bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2025–12–14
thirty-six papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Mutant GNAS drives a pyloric metaplasia with tumor suppressive glycans in intraductal papillary mucinous neoplasia.
  2. Target cell cortical tension regulates macrophage trogocytosis.
  3. Adaptation of redox metabolism in drug-tolerant persister cells is a vulnerability to prevent relapse in pancreatic cancer.
  4. A step-by-step guide to performing cancer metabolism research using custom-made media.
  5. Acyl-chain saturation drives lipid sorting to model lipid droplets.
  6. Six highlights from pancreatic cancer research.
  7. Endoplasmic reticulum disruption stimulates nuclear membrane mechanotransduction.
  8. Neutrophils preserve energy storage in sympathetically activated adipocytes.
  9. scDrugMap: benchmarking large foundation models for drug response prediction.
  10. Cancer-Associated Cachexia in the Era of Obesity.
  11. The pancreatic cancer models helping to drive innovation in the field.
  12. A breathalyser-style test for detecting pancreatic cancer.
  13. A single vesicle fluorescence microscopy platform to quantify phospholipid scrambling.
  14. Chronic enteritis triggered by diet westernization is driven by epithelial ATG16L1-mediated autophagy.
  15. Transcriptomic analyses of normal human pancreata reveal the presence of cancer subtypes that correlate with acinar ductal metaplasia and donor ancestry.
  16. Targeting ferroptosis in cancer.
  17. Transcriptomic Plasticity is a Hallmark of Metastatic Pancreatic Cancer.
  18. Unifying proteomic technologies with ProteinProjector.
  19. Catabolic rewiring in cancer impacts dietary interventions.
  20. Uncoupling Metastasis and Epithelial-to-Mesenchymal Transition in sgP19/kRAS-Driven Spontaneous Metastatic Liver Tumor Model.
  21. Biophysical-to-DNA Catalytic Cumulative Birecorder for Measuring Continuous Membrane Fluidity.
  22. Editorial: Cancer metastases: mechanisms of tumor dissemination, formation of metastatic niche and anti-metastatic therapy.
  23. European cancer research requires renewed urgency.
  24. Mitochondrial superoxide dismutase controls metabolic plasticity in pancreatic cancer.
  25. Measuring molecular forces inside living cells using magnetic tweezers.
  26. Impact of pancreatic proenzymes on pancreatic ductal adenocarcinoma associated fibroblasts.
  27. A direct role for a mitochondrial targeting sequence in signalling stress.
  28. Evaluating MINFLUX experimental performance in silico.
  29. Exercise attenuates the hallmarks of aging: Novel perspectives.
  30. CellSAM: a foundation model for cell segmentation.
  31. Time Toxicity of Cancer Care-A Call to Action.
  32. High content 3D imaging by dual-view oblique plane microscopy.
  33. Key developments in the cancer neuroscience field.
  34. Cell typing by electrophysiology.
  35. Translational Relevance of the Genomic Landscape of KRASG12D-Mutant Colorectal and Pancreatic Cancers.
  36. Chloroquine Overcomes Chemotherapy Resistance and Suppresses Cancer Metastasis by Eradicating Dormant Cancer Cells.
  1. Cell Rep. 2025 Dec 09. pii: S2211-1247(25)01456-1. [Epub ahead of print]44(12): 116684
    Mutant GNAS drives a pyloric metaplasia with tumor suppressive glycans in intraductal papillary mucinous neoplasia.
    Vincent Quoc-Huy Trinh, Katherine E Ankenbauer, Sabrina M Torbit, Christopher P Taranto, Jiayue Liu, Maelle Batardiere, Bhoj Kumar, H Carlo Maurer, Frank Revetta, Zhengyi Chen, Angela R S Kruse, Audra M Judd, Celina Copeland, Jahg Wong, Olivia Ben-Levy, Brenda Jarvis, Monica Brown, Jeffrey W Brown, Koushik Das, Yuki Makino, Jeffrey M Spraggins, Ken S Lau, Parastoo Azadi, Anirban Maitra, Marcus C B Tan, Kathleen E DelGiorno.
      Intraductal papillary mucinous neoplasms (IPMNs) are cystic lesions and bona fide precursors of pancreatic ductal adenocarcinoma (PDAC), one of the deadliest solid tumors. Although ∼90% of IPMNs are detected before PDAC forms, markers distinguishing benign from malignant disease are lacking, resulting in an abundance of unnecessary, invasive surgeries. Recent studies show that pancreatic precancer assumes a pyloric phenotype. To identify the regulators of this plasticity, cell lines, organoids, tumors from mouse models of IPMNs, and patient samples underwent multiplex immunostaining, RNA sequencing, glycosylation profiling, and computational analysis. These data revealed that GNASR201C drives an indolent phenotype in IPMNs by amplifying a differentiated, pyloric phenotype through SPDEF/CREB3L1, which is characterized by distinct glycans. Acting as a glycan rheostat, GNASR201C elevates LacdiNAcs at the expense of pro-tumorigenic acidic Lewis epitopes, inhibiting cancer cell invasion and disease progression. LacdiNAcs and 3'-sulfo-LeA/C are mutually exclusive and may serve as markers to risk stratify IPMN patients for surgery.
    Keywords:  CP: cancer; CREB3L1; GNAS; SPDEF; glycans; intraductal papillary mucinous neoplasm; pancreatic cancer; pyloric metaplasia
    DOI:  https://doi.org/10.1016/j.celrep.2025.116684
  2. Nat Cell Biol. 2025 Dec 12.
    Target cell cortical tension regulates macrophage trogocytosis.
    Caitlin E Cornell, Aymeric Chorlay, Deepak Krishnamurthy, Nicholas R Martin, Lucia Baldauf, Daniel A Fletcher.
      Macrophages are known to engulf small membrane fragments, or trogocytose, target cells and pathogens, rather than fully phagocytose them. However, little is known about what causes macrophages to choose trogocytosis versus phagocytosis. Here we report that cortical tension of target cells is a key regulator of macrophage trogocytosis. At low tension, macrophages will preferentially trogocytose antibody-opsonized cells, while at high tension, they tend towards phagocytosis. Using model vesicles, we demonstrate that macrophages will rapidly switch from trogocytosis to phagocytosis when membrane tension is increased. Stiffening the cortex of target cells also biases macrophages to phagocytose them, a trend that can be countered by increasing antibody surface density and is captured in a mechanical model of trogocytosis. This work suggests that the target cell, rather than the macrophage, determines whether phagocytosis or trogocytosis occurs, and that macrophages do not require a distinct molecular pathway for trogocytosis.
