    SUMMARY: This review highlights the overlap between CC and other PNS. Exploring these shared mechanisms can bridge research gaps and improve CC treatment strategies. Similar insights may be gained by examining other conditions which overlap with CC such as eating disorders, bariatric surgery and sepsis.
    Keywords:  cachexia; cancer; inflammation; paraneoplastic; pathophysiology
    DOI:  https://doi.org/10.1097/SPC.0000000000000762
  33. Nature. 2025 Apr 23.
    A protein tunnel that shuttles lipids around the cell.
      
    Keywords:  Cell biology; Structural biology
    DOI:  https://doi.org/10.1038/d41586-025-01167-z
  34. J Cell Sci. 2025 May 01. pii: jcs263780. [Epub ahead of print]138(9):
    Origin and evolution of mitochondrial inner membrane composition.
    Kailash Venkatraman, Nicolas-Frédéric Lipp, Itay Budin.
      Unique membrane architectures and lipid building blocks underlie the metabolic and non-metabolic functions of mitochondria. During eukaryogenesis, mitochondria likely arose from an alphaproteobacterial symbiont of an Asgard archaea-related host cell. Subsequently, mitochondria evolved inner membrane folds known as cristae alongside a specialized lipid composition supported by metabolic and transport machinery. Advancements in phylogenetic methods and genomic and metagenomic data have suggested potential origins for cristae-shaping protein complexes, such as the mitochondrial contact site and cristae-organizing system (MICOS). MICOS protein homologs function in the formation of cristae-like intracytoplasmic membranes (ICMs) in diverse extant alphaproteobacteria. The machinery responsible for synthesizing key mitochondrial phospholipids - which cooperate with cristae-shaping proteins to establish inner membrane architecture - could have also evolved from a bacterial ancestor, but its origins have been less explored. In this Review, we examine the current understanding of mitochondrial membrane evolution, highlighting distinctions between prokaryotic and eukaryotic mitochondrial-specific proteins and lipids and their differing roles in shaping cristae and ICM architecture, and propose a model explaining the concurrent specialization of the mitochondrial lipidome and inner membrane structure in eukaryogenesis. We discuss how advancements across a range of disciplines are shedding light on how multiple membrane components co-evolved to support the central functions of eukaryotic mitochondria.
    Keywords:  Cardiolipin; Cristae; Curvature; Evolution; Mitochondria; Phospholipids
    DOI:  https://doi.org/10.1242/jcs.263780
  35. STAR Protoc. 2025 Apr 17. pii: S2666-1667(25)00190-X. [Epub ahead of print]6(2): 103784
    Protocol on utilizing murine gastric cancer organoids for modeling subcutaneous, orthotopic primary, and liver metastatic disease in mice.
    Joshua Konecnik, Ryan N O'Keefe, Kiruthiga Raghunathan, Saumya P Jacob, Megan O'Brien, Anne Huber, Purva Trivedi, Christine Dijkstra, Amr H Allam, Michael Buchert, Matthias Ernst, Moritz F Eissmann.
      Tumor initiation, growth, and spread are influenced by cancer cell intrinsic and tissue microenvironment factors of the organ the tumor resides in. Here, we provide a protocol on utilizing murine gastric cancer (GC) organoids as transplantable mouse models for subcutaneous, orthotopic primary, and liver metastatic disease. We provide detailed instructions for organoid expansion; processing of GC organoids; and their subsequent subcutaneous, intra-stomach wall, and intra-splenic transplantation. We then detail steps for post-procedure tumor and metastasis monitoring and outcomes. For complete details on the use and execution of this protocol, please refer to Huber et al.1.
    Keywords:  Cancer; Model Organisms; Organoids
    DOI:  https://doi.org/10.1016/j.xpro.2025.103784
  36. EMBO J. 2025 Apr 22.
    Autophagosomes anchor an AKAP11-dependent regulatory checkpoint that shapes neuronal PKA signaling.
    Ashley Segura-Roman, Y Rose Citron, Myungsun Shin, Nicole Sindoni, Alex Maya-Romero, Simon Rapp, Claire Goul, Joseph D Mancias, Roberto Zoncu.
