bims-cagime 2025-10-12 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2025–10–12
forty-one papers selected by
Kıvanç Görgülü, Technical University of Munich

FNDC4 Drives Metastasis and Immune Evasion in Pancreatic Cancer.
Tissue Fluidity Mediates a Trade-off Between the Speed and Accuracy of Multicellular Patterning by Cell Sorting.
Pancreatic Damage in Ovarian Cancer-Associated Cachexia Is Driven by Activin A Signalling.
Acidosis orchestrates adaptations of energy metabolism in tumors.
Inducible CRISPR-Cas9 screening platform to interrogate non-proliferative cellular states.
Decoding ferroptosis for cancer therapy.
Cancer cachexia contender enters first pivotal trial.
Enhanced maximum intensity projection (eMIP) for improving the fidelity of optoacoustic images.
Toggle-Untoggle: A cell segmentation tool with an interactive user verification interface.
Clues to why the weight-loss condition cachexia arises when cancer occurs.
Modular Nanoassemblies Mimicking p62 Aggregates for Targeted Organelle Sequestration and Degradation against Breast Cancer.
Guiding Cell Migration with Electric Fields: Mechanisms and Applications of Galvanotaxis.
Physical traits of supercompetitors in cell competition.
The energy resistance principle.
A model for membrane curvature generation by caveolin discs driven by differential contact interaction.
Lifetime stressor exposure and depression among patients with pancreatic cancer: insights from the Florida Pancreas Collaborative.
CD40 agonist mitazalimab with mFOLFIRINOX in untreated metastatic pancreatic cancer: Biomarkers associated with outcomes from OPTIMIZE-1.
Unravelling the Diversity Observed in Cancer Cachexia.
A cellular and spatial atlas of TP53-associated tissue remodeling defines a multicellular tumor ecosystem in lung adenocarcinoma.
The biophysical mechanism of mitochondrial pearling.
Mechanical Regulation And Activity of Nuclear Condensates.
Bending the rules: curvature's impact on cell biology.
PhaSepDB 3.0: a comprehensive knowledgebase of phase separation-related proteins from AI-assisted curation.
A molecular census to elucidate the demixing mechanism of membraneless organelles.
Filter-aided expansion proteomics for the spatial analysis of single cells and organelles in FFPE tissue samples.
Distinct Structural Responses of Lipid Bilayers to Horizontal and Vertical Electric Fields.
An Inverse Electron-Demand Diels-Alder Approach to Selective Activity-Based Sensing of Acetaldehyde in Living Cells.
Targeting SREBP-dependent lipogenesis potentiates the anti-tumor activity of docetaxel by increasing membrane permeability and intracellular drug accumulation.
A central research portal for mining pancreatic clinical and molecular datasets and accessing biobanked samples.
Heterogeneity of Cellular Senescence: Subtype-Specific Mechanisms and the Emerging Role of Plasma Membrane Damage.
Bioelectric characterization of senescing human keratinocytes.
Primary tumor chromatin landscape governs metastatic organotropism.
Spatial proteomics for investigating solid tumor resistance mechanisms.
Translating cellular senescence research into clinical practice for metabolic disease.
Phosphatidylserine exposure and plasma membrane perforation as ferroptotic signatures for in vivo imaging.
A Structured Framework of Cytoskeletal Proteins and Non-centrosomal Microtubules Promote the Initiation and Elongation of Invadopodia.
Spatiotemporal temperature control by holographic heating microscopy unveils cellular thermosensitive calcium signalling.
A parabrachial hub for need-state control of enduring pain.
T cell cholesterol transport links intestinal immune responses to dietary lipid absorption.
Why did Bob stop losing weight? We need to talk about energy expenditure compensation.
Translational regulation in stress biology.

Cancer Res. 2025 Oct 09.

FNDC4 Drives Metastasis and Immune Evasion in Pancreatic Cancer.

Jingwei Li, Renfei Wu, Xiaohan Jin, Yuntao Yang, Ke Jiang, Yilin Wang, Shenghui Huang, Serena Tondi, Chu-Hu Lai, Shuang Dong, Berina Sabanovic, Miriam Roberto, Chenlei Wen, Yu Jiang, Da Fu, Alexandra Aicher, Baiyong Shen, Christopher Heeschen.