    DOI:  https://doi.org/10.1038/s41556-025-01807-6
  3. Oncogenesis. 2025 Dec 09. 14(1): 48
    Adaptation of redox metabolism in drug-tolerant persister cells is a vulnerability to prevent relapse in pancreatic cancer.
    Nadine Abdel Hadi, Gabriela Reyes-Castellanos, Tristan Gicquel, Scarlett Gallardo-Arriaga, Emma Cosialls, Emeline Boet, Jean-Emmanuel Sarry, Rawand Masoud, Juan Iovanna, Alice Carrier.
      Pancreatic Ductal Adenocarcinoma (PDAC) remains a major unresolved disease because of its remarkable therapeutic resistance. Even patients who respond to initial therapy experience relapse in most cases. The mechanisms underlying therapy-acquired resistance supporting relapse are poorly understood. In this study, we aimed to determine the metabolic features of PDAC during relapse, specifically adaptations of mitochondrial oxidative metabolism. We used preclinical PDAC mouse models (patient-derived xenografts and murine syngeneic allografts) that present regression under initial chemotherapeutic treatment but relapse after a certain time. Relapsed tumors were analyzed ex vivo by flow cytometry to measure mitochondrial and redox characteristics. Molecular mechanisms were investigated by quantification of ATP and antioxidants levels, bulk RNA-sequencing and RT-qPCR. We show increased mitochondrial mass, ATP levels, mitochondrial superoxide anions, and total ROS levels, in relapsed compared to control tumors in both models; mitochondrial membrane potential is increased in the xenografts model only. These metabolic features are also observed in tumors during treatment-induced regression and at relapse onset. At the molecular level, antioxidant defenses are increased in relapsed tumors and during treatment. These data suggest that metabolic adaptations occurring during treatment-induced regression may favor the survival of drug-tolerant persister (DTP) cells, which persist during the subsequent minimal residual disease and are responsible for cancer relapse. Finally, the combined treatment of arsenic trioxide (ROS inducer) and buthionine sulfoximine (glutathione synthesis inhibitor) is able to completely prevent relapse in PDAC xenografts. In conclusion, redox metabolism is a vulnerability of pancreatic DTP cancer cells that can be targeted to prevent relapse.
    DOI:  https://doi.org/10.1038/s41389-025-00591-0
  4. Life Sci Alliance. 2026 Feb;pii: e202503529. [Epub ahead of print]9(2):
    A step-by-step guide to performing cancer metabolism research using custom-made media.
    Sophie Seifert, Francisco Yanqui-Rivera, Tim Kühn, Lena Elise Høyland, Toman Borteçen, Bella Agranovich, Lara Elea Eckhardt, Martin Herdt, Alessa Henneberg, Verena Panitz, Faisal Hayat, Marie Migaud, Gernot Poschet, Ifat Abramovich, Eyal Gottlieb, Jeroen Krijgsveld, Mathias Ziegler, Mirja Tamara Prentzell, Christiane A Opitz.
      The preparation of custom-made media offers precise control over nutrient composition, enabling detailed studies of cellular metabolism. We demonstrate how self-made media formulations enable diverse assay designs and readouts to assess cancer metabolism. Self-made media can be used in Seahorse assays to measure mitochondrial respiration under defined conditions. In nutrient deprivation experiments, amino acid or vitamin removal can uncover how cancer cells adapt to metabolic stress. Using labeled amino acids enables analysis of nascent protein synthesis and translational regulation, while stable-isotope tracing reveals metabolic fluxes through key pathways. This guide presents a suite of metabolic assays using custom-made media, covering experimental design, the selection of controls, sample preparation, data acquisition, and interpretation. The accompanying online media calculator "Media Minds" streamlines the creation of custom media formulations, ensuring accuracy and reproducibility.
    DOI:  https://doi.org/10.26508/lsa.202503529
  5. Biophys J. 2025 Dec 09. pii: S0006-3495(25)03470-8. [Epub ahead of print]
    Acyl-chain saturation drives lipid sorting to model lipid droplets.
    Sami Kchir, Murphy McDermott, Valeria Zoni, Alexandre Santinho, Azeline Efferzt, Lisa Kauffmann, Vincent Faugeras, Kalthoum Ben Mbarek, Stefano Vanni, Abdou Rachid Thiam.
      Lipid droplets (LDs) originate from the endoplasmic reticulum (ER), involving lipid exchange between the ER bilayer and the nascent LD monolayer. However, the spontaneous partitioning of lipids based on their chemistry remains unclear. In this study, we use model systems to investigate how saturated and monounsaturated phospholipids partition between the bilayer and the droplet monolayer. Our results demonstrate that lipid saturation influences partitioning, depending on the neutral lipid composition of the droplet. Saturated phospholipids generally disfavor artificial LDs (aLDs) compared to monounsaturated ones. Adding cholesteryl oleate to triolein significantly decreases the amount of phospholipids in aLDs, especially saturated lipids. Furthermore, we found that membranes containing liquid-disordered (Ld) regions preferentially contain neutral lipids, particularly triolein. In contrast, membranes with liquid-ordered (Lo) regions, rich in saturated lipids and cholesterol, tend to exclude them. Molecular dynamics simulations confirmed this observation. As a result, triolein-based aLDs consistently localize to cholesterol-induced Ld regions, serving as the primary interface for neutral lipid exchange. Our study provides a unique insight into how lipid saturation and neutral lipid chemistry interact to determine lipid composition and distribution within a bilayer and an aLD, raising essential questions about how cells regulate spontaneous lipid sorting in the ER and LDs.
    DOI:  https://doi.org/10.1016/j.bpj.2025.12.012
  6. Nature. 2025 Dec;648(8093): S61-S62
    Six highlights from pancreatic cancer research.
    Laura Vargas-Parada.
      
    Keywords:  Cancer; Diseases; Immunology
    DOI:  https://doi.org/10.1038/d41586-025-03948-y
  7. Nat Cell Biol. 2025 Dec 09.
    Endoplasmic reticulum disruption stimulates nuclear membrane mechanotransduction.
    Zhouyang Shen, Zaza Gelashvili, Philipp Niethammer.