      Protein Kinase A (PKA) is regulated spatially and temporally via scaffolding of its catalytic (Cα) and regulatory (RI/RII) subunits by the A-kinase-anchoring proteins (AKAP). By binding to an AKAP11 scaffold, PKA engages in poorly understood interactions with autophagy, a key degradation pathway for neuronal cell homeostasis. Mutations in AKAP11 promote schizophrenia and bipolar disorders (SZ-BP) through unknown mechanisms. Here, through proteomic-based analyses of immunopurified lysosomes, we identify the Cα-RIα-AKAP11 holocomplex as a prominent autophagy-associated protein-kinase complex. AKAP11 scaffolds Cα-RIα interaction with the autophagic machinery via its LC3-interacting region (LIR), enabling both PKA regulation by upstream signals, and its autophagy-dependent degradation. We identify Ser83 on the RIα linker-hinge region as an AKAP11-dependent phospho-residue that modulates RIα-Cα binding to the autophagosome and cAMP-induced PKA activation. Decoupling AKAP11-PKA from autophagy alters downstream phosphorylation events, supporting an autophagy-dependent checkpoint for PKA signaling. Ablating AKAP11 in induced pluripotent stem cell-derived neurons reveals dysregulation of multiple pathways for neuronal homeostasis. Thus, the autophagosome is a platform that modulates PKA signaling, providing a possible mechanistic link to SZ/BP pathophysiology.
    Keywords:  AKAP11; Autophagy; Phosphoproteomics; Protein kinase A; Signaling
    DOI:  https://doi.org/10.1038/s44318-025-00436-x
  37. N Engl J Med. 2025 Apr 24. 392(16): 1594-1608
    Tumor-Infiltrating Clonal Hematopoiesis.
    Oriol Pich, Elsa Bernard, Maria Zagorulya, Andrew Rowan, Constandina Pospori, Ramy Slama, Hector Huerga Encabo, Jennifer O'Sullivan, Despoina Papazoglou, Panayiotis Anastasiou, Chrysante S Iliakis, Sally-Ann Clark, Krijn K Dijkstra, Vittorio Barbè, Chris Bailey, Aaron J Stonestrom, Katey S S Enfield, Mary Green, Charlotte K Brierley, Alastair Magness, David R Pearce, Robert E Hynds, Rija Zaidi, Jayant K Rane, Ángel F Álvarez-Prado, Kerstin Thol, Rachel Scott, Supreet Kaur Bola, Elena Hoxha, Steve K Harris, Karl S Peggs, Sergio A Quezada, Allan Hackshaw, Simone Zaccaria, Johanna A Joyce, Ilaria Malanchi, Michael F Berger, Mariam Jamal-Hanjani, Andreas Wack, Julian Downward, William Grey, Cristina Lo Celso, Eva Grönroos, Charles M Rudin, Adam J Mead, Dominique Bonnet, Elli Papaemmanuil, Charles Swanton.
       BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition associated with increased mortality among patients with cancer. CHIP mutations with high variant-allele frequencies can be detected in tumors, a phenomenon we term tumor-infiltrating clonal hematopoiesis (TI-CH). The frequency of TI-CH and its effect on tumor evolution are unclear.
    METHODS: We characterized CHIP and TI-CH in 421 patients with early-stage non-small-cell lung cancer (NSCLC) from the TRACERx study and in 49,351 patients from the MSK-IMPACT pan-cancer cohort. We studied the association of TI-CH with survival and disease recurrence and evaluated the functional effect of TET2-mutant CHIP on the biologic features of lung tumors.
    RESULTS: Among patients with NSCLC, 42% of those with CHIP had TI-CH. TI-CH independently predicted an increased risk of death or recurrence, with an adjusted hazard ratio of 1.80 (95% confidence interval [CI], 1.23 to 2.63) as compared with the absence of CHIP and an adjusted hazard ratio of 1.62 (95% CI, 1.02 to 2.56) as compared with CHIP in the absence of TI-CH. Among patients with solid tumors, 26% of those with CHIP had TI-CH. TI-CH conferred a risk of death from any cause that was 1.17 times (95% CI, 1.06 to 1.29) as high as the risk with CHIP in the absence of TI-CH. TET2 mutations were the strongest genetic predictor of TI-CH; such mutations enhanced monocyte migration to lung tumor cells, fueled a myeloid-rich tumor microenvironment in mice, and resulted in the promotion of tumor organoid growth.