Pancreatic ductal adenocarcinoma (PDAC) is highly metastatic and largely refractory to current therapies, underscoring the need to uncover the molecular drivers of progression to identify targetable vulnerabilities. Here, we found that fibronectin type III domain containing 4 (FNDC4), known for its role in macrophage polarization and metabolic regulation, was elevated in metastatic PDAC cells and correlated with poor patient outcomes. FNDC4 knockdown reduced tumor growth and metastasis in a diverse set of aggressive PDAC models. Mechanistically, FNDC4 enhanced CCAR1 stability, thereby sustaining CCAR1/β-catenin signaling. FNCD4 deficiency led to reduced CCAR1 and β-catenin expression and consequently impaired invasion and colony formation. Moreover, FNDC4 promoted immune evasion by driving macrophage polarization toward a pro-tumorigenic M2 phenotype. FNDC4 loss shifted macrophage polarization toward an anti-tumor profile and increased CD4+ and CD8+ T cell infiltration. Together, the effects of FNDC4 targeting resulted in reduced tumor burden, suppression of metastasis, and improved survival in immunocompetent murine PDAC models. Unexpectedly, FNDC4 localized to the nucleus, pointing to potential intranuclear activity. Transcriptomic and functional analyses further identified CCL5 as a critical downstream effector, required for recruiting CCR5⁺ T-cells and mediating the immune effects of FNDC4 inhibition. Upstream, BHLHE40 directly activated FNDC4 transcription, which was stimulated by induction of epithelial-mesenchymal transition. Importantly, combining FNDC4 inhibition with CLDN18.2 CAR-T cells or chemotherapy resulted in enhanced tumor control compared to monotherapy. Together, these findings underscore the role of FNDC4 in promoting PDAC progression and the potential of FNDC4 as a target for innovative multimodal treatment strategies.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-1001
Biophys J. 2025 Oct 07. pii: S0006-3495(25)00652-6. [Epub ahead of print]

Tissue Fluidity Mediates a Trade-off Between the Speed and Accuracy of Multicellular Patterning by Cell Sorting.

Rikki M Garner, Sean E McGeary, Allon M Klein, Sean G Megason.

  The organization of cells into spatial patterns is a fundamental aspect of multicellularity. One major mechanism underlying tissue patterning is adhesion-based cell sorting, in which a heterogeneous mixture of cell types spontaneously separates into distinct domains based on differences in adhesion protein expression. Here, we identify tissue fluidity-the extent to which cells can move freely within a tissue-as a critical regulator of adhesion-based sorting. First, we describe a physically well-understood minimal tissue model that can integrate both tissue fluidity and adhesion-based sorting, and demonstrate that this model can quantitatively reproduce experimentally measured sorting dynamics in a fibroblast cell culture assay. We go on to show that altering tissue fluidity by any mechanism in the model leads to substantial changes in the rate or accuracy of sorting (or both). We further demonstrate that the balance between cell motility, which acts to fluidize the tissue, and homotypic cell-cell adhesion, which acts to solidify the tissue, sensitively tunes a fundamental trade-off between the rate and accuracy of sorting-such that sorting can only occur when motility and adhesion are tightly coupled. Intriguingly, best fits of the simulations to the experiments across a range of adhesion protein expression conditions suggest that cells may naturally scale their motility strength with their adhesion strength - thereby maintaining a permissive fluidity for sorting. Overall, our results indicate that tissue fluidity must be tightly regulated for sorting to occur, and that cells may have evolved a mechanism to naturally co-regulate their mechanical properties in order to sustain a patterning-competent fluidity.

Keywords:  Kawasaki Ising model; L929 fibroblasts; cadherin; cell motility; cell sorting; cell–cell adhesion; kinetics; statistical mechanics; tissue fluidity; viscosity

DOI:  https://doi.org/10.1016/j.bpj.2025.10.001
J Cachexia Sarcopenia Muscle. 2025 Oct;16(5): e70096

Pancreatic Damage in Ovarian Cancer-Associated Cachexia Is Driven by Activin A Signalling.