      Cytosolic phospholipase A2 (cPLA2) controls some of the most powerful inflammatory lipids in vertebrates by releasing their metabolic precursor, arachidonic acid, from the inner nuclear membrane (INM). Ca2+ and INM tension (TINM) are thought to govern the interactions and activity of cPLA2 at the INM. However, as compensatory membrane flow from the contiguous endoplasmic reticulum (ER) may prevent TINM, the conditions permitting nuclear membrane mechanotransduction by cPLA2 or other mediators remain unclear. To test whether the ER buffers TINM, we created the genetically encoded, Ca²⁺-insensitive TINM biosensor amphipathic lipid-packing domain inside the nucleus (ALPIN). Confocal time-lapse imaging of ALPIN- or cPLA2-INM interactions, along with ER morphology, nuclear shape/volume and cell lysis revealed a link between TINM and disrupted ER-nuclear membrane contiguity in osmotically or ferroptotically stressed mammalian cells and at zebrafish wound margins in vivo. By combining ALPIN imaging with Ca2+-induced ER disruption, we reveal the causality of this correlation, which suggests that compensatory membrane flow from the ER buffers TINM without preventing it. Besides consolidating the biomechanical basis of cPLA2 activation by nuclear deformation, our results identify cell stress- and cell death-induced ER disruption as an additional nuclear membrane mechanotransduction trigger.
    DOI:  https://doi.org/10.1038/s41556-025-01820-9
  8. Nature. 2025 Dec 10.
    Neutrophils preserve energy storage in sympathetically activated adipocytes.
    Seunghwan Son, Cindy Xu, Haipeng Fu, Churaibhon Wisessaowapak, Joseph M Valentine, Garam An, Janice Jang, Maddox Dinh, Yang Dai, Weiwei Fan, Ruth T Yu, Michael Downes, Wei Ying, Yuliya Skorobogatko, Ronald M Evans, Alan R Saltiel.
      Adipose tissue maintains energy homeostasis by storing lipids during nutrient surplus and releasing them through lipolysis in times of energy demand1,2. While lipolysis is essential for short-term metabolic adaptation, prolonged metabolic stress requires adaptive changes that preserve energy reserves2,3. Here we report that β3-adrenergic activation of adipocytes induces a transient and depot-specific infiltration of neutrophils into white adipose tissue (WAT), particularly in lipid-rich visceral WAT. Neutrophil recruitment requires the stimulation of both lipolysis and p38 MAPK in adipocytes, and is mediated by the secretion of leukotriene B4. Recruited neutrophils undergo activation in situ, and locally secrete IL-1β, which suppresses lipolysis and limits excessive energy loss. Neutrophil depletion or blockade of IL-1β production increases lipolysis, leading to reduced WAT mass after repeated β3-adrenergic stimulation. Together, these findings reveal a role of neutrophil-derived IL-1β in preserving lipid stores during metabolic stress, highlighting a physiological function of innate immune cells in limiting lipid loss and maintaining energy homeostasis.
    DOI:  https://doi.org/10.1038/s41586-025-09839-6
  9. Nat Commun. 2025 Dec 11.
    scDrugMap: benchmarking large foundation models for drug response prediction.
    Qing Wang, Yining Pan, Minghao Zhou, Zijia Tang, Yanfei Wang, Guangyu Wang, Qianqian Song.
      Drug resistance remains a major challenge in cancer treatment. While single-cell profiling offers unprecedented resolution for uncovercovering resistance mechanisms, the potential of emerging foundation models for drug response prediction at the single-cell level is still largely unknown. Here, we introduce scDrugMap, a unified framework featuring both Python toolkits and an interactive web server for benchmarking and predicting drug responses with state-of-the-art foundation models. scDrugMap evaluates eight single-cell foundation models and two large language models across 495,000 cells from 60 datasets, spanning diverse tissues, drugs, cancer types, and treatment conditions. In pooled-data evaluation, scFoundation delivered the strongest performance, particularly in tumor tissue. In cross-data analysis, UCE performed best after fine-tuning, while in zero-shot settings, scGPT achieved the highest accuracy. Together, scDrugMap provides the first systematic benchmark of foundation models for single-cell drug response prediction and offers a powerful, user-friendly platform to accelerate drug discovery and translational precision oncology.
    DOI:  https://doi.org/10.1038/s41467-025-67481-2
  10. Int J Mol Sci. 2025 Nov 30. pii: 11626. [Epub ahead of print]26(23):
    Cancer-Associated Cachexia in the Era of Obesity.
    Joyce Cristina Ferreira de Resende, Márcia Fábia Andrade, Fabiana Amaral Ferreira, José Pinhata Otoch, Lívia Clemente Motta-Teixeira, Marilia Seelaender.
      Obesity and cancer cachexia represent opposite ends of the body mass index (BMI) spectrum. However, despite this apparent dichotomy, both conditions share critical metabolic alterations, primarily driven by inflammation, metabolic alterations and changes in adipose tissue biology. Obesity is characterised by chronic low-grade inflammation and increased fat storage, while cancer cachexia involves severe weight loss, muscle atrophy, and lipolysis, with inflammation playing a central role in both conditions. Inflammatory cytokines such as TNF-α and IL-6 are increased in both scenarios, contributing to metabolic dysregulation and systemic energy imbalance. This review explores the shared inflammatory and metabolic pathways underlying obesity and cancer cachexia, with particular regard to the role of white adipose tissue (WAT). Moreover, we intend to highlight the importance of understanding the common mechanisms for the development of more effective therapeutic strategies for managing these complex metabolic disorders.
    Keywords:  adipose tissue; cachexia; cancer; inflammation; obesity
    DOI:  https://doi.org/10.3390/ijms262311626
  11. Nature. 2025 Dec;648(8093): S51-S53
    The pancreatic cancer models helping to drive innovation in the field.
    Rachel Nuwer.
      
    Keywords:  Cancer; Diseases; Machine learning
    DOI:  https://doi.org/10.1038/d41586-025-03944-2
  12. Nature. 2025 Dec;648(8093): S57
    A breathalyser-style test for detecting pancreatic cancer.
    Esme Hedley.
      
    Keywords:  Cancer; Drug discovery; Health care
    DOI:  https://doi.org/10.1038/d41586-025-03946-0
  13. bioRxiv. 2025 Dec 01. pii: 2025.04.17.649308. [Epub ahead of print]
    A single vesicle fluorescence microscopy platform to quantify phospholipid scrambling.
    Sarina Veit, Grace I Dearden, Kartikeya M Menon, Faria Noor, Indu Menon, Takefumi Morizumi, Oliver P Ernst, Anant K Menon, Thomas Günther Pomorski.