    CONCLUSIONS: TI-CH increased the risk of disease recurrence or death among patients with NSCLC and the risk of death from any cause among patients with solid tumors. TI-CH remodeled the tumor immune microenvironment and accelerated tumor organoid growth, findings that support a role for an aging-related hematologic clonal proliferation in cancer evolution. (Funded by the Royal Society and others.).
    DOI:  https://doi.org/10.1056/NEJMoa2413361
  38. Nat Cell Biol. 2025 Apr 21.
    Tumour interstitial fluid-enriched phosphoethanolamine suppresses T cell function.
    Yupeng Wang, Drew Wilfahrt, Patrick Jonker, Konstantinos Lontos, Chufan Cai, Benjamin Cameron, Bingxian Xie, Ronal M Peralta, Emerson R Schoedel, William G Gunn, Roya AminiTabrizi, Hardik Shah, Dayana B Rivadeneira, Alexander Muir, Greg M Delgoffe.
      Nutrient stress represents an important barrier for anti-tumour immunity, and tumour interstitial fluid often contains metabolites that hinder immune function. However, it is difficult to isolate the effects of tumour nutrient stress from other suppressive factors. Thus, we used a chemically defined cell culture medium based on the metabolomic profile of tumour interstitial fluid: tumour interstitial fluid medium (TIFM). Culture of CD8+ T cells in TIFM limited cell expansion and impaired CD8+ T cell effector functions upon restimulation, suggesting that tumour nutrient stress alone is sufficient to drive T cell dysfunction. We identified phosphoethanolamine (pEtn), a phospholipid intermediate, as a driver of T cell dysfunction. pEtn dampened T cell receptor signalling by depleting T cells of diacylglycerol required for T cell receptor signal transduction. The reduction of pEtn accumulation in tumours improved intratumoural T cell function and tumour control, suggesting that pEtn accumulation plays a dominant role in immunosuppression in the tumour microenvironment.
    DOI:  https://doi.org/10.1038/s41556-025-01650-9
  39. Adv Sci (Weinh). 2025 Apr 24. e2417805
    Mechanisms and Therapeutic Strategies for Minority Cell-Induced Paclitaxel Resistance and Tumor Progression Mediated by Mechanical Forces.
    Xueyan Feng, Di Zhang, Guoxun Wang, Liwei Lu, Feng Feng, Xiuyu Wang, Chanchan Yu, Yahong Chai, Jin Zhang, Wenchao Li, Jing Liu, Hongxia Sun, Li Yao.
      Chemotherapy remains a prevalent strategy in cancer therapy; however, the emergence of drug resistance poses a considerable challenge to its efficacy. Most drug resistance arises from the accumulation of genetic mutations in a minority of resistant cells. The mechanisms underlying the emergence and progression of cancer resistance from these minority-resistant cells (MRCs) remain poorly understood. This study employs force-induced remnant magnetization spectroscopy (FIRMS) alongside various biological investigations to reveal the mechanical pathways for MRCs fostering drug resistance and tumor progression. The findings show that minority Paclitaxel-resistant cancer cells have enhanced mechanical properties. These cells can transmit high-intensity forces to surrounding sensitive cells (SCs) through the force transducer, Merlin. This force transmission facilitates the assimilation of surrounding SCs, subsequently strengthening the contraction and adhesion of tumor cells. This process is termed "mechano-assimilation," which accelerates the development of drug resistance and tumor progression. Interestingly, disturbances and reductions of mechano-assimilation within tumors can restore sensitivity to Paclitaxel both in vitro and in vivo. This study provides preliminary evidence highlighting the contribution of MRCs to the development of drug resistance and malignancy, mediated through mechanical interactions. It also establishes a foundation for future research focused on integrating mechanical factors into innovative cancer therapies.
    Keywords:  cancer therapy; mechanical force; mechano‐assimilation; minority Paclitaxel‐resistant cancer cells; tumor microenvironment
    DOI:  https://doi.org/10.1002/advs.202417805
  40. J Cell Sci. 2025 Apr 15. pii: jcs263786. [Epub ahead of print]138(8):
    Epithelial cell extrusion at a glance.
    Aline Grata, Romain Levayer.