      Scramblases play important roles in physiology by translocating phospholipids bidirectionally across cell membranes. For example, scrambling facilitated by dimers of the Voltage-Dependent Anion Channel 1 (VDAC1) enables endoplasmic reticulum-derived phospholipids to cross the outer membrane to enter mitochondria. Precise quantification of lipid scrambling, while critical for mechanistic understanding, cannot be obtained from ensemble averaged measurements of reconstituted scramblases. Here, we describe a microscopy platform for high-throughput imaging of single vesicles reconstituted with fluorescently labeled phospholipids and heterogeneously crosslinked VDAC1 dimers. For each vesicle, we quantify size, protein occupancy and scrambling rate. Notably, we find that individual VDAC1 dimers have different activities, ranging from <100 to >10,000 lipids per second. This kinetic heterogeneity, masked in ensemble measurements, reveals that only some dimer interfaces are capable of promoting rapid scrambling, as suggested by molecular dynamics simulations. We extend our analyses to opsin, a monomeric G protein-coupled receptor scramblase, thereby demonstrating the versatility of our platform for quantifying transbilayer lipid transport and exploring its regulation.
    DOI:  https://doi.org/10.1101/2025.04.17.649308
  14. Autophagy. 2025 Dec 11.
    Chronic enteritis triggered by diet westernization is driven by epithelial ATG16L1-mediated autophagy.
    Lisa Mayr, Julian Schwärzler, Laura Scheffauer, Zhigang Rao, Dietmar Rieder, Felix Grabherr, Moritz Meyer, Jakob Scheler, Almina Jukic, Luis Zundel, Verena Wieser, Andreas Zollner, Anna Simonini, Stefanie Auer, Lisa Amann, Maureen Philipp, Johannes Leierer, Richard Hilbe, Günter Weiss, Patrizia Moser, Philip Rosenstiel, Qitao Ran, Richard S Blumberg, Arthur Kaser, Andreas Koeberle, Zlatko Trajanoski, Herbert Tilg, Timon E Adolph.
      Macroautophagy/autophagy exerts multilayered protective functions in intestinal epithelial cells (IECs) while a loss-of-function genetic variant in ATG16L1 (autophagy related 16 like 1) is associated with risk for developing Crohn disease (CD). Westernization of diet, partly characterized by excess of long-chain fatty acids, contributes to CD, and a metabolic control of intestinal inflammation is emerging. Here, we report an unexpected inflammatory function for ATG16L1-mediated autophagy in Crohn-like metabolic enteritis of mice induced by polyunsaturated fatty acid (PUFA) excess in a western diet. Dietary PUFAs induce ATG16L1-mediated conventional autophagy in IECs, which is required for PUFA-induced chemokine production and metabolic enteritis. By transcriptomic and lipidomic profiling of IECs, we demonstrate that ATG16L1 is required for PUFA-induced inflammatory stress signaling specifically mediated by TLR2 (toll-like receptor 2) and the production of arachidonic acid metabolites. Our study identifies ATG16L1-mediated autophagy in IECs as an inflammatory hub driving metabolic enteritis, which challenges the perception of protective autophagy in the context of diet westernization.Abbreviations: AA: arachidonic acid; ATG16L1: autophagy related 16 like 1; CD: Crohn disease; CXCL1: C-X-C motif chemokine ligand 1; ER: endoplasmic reticulum; GFP: green fluorescent protein; GPX4: glutathione peroxidase 4; IBD: inflammatory bowel disease; IECs: intestinal epithelial cells; PTGS2/COX2: prostaglandin-endoperoxide synthase 2; PUFA: polyunsaturated fatty acid; SDA: stearidonic acid; TLR2: toll-like receptor 2; WT: wild-type.
    Keywords:  ATG16L1; Crohn disease; glutathione peroxidase 4; intestinal epithelial cells; intestinal inflammation; polyunsaturated fatty acids
    DOI:  https://doi.org/10.1080/15548627.2025.2600906
  15. Cancer Res Commun. 2025 Dec 10.
    Transcriptomic analyses of normal human pancreata reveal the presence of cancer subtypes that correlate with acinar ductal metaplasia and donor ancestry.
    Corey M Perkins, Jinmai Jiang, Kalyanee Shirlekar, Zachary Greenberg, Md Abu Talha Siddique, Jason Brant, Kiley Graim, Mei He, Sarah Kim, Diana J Wilkie, Bo Han, Jamel Ali, Pascal Belleau, Astrid Deschênes, Alexander Krasnitz, Mazhar Kanak, Thomas D Schmittgen.
      Molecular subtypes exist in pancreatic ductal adenocarcinoma (PDAC), however comparable subtypes are not known to exist in normal pancreas. A large, racially diverse cohort of normal, human pancreatic acinar cells were obtained from islet transplantation centers. RNA isolated from uncultured acini and those acini that had undergone acinar ductal metaplasia (ADM) was sequenced. Data analysis from 69 uncultured, normal acini showed two clusters of samples, one that aligns with exocrine resembling tissue (ERT) signatures and another with the classical and basal (C/B) subtypes. Gene expression associated with the ERT signature decreased following 6 days of ADM transdifferentiation while those assigned to the C/B subtype increased. Subtype classification findings were confirmed in two independent cohorts of transcriptomic data of normal pancreas. A direct correlation exists between ancestral admixture and the molecular index of ADM; those specimens with higher African ancestral admixture showed a greater propensity for ADM compared to those with a higher Ameridigenous admixture. The extent of morphological ADM decreased in the order of Black>White>Hispanic race. Analysis of associated metadata revealed that potential confounders such as diabetes, obesity, age, gender or specimen handling and processing variables did not influence the distribution of samples across subtype classification. We report that normal human pancreatic acinar tissues group into molecular subtypes like those used to classify PDAC and that subtype assignment and ADM are influenced by the donor's race.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-25-0411
  16. Nat Genet. 2025 Dec;57(12): 2942
    Targeting ferroptosis in cancer.
    Safia Danovi.
      
    DOI:  https://doi.org/10.1038/s41588-025-02456-z
  17. Cancer Res. 2025 Dec 11.
    Transcriptomic Plasticity is a Hallmark of Metastatic Pancreatic Cancer.
    Alejandro Jiménez-Sánchez, Sitara Persad, Akimasa Hayashi, Shigeaki Umeda, Roshan Sharma, Yubin Xie, Arnav Mehta, Wungki Park, Ignas Masilionis, Tinyi Chu, Feiyang Zhu, Jungeui Hong, Ronan Chaligne, Eileen M O'Reilly, Linas Mazutis, Tal Nawy, Itsik Pe'er, Christine A Iacobuzio-Donahue, Dana Pe'er.
      Metastasis is the leading cause of cancer deaths. To develop strategies for intercepting metastatic progression, a better understanding of how tumor cells adapt to vastly different organ contexts is needed. To investigate this question, a single-cell transcriptomic atlas of primary tumor and diverse metastatic samples (liver, omentum, peritoneum, stomach wall, lymph node, and diaphragm) from a patient with pancreatic ductal adenocarcinoma who underwent rapid autopsy was generated. Using unsupervised archetype analysis, both shared and site-specific gene programs were identified, including lipid metabolism and gastrointestinal programs prevalent in peritoneal and stomach wall lesions, respectively. We developed PICASSO as a probabilistic approach for inferring clonal phylogeny from single-cell and matched whole-exome sequencing data. Comparison of PICASSO-generated clonal structure with phenotypic signatures revealed that pancreatic cancer cells adapted to local environments with minimal contribution from clonal genotype. Our results suggest a paradigm whereby strong environmental effects are imposed on highly plastic cancer cells during metastatic dissemination.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-1117
  18. Bioinform Adv. 2025 ;5(1): vbaf266
    Unifying proteomic technologies with ProteinProjector.
    Leah V Schaffer, Mayank Jain, Rami Nasser, Roded Sharan, Trey Ideker.
       Summary: Proteomics has developed many approaches to inform the subcellular organization of proteins, each with differing coverage and sensitivity to distinct scales. Here, we develop a self-supervised deep learning framework, ProteinProjector, that flexibly integrates all available data for a protein from any number of modalities, resulting in a unified map of protein position. As initial proof-of-concept we integrate four proteome-wide characterizations of HEK293 human embryonic kidney cells, including protein affinity purification, proximity ligation, and size-exclusion-chromatography mass spectrometry (AP-MS, PL-MS, SEC-MS), as well as protein fluorescent imaging. Map coverage and accuracy grow substantially as new data modes are added, with maximal recovery of known complexes observed when using all four proteomic datasets. We find that ProteinProjector outperforms individual modalities and other integration methods in recovery of orthogonal functional and physical associations not used during training. ProteinProjector provides a foundation for integration of diverse modalities that characterize subcellular structure.
    Availability and implementation: ProteinProjector is available as part of the Cell Mapping Toolkit at https://github.com/idekerlab/cellmaps_coembedding.
    DOI:  https://doi.org/10.1093/bioadv/vbaf266
  19. Commun Biol. 2025 Dec 08.
    Catabolic rewiring in cancer impacts dietary interventions.
    Christos Chinopoulos.
      Tumors exhibit metabolic fuel requirements resembling those of embryonic and other highly proliferative tissues, a similarity that can be exploited to combat neoplasia. However, several challenges limit the efficacy of dietary modifications in cancer therapy. This review explores how cancer cells acquire and catabolize macromolecules to harness energy and assesses the feasibility of influencing these pathways through dietary changes. Although dietary interventions modulate the energetic substrate supply to tumors only to a limited extent, they offer significant ancillary benefits by imposing hormonal states that burden cancer metabolism, enhancing immune responses, and reducing inflammation. Integrating dietary considerations into the standard of care for cancer patients represents a promising adjunct to traditional treatments, despite their dampened impact on nutrient availability for tumor energy metabolism.
    DOI:  https://doi.org/10.1038/s42003-025-09333-9
  20. Adv Sci (Weinh). 2025 Dec 07. e14198
    Uncoupling Metastasis and Epithelial-to-Mesenchymal Transition in sgP19/kRAS-Driven Spontaneous Metastatic Liver Tumor Model.
    Jingwen Wang, Zijing Xu, Lei Xu, Lishan Wang, Jiahao Geng, Xue Wang, Meng Xu, Daphne Superville, Melissa Reeves, Matthias Evert, Diego F Calvisi, Xin Chen, Xinhua Song.
      Epithelial-to-mesenchymal transition (EMT) is an early event during tumor metastasis. Here, the relevance of EMT in liver carcinogenesis and metastasis is sought to be determined in a murine mixed typical intrahepatic cholangiocarcinoma (iCCA)/sarcomatoid iCCA liver tumor model using CRISPR/Cas9-based gene deletion of p19 (sgP19) in combination with transposon-based expression of the activated form of pCaggs-kRASG12D (kRAS) in the mouse liver (sgP19/kRAS mixed model). It discovered that metastasis in the lymph node, lung, or kidney occurred in the sgP19/kRAS mixed model. Both typical iCCA tumor cells with epithelial features and sarcomatoid tumor cells with mesenchymal features could be detected in this model. Lineage tracing technology is applied to confirm the metastasis induced in the sgP19/kRAS model. Subsequently, the gain of expression of mesenchymal marker vimentin in tumor cells revealed the induction of EMT in the sgP19/kRAS model, and it is induced by activating the TGFβ/ZEB1 signaling pathway. Altogether, the study suggests that TGFβ/ZEB1 mediates the induction of EMT in iCCA, while targeting EMT failed to inhibit iCCA development or tumor metastasis, disputing the claims that EMT is a major molecular event leading to tumor metastasis.
    Keywords:  TGFβ; ZEB1; epithelial‐to‐mesenchymal transition; intrahepatic cholangiocarcinoma; metastasis
    DOI:  https://doi.org/10.1002/advs.202514198
  21. J Am Chem Soc. 2025 Dec 09.
    Biophysical-to-DNA Catalytic Cumulative Birecorder for Measuring Continuous Membrane Fluidity.
    Mengying Ye, Xinyin Li, Lu Huang, Xinru Mei, Huahang Yu, Ke Cao, Feng Chen, Yongxi Zhao.
      Recording biophysical processes is crucial to understanding the cellular history and stimuli-responsive behaviors. The construction of memory machines for continuous membrane fluidity, however, remain challenging. Here, we report a biophysical-to-DNA catalytic cumulative birecorder (BioDIMER) for making individual recordings of continuous membrane fluidity events into both fluorescent signals and DNA unique molecular identifiers (UMIs) sequencing. We do this through engineered DNAzyme probe sets that accumulate bimodal signals responsive to each transient encounter on cell membrane. This in situ imaging captures spatiotemporal information, and the UMIs sequencing counts the number of transient encounters over time by digital quantification. The DNA catalytic bimodal signals enable continuous records of new events without corrupting the records of older events and achieve multidimensional interpretation of membrane fluidity timing. Using this proof-of-concept method, we recorded and deciphered differential cell membrane dynamics across diverse cell types and states, including cell cycle phases, cardiac hypertrophy, myotube differentiation, and cellular senescence. We found the first decreased and then increased change of membrane fluidity during the cell circle phases. In cardiac hypertrophy, we visualized an enhanced membrane fluidity. Oppositely, cellular senescence caused a significant reduction in membrane fluidity. They implied a highly dynamic organization of cell membrane components.