      The robustness and plasticity of epithelial tissues rely on the capacity of such tissues to eliminate cells without affecting their sealing. This is achieved by epithelial cell extrusion - a well-orchestrated series of remodelling steps involving the eliminated cell and its neighbours - which ensures the constant maintenance of mechanical and chemical barrier properties while allowing cell expulsion. In this Cell Science at a Glance and the accompanying poster, we describe the remodelling steps that take place within dying or extruding cells, as well as neighbouring cells, outlining the commonalities and variations between tissues and organisms. These steps include reorganization of the cytoskeleton and remodelling of cell-cell junctions that alters their contribution to mechanical coupling and mechanotransduction. We also discuss larger-scale coordination between cells and the contribution of cell extrusion to tissue morphogenesis, epithelial surveillance mechanisms, and pathologies such as cancer and chronic inflammation. Altogether, we outline the complexity and plasticity of this minimalist morphogenetic process.
    Keywords:  Actomyosin; Apoptosis; Caspases; Cell extrusion; Cell–cell adhesion; Epithelium; Junctions
    DOI:  https://doi.org/10.1242/jcs.263786
  41. J Phys Chem B. 2025 Apr 24.
    Collective Vibration Decoupling of Confined Water in Membrane Channels.
    Yang Liu, Bin Liao, Qi-Lin Zhang.
      We previously reported that the asymmetric IR absorption of monolayer water confined within two-dimensional nanochannels is capable of nonthermally inducing a unidirectional flow [Zhang, Q. L. Phys. Rev. Lett. 2024, 132, 184003], while the reason for the difference in the collective vibration IR spectrum between the confined water (CW) and bulk water is still not fully understood. Here, using molecular dynamics simulations, we systematically demonstrated that the CW in narrow graphene membrane channels will appear as a predominant fingerprint-peak and a subpeak in the collective vibration spectrum band. A comparison with the calculated IR spectrum for the CW in the channels with different interlayer spacings revealed that the double-peaked pattern originates from the decoupling of the CW's collective vibration. The highlight spectral intensity of the fingerprint-peak is attributed to the low-cost out-of-plane vibration (wag mode) of the CW molecules. These findings help us understand the physical origins of the unique IR spectra of CW in nanochannels, thereby providing a robust theoretical support for the regulation of the CW's structure and dynamics properties by a remote terahertz stimulation.
    DOI:  https://doi.org/10.1021/acs.jpcb.5c00172
  42. Shock. 2025 Apr 16.
    SVF mediates immunometabolic alterations in burn-induced hypermetabolic adipose tissue via mitochondrial transfer.
    Lauar de Brito Monteiro, Shayahati Bieerkehazhi, Ayesha Aijaz, Carly M Knuth, Graham Rix, Ju Hee Lee, Hoon-Ki Sung, Mahmoud Farahat, Marc G Jeschke.
       ABSTRACT: Adipose tissue (AT) browning promotes systemic alterations in energy expenditure as a response to catecholamine-induced hypermetabolism in severe burn trauma. The AT is composed of the stromal vascular fraction (SVF) and adipocytes. SVF contains a vast population of immune cells that maintain AT homeostasis. Despite evidence that local immune cell accumulation contributes to hypermetabolism, the underlying mechanism of persistent browning response is not known. Thus, we hypothesized that a specific cellular communication between adipocytes and SVF can mediate the severe metabolic alterations associated with hypermetabolism. Therefore, we used a murine burn model to show that post-burn hypermetabolism compromises mitochondria respiration and alters the immune cell profile of the AT-SVF. We found that adipocyte-derived signals promote metabolic reprogramming and inflammatory responses by SVF after burns in both mice and humans. Interestingly, adipocytes transfer mitochondria to cells in the SVF including different immune cells (macrophages, T cells, B cells) uptake mitochondria from adipocytes. Such data was replicated in human samples as well. These results indicate that adipocytes play a major role in immunometabolic reprogramming following severe burns through crosstalk with the adipose immune cell population. Therefore, targeting immune cell metabolism restoration is a potential strategy to mitigate the detrimental effects of post-burn hypermetabolism on systemic energy balance.
    Keywords:  Adipose tissue; Browning; Hypermetabolism; Immunometabolism; Inflammation; Mitochondria biology
    DOI:  https://doi.org/10.1097/SHK.0000000000002608
This page is being maintained by Thomas Krichel. It was last updated on 2025‒04‒27 at 18:49.