    DOI:  https://doi.org/10.1021/jacs.5c16545
  22. Front Immunol. 2025 ;16 1746602
    Editorial: Cancer metastases: mechanisms of tumor dissemination, formation of metastatic niche and anti-metastatic therapy.
    Sergei Kusmartsev, Yingcheng Wu, Elena Voronov, Julia Schueler.
      
    Keywords:  cancer immuno therapy; cancer metastasis; immune evasion; myeloid immunosuppressive cells; tumor dissemination; tumor micro environment (TME)
    DOI:  https://doi.org/10.3389/fimmu.2025.1746602
  23. Nat Cancer. 2025 Dec 10.
    European cancer research requires renewed urgency.
    René Bernards, Anton Berns, Johanna A Joyce, Michael Baumann.
      
    DOI:  https://doi.org/10.1038/s43018-025-01062-6
  24. Cell Commun Signal. 2025 Dec 06. 23(1): 524
    Mitochondrial superoxide dismutase controls metabolic plasticity in pancreatic cancer.
    Sankaranarayanan Ramasubramanian, Rupert Öllinger, Carola Eberhagen, Hans Zischka, Roland M Schmid, Henrik Einwächter.
       BACKGROUND: The role of reactive oxygen species (ROS) in cancer is debated. One main antioxidant enzyme is mitochondrial superoxide dismutase (SOD2) which has been shown to influence tumor initiation and metastatic progression in several cancer types.
    METHODS: To investigate the impact of Sod2 deletion on pancreatic cancer biology and metabolism, we used CRISPR/Cas9 gene editing to generate 3 independent Sod2-deficient cell lines from murine KrasG12D pancreatic cancer cell lines and analyzed them for proliferation, colony forming, mitochondrial respiration and RNA expression. In addition, mass spectrometry and isotope tracing were performed.
    RESULTS: Proliferation and wound healing capacity were significantly impaired in Sod2 deficient cell lines. Myc levels were significantly elevated in Sod2-deficient cells, and mitochondrial respiration was consecutively increased. This resulted in increased tolerance to glucose deprivation. Mechanistically, we detected a significantly reduced activity of succinate dehydrogenase (SDH) in Sod2-deficient cells. This resulted in increased peroxynitrite formation which was the cause of increased Myc activation.
    CONCLUSIONS: These findings reveal that Sod2 shapes cellular metabolism in pancreatic cancer through peroxynitrite formation and Myc activation.
    Keywords:  Myc Proto-Oncogene Proteins; Pancreatic Neoplasms; Superoxide Dismutase (SOD2)
    DOI:  https://doi.org/10.1186/s12964-025-02555-8
  25. Biophys Rev. 2025 Aug;17(4): 1081-1092
    Measuring molecular forces inside living cells using magnetic tweezers.
    Abhinav Kongari, Maxim Molodtsov.
      To change shape, move, grow and divide, cells employ various motor and non-motor proteins that convert chemical energy into the generation of mechanical force. Force spectroscopy tools that allow the measurement of these forces generated by individual molecules revolutionised our understanding of single-molecule mechanics over the past three decades. These techniques, however, remain largely confined to studies with purified components outside cells. A critical, unresolved challenge lies in deciphering how these force-generating and force-sensing molecules coordinate their activities inside living cells. In this review, we discuss advances in magnetic tweezers designed to measure and apply mechanical forces intracellularly. We highlight recent progress in magnetic tweezers that began to provide an understanding of how active mechanical forces drive rearrangements of biological structures. We also discuss challenges associated with applying forces locally and precisely. We identify two key areas that hold potential for the development of tools for direct mechanical manipulations of specific molecules inside living cells: (1) instrument design to generate and control magnetic gradients at the single-cell scale, and (2) development of magnetic biofunctionalised particles capable of targeting specific structures. The integration of these advances should enable unprecedented ability to manipulate intracellular forces, opening new avenues to study intracellular organisation, mechanotransduction pathways, cell division and migration. By addressing current limitations in specificity and resolution, next-generation magnetic tweezers may finally bridge the gap between single-molecule biophysics in vitro and cell-scale mechanobiology in living cells.
    Keywords:  Cell mechanics; Force spectroscopy; Intracellular force measurement; Magnetic tweezers; Mechanical forces; Mechanobiology; Superparamagnetic particles
    DOI:  https://doi.org/10.1007/s12551-025-01349-z
  26. Sci Rep. 2025 Dec 12.
    Impact of pancreatic proenzymes on pancreatic ductal adenocarcinoma associated fibroblasts.
    Belén Toledo, Aitor González-Titos, Pablo Hernández-Camarero, Elena López-Ruiz, Carmen Griñán-Lisón, Elisa Giovannetti, Juan Antonio Marchal, Macarena Perán.
      The tumor microenvironment (TME) plays a pivotal role in tumor initiation, progression, and the formation of pre-metastatic niches. Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense fibrotic stroma containing a significant enriched population of cancer-associated fibroblasts (CAFs). The interplay between CAFs and tumor cells is crucial in driving tumor advancement and metastasis, underscoring the potential benefits of novel therapeutic strategies targeting stromal cells to improve patient survival. Pancreatic (pro)enzymes have shown efficacy in cancer treatment. In this study, we evaluated a formulation of Trypsinogen and Chymotrypsinogen A (PRP) on a model of PDAC-CAFs dynamics. Our findings demonstrated PRP multifaceted effects, including: (i) inhibition of the acquisition of a pro-tumoral phenotype by normal fibroblasts; (ii) enhanced expression of E-cadherin and decreased expression of epithelial-mesenchymal transition (EMT)-associated genes; (iii) blockade of the crosstalk between CAFs and cancer cells, leading to a decrease in the proliferation and migration rate of the pancreatic cancer cells; (iv) modulation of CAFs-induced alteration on endothelial cells; (v) induction of Meflin expression, associated with a less pro-tumoral phenotype; (vi) inhibition of the TGF-β pathway, reducing the activation of Smad2/3 proteins involved in fibroblast phenotypic alteration; (vii) selective induction of apoptosis in CAFs by PRP, as evidenced by increased expression of the BAX biomarker; (viii) impaired fibrotic tissue formation, as tested in an in vivo model of PDAC, by reducing the population of CAFs within the TME. Collectively, these results underscore the potential of PRP as a therapeutic candidate for disrupting the intricate interactions within the PDAC TME. Further research and clinical investigations are necessary to validate the translational potential of PRP as an adjunct therapy for PDAC.
    Keywords:  Cancer associated fibroblast; Epithelial-mesenchymal transition; Pancreatic (Pro)enzymes; Pancreatic ductal adenocarcinoma; Reprogramming therapy; Tumor microenvironment
    DOI:  https://doi.org/10.1038/s41598-025-24863-2
  27. Nature. 2025 Dec 10.
    A direct role for a mitochondrial targeting sequence in signalling stress.
    Zixuan Yuan, Megan Balzarini, Marina Volpe, Madeleine Goldstein, Tony Shengzhe Peng, Elizabeth Hui, Nancy Neng Fang, Waleed S Albihlal, Melika Hajimohammadi, Kevin Wei, Calvin K Yip, Folkert J van Werven, Thibault Mayor, Hilla Weidberg.
      Mitochondrial protein import is required for maintaining organellar function1. Perturbations in this process are associated with various physiological and disease conditions2. Several stress responses, including the mitochondrial compromised protein import response (mitoCPR), combat damage caused by mitochondrial protein import defects2. However, how this defect is sensed remains largely unknown. Here we reveal that the conserved mitochondrial Hsp70 co-chaperone, Mge1, acts as a stress messenger in budding yeast. During mitochondrial stress, unimported Mge1 entered the nucleus and triggered the transcription of mitoCPR target genes. This was mediated by the interaction of Mge1 with the transcription factor Pdr3 on DNA regulatory elements. The mitochondrial targeting sequence of Mge1 was both sufficient and essential for mitoCPR induction, demonstrating that in addition to their roles in mitochondrial protein import, targeting sequences can also function as signalling molecules. As protein import defects are a common consequence of various types of mitochondrial damage3,4, these findings suggest a novel function for the targeting sequence of Mge1 as an indicator of mitochondrial health.
    DOI:  https://doi.org/10.1038/s41586-025-09834-x
  28. Nat Commun. 2025 Dec 06.
    Evaluating MINFLUX experimental performance in silico.
    Zach Marin, Jonas Ries.
      MINFLUX is a super-resolution microscopy technique with remarkable resolution for imaging and tracking. Its optical resolution is well understood under idealized conditions, but because of system complexity and experimental imperfections, actual performance can be much worse. Here we present SimuFLUX, a comprehensive and realistic simulator for MINFLUX. We use it to investigate performance limits caused by fluorophore dynamics, background, estimators, and misalignment, and to simulate experiments to optimize parameters and assess feasibility.
    DOI:  https://doi.org/10.1038/s41467-025-66952-w
  29. J Sport Health Sci. 2025 Dec 04. pii: S2095-2546(25)00116-4. [Epub ahead of print] 101108
    Exercise attenuates the hallmarks of aging: Novel perspectives.
    Yan Qiu, Benjamin Fernández-García, H Immo Lehmann, Guoping Li, Guido Kroemer, Carlos López-Otín, Junjie Xiao.
      The number and proportion of individuals aged 60 years and older are steadily increasing. However, increased life expectancy is accompanied by a decline in functional capacity and a heightened risk of age-related diseases, ultimately leading to reduced quality of life. Interventions that support physiological function in later life and hence extend healthspan are therefore of considerable importance. Among these, regular physical exercise is strongly associated with numerous health benefits and is recognized as a key strategy for promoting healthy aging and extending healthspan. In this review, we highlight the impact of an active lifestyle, particularly regular physical activity, on the major hallmarks of aging. These include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, impaired macroautophagy, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, changes in the extracellular matrix, stem cell exhaustion, altered intercellular communication, chronic inflammation, dysbiosis, and psychosocial isolation. A deeper understanding of the mechanisms by which exercise confers these benefits will aid in enhancing both physical and mental health in the elderly and in mitigating the onset of aging-associated diseases.
    Keywords:  Exercise; Hallmarks of aging; Healthspan; Healthy aging
    DOI:  https://doi.org/10.1016/j.jshs.2025.101108
  30. Nat Methods. 2025 Dec;22(12): 2585-2593
    CellSAM: a foundation model for cell segmentation.
    Markus Marks, Uriah Israel, Rohit Dilip, Qilin Li, Changhua Yu, Emily Laubscher, Ahamed Iqbal, Elora Pradhan, Ada Ates, Martin Abt, Caitlin Brown, Edward Pao, Shenyi Li, Alexander Pearson-Goulart, Pietro Perona, Georgia Gkioxari, Ross Barnowski, Yisong Yue, David Van Valen.
      Cells are a fundamental unit of biological organization, and identifying them in imaging data-cell segmentation-is a critical task for various cellular imaging experiments. Although deep learning methods have led to substantial progress on this problem, most models are specialist models that work well for specific domains but cannot be applied across domains or scale well with large amounts of data. Here we present CellSAM, a universal model for cell segmentation that generalizes across diverse cellular imaging data. CellSAM builds on top of the Segment Anything Model (SAM) by developing a prompt engineering approach for mask generation. We train an object detector, CellFinder, to automatically detect cells and prompt SAM to generate segmentations. We show that this approach allows a single model to achieve human-level performance for segmenting images of mammalian cells, yeast and bacteria collected across various imaging modalities. We show that CellSAM has strong zero-shot performance and can be improved with a few examples via few-shot learning. Additionally, we demonstrate how CellSAM can be applied across diverse bioimage analysis workflows. A deployed version of CellSAM is available at https://cellsam.deepcell.org/ .
    DOI:  https://doi.org/10.1038/s41592-025-02879-w
  31. JAMA Netw Open. 2025 Dec 01. 8(12): e2547930
    Time Toxicity of Cancer Care-A Call to Action.
    Sahil D Doshi, Jeffrey A Rappaport, Erin M Bange.
      
    DOI:  https://doi.org/10.1001/jamanetworkopen.2025.47930
  32. PNAS Nexus. 2025 Dec;4(12): pgaf370
    High content 3D imaging by dual-view oblique plane microscopy.
    Hugh Sparks, Leo Rowe-Brown, Yuriy Alexandrov, Nils Gustafsson, Liuba Dvinskikh, Nathan Curry, Jayne Culley, Martin Lee, Alix Le Marois, Colin D H Ratcliffe, Thomas A Phillips, Claudia Owczarek, Mar Arias Garcia, Montserrat Llanses, Theresa Suckert, Joffrey Pelletier, Carme Cortina, Wenzhi Hong, Edwin Garcia, Zhizhen Xu, Shengjie Zhang, Giorgio Stassi, Eduard Batlle, Julien Colombelli, Maddy Parsons, Chris Bakal, Neil O Carragher, Erik Sahai, Chris Dunsby.
      Oblique plane microscopy (OPM) is a form of light-sheet fluorescence microscopy (LSFM) employing a single microscope objective at the sample for both fluorescence excitation and detection. Dual-view OPM (dOPM) is an optically folded form of OPM. We present an improved dOPM system employing a 60×/1.2NA water immersion primary objective and measure the spatial resolution and fluorescence collection efficiency for illumination angles of 35° and 45° with respect to the coverslip. Illumination at 35° provides slightly better lateral resolution and collection efficiency. Collection efficiency measurements are compared to a full vectorial raytracing simulation of the system. Using a light-sheet angle of 35°, the median bead FWHM for 100 nm diameter fluorescent beads in x, y, and z and the optical sectioning strength were measured over a volume of 100 × 100 × 100 μm3 to be 0.29, 0.31, 0.83, and 2.45-3.00 μm, respectively when the two dOPM views are fused. We demonstrate less photobleaching in time-lapse dOPM of live mEmerald-expressing organoids compared to widefield epi-fluorescence z-stack imaging under the condition of equal detected fluorescence signal from a point object in focus. We demonstrate dOPM for multifield-of-view 3D imaging of biological samples in 96-well plates and apply it to imaging cells in collagen gel and quantifying the FUCCI cell-cycle reporter to provide drug dose-response curves in spheroids. We also use it to perform time-lapse multifield-of-view imaging and demonstrate the detection of organoid lumen closure and reopening, organoid migration within a collagen gel and observing dynamic events in arrays of ex vivo tissue slices.
    DOI:  https://doi.org/10.1093/pnasnexus/pgaf370
  33. Nat Cancer. 2025 Dec 10.
    Key developments in the cancer neuroscience field.
    Michelle Monje, Frank Winkler.
      
    DOI:  https://doi.org/10.1038/s43018-025-01082-2
  34. Nat Methods. 2025 Dec;22(12): 2495-2496
    Cell typing by electrophysiology.
    Nina Vogt.
      
    DOI:  https://doi.org/10.1038/s41592-025-02955-1
  35. Target Oncol. 2025 Dec 11.
    Translational Relevance of the Genomic Landscape of KRASG12D-Mutant Colorectal and Pancreatic Cancers.
    Khalid Jazieh, Jill Tsai, Sheila Solomon, Mojun Zhu, Katrina S Pedersen, Martin E Fernandez-Zapico, Hao Xie.
       BACKGROUND: KRASG12D is one of the most prevalent driver mutations in patients with pancreatic ductal adenocarcinoma (PDAC) and colorectal adenocarcinoma (CRC). Although this genetic alteration is associated with poor prognosis and resistance to chemotherapy, additional genomic features may contribute to the behavior of KRAS-mutant PDACs and CRCs.
    OBJECTIVE: Here, we aimed at defining the landscape of these additional genomic features of KRASG12D-mutant PDAC and CRC, and their impact on clinical outcomes.
    PATIENTS AND METHODS: This retrospective analysis utilized circulating tumor DNA data from two cohorts with advanced CRC and PDAC: a national cohort from Guardant (n = 27,497) and a Mayo Clinic cohort (n = 1434). Patients were categorized into three groups: KRASG12D alone, KRASG12D with putative resistance alterations, and KRAS not detected (ND). Genomic co-occurrences were summarized. Overall survival (OS) was compared among groups using Kaplan-Meier and multivariable survival analysis.
    RESULTS: Among patients with KRASG12D mutation, additional oncogenic alterations were detected in 34.5% of CRC and 11.5% of PDAC in the national cohort; 38.9% of CRC, and 17.4% of PDAC in the Mayo cohort. Common additional oncogenic alterations included EGFR amplifications, additional KRAS point mutations, and alterations in NRAS, BRAF, and PIK3CA. Patients with KRASG12D and these alterations had significantly shorter median OS compared with those with KRASG12D alone and KRAS ND for CRC (p < 0.0001) and PDAC (p < 0.0001). Presence of KRASG12D and additional oncogenic alterations was the only variable significantly associated with OS outcomes in both CRC and PDAC.
    CONCLUSIONS: We described the genomic landscape of KRASG12D-mutant CRC and PDAC, demonstrating that cases often have additional oncogenic alterations linked to resistance to KRAS inhibition. These alterations are also associated with a worse prognosis. Recognizing these alterations may inform new therapeutic strategies. Further studies are warranted to validate these findings in ongoing clinical trials.
    DOI:  https://doi.org/10.1007/s11523-025-01191-z
  36. Cell Death Dis. 2025 Dec 10.
    Chloroquine Overcomes Chemotherapy Resistance and Suppresses Cancer Metastasis by Eradicating Dormant Cancer Cells.
    Marina A Mikeladze, Liubov S Kuznetcova, Elena Y Komarova, Margarita A Galcheva, Vladimir F Lazarev, Lev A Khamaev, Maria A Konanova, Yana A Gladova, Anna B Danilova, Boris A Margulis, Bashar A Alhasan, Irina V Guzhova.
      Cancer cell resistance and tumor relapse remain major challenges in cancer treatment. Chloroquine, an FDA-approved antimalarial drug currently undergoing clinical trials for various cancers, has emerged as a promising candidate for combination therapy with conventional anticancer agents. In this study, we demonstrate that in patients-derived osteosarcoma cells who had undergone multiple chemotherapy treatments, as well as in murine colorectal cancer cells, administration of standard chemotherapeutic agents induces autophagy, which likely serves as a cytoprotective mechanism promoting therapy resistance in at least of part of tumor population. Incorporating chloroquine into the treatment regimen effectively suppressed autophagy, significantly enhancing osteosarcoma cell death in both 2D and 3D models while simultaneously reducing cell proliferation and migration capacity. In an orthotopic in vivo model of colorectal cancer, the combination of chloroquine and oxaliplatin not only impaired tumor growth but also prevented metastatic dissemination and inhibited the formation of metastasis. Notably, comparative analyses of proliferating and dormant tumor cell populations revealed that chloroquine exerts preferential cytotoxicity toward dormant cancer cells. This suggests a dual therapeutic advantage, wherein cytostatic agents primarily eliminate proliferating cells, while chloroquine specifically eradicates dormant cancer cells, which are often implicated in tumor recurrence. Collectively, these findings highlight the potential of autophagy inhibition to enhance the chemotherapy efficacy and suggest chloroquine-based combination therapy as a promising strategy for suppressing tumor growth and metastasis, ultimately improving treatment outcomes in cancer patients.
    DOI:  https://doi.org/10.1038/s41419-025-08304-6
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