Amirhossein Abazarikia, Wonmi So, Yi Luan, Chandramohan Kattamuri, Thomas B Thompson, So-Youn Kim.

   BACKGROUND: Cancer-associated cachexia (CAC) is a severe metabolic disorder characterized by involuntary weight loss, skeletal muscle atrophy and adipose tissue depletion. It is a major contributor to morbidity and mortality in the advanced stages of various cancers. However, the impact of CAC on the pancreas remains largely unexplored.
METHODS: We used mice with constitutively active PI3K in oocytes, generated through a Cre-inducible Pik3ca* knock-in allele driven by Gdf9-icre and performed histological and molecular analyses of the pancreas during cachexia development. Additionally, we examined pancreatic changes following ovariectomy and administration of Follistatin 288 (FST288).
RESULTS: Mice that developed cachexia symptoms associated with granulosa cell tumour (GCT) growth exhibited significant pancreatic atrophy compared to controls (Cre+ vs. Cre- at PD83, p < 0.0001), including reduced size of individual acinar cells (102.99 ± 12.19 μm2 vs. 207.94 ± 24.85 μm2 at PD83, p < 0.0001) and acinar units (346.41 ± 169.22 μm2 vs. 1193.59 ± 136.01 μm2 at PD83, p < 0.0001), despite comparable food intake between groups. Acinar cells exhibited a decrease in zymogen granules, reduced amylase expression and diminished amylase activity in both serum (0.29 ± 0.08 vs. 1.41 ± 0.40, p < 0.001) and tissue (0.37 ± 0.14 vs. 1.05 ± 0.29, p < 0.01). In contrast, pancreatic islets remained intact, as evidenced by histological analysis and preserved insulin expression. The pancreas of PD83 Cre+ mice also developed fibrosis and acinar cell death, characterized by elevated expression of collagen IV and α-SMA, and TUNEL-positive signals in acinar cells, respectively. Ovariectomy preserved body weight (2.66 ± 1.30 g for Cre+/OVX vs. 1.60 ± 0.97 g for Cre-) compared to Cre+ mice (-3.66 g) and maintained pancreatic function, suggesting that tumour-derived factors from GCT contribute to the severity of cachexia. Acinar cells showed high expression of ACVR2B, leading to activation of downstream p-SMAD3 signalling. Accordingly, activin A directly induced acinar cell atrophy in both ex vivo cultured pancreas (79.27 ± 19.03 μm2 vs. 171.14 ± 27.01 μm2, p < 0.0001) and 266-6 acinar cells, as evidenced by reduced acinar cell size and decreased amylase production. Injection of FST288, an activin A inhibitor, rescued pancreatic acinar atrophy (252.95 ± 11.59 μm2 in Cre+/FST288 vs. 97.25 ± 12.37 μm2 in Cre+, p < 0.001) without affecting GCT tumour size. Ex vivo culture of pancreas and 266-6 acinar cells exposed to activin A confirmed that activin A directly induces pancreatic damage.
CONCLUSIONS: These findings demonstrate pancreatic damage occurs during CAC development and highlight the critical role of activin A in this process. Targeting activin A signalling may represent a promising therapeutic strategy to mitigate cachexia in cancer patients and preserve pancreatic function.

Keywords:  acinar cell atrophy; activin A; amylase; cachexia; follistatin 288

DOI:  https://doi.org/10.1002/jcsm.70096
Science. 2025 Oct 09. 390(6769): eadp7603

Acidosis orchestrates adaptations of energy metabolism in tumors.

Sven Groessl, Robert Kalis, Marteinn T Snaebjornsson, Leon Wambach, Jakob Haider, Florian Andersch, Almut Schulze, Wilhelm Palm, Johannes Zuber.

Malignant tumors are characterized by diverse metabolic stresses, including nutrient shortages, hypoxia, and buildup of metabolic by-products. To understand how cancer cells adapt to such challenges, we conducted sequential CRISPR screens to identify genes that affect cellular fitness under specific metabolic stress conditions in cell culture and to then probe their relevance in pancreatic tumors. Comparative analyses of hundreds of fitness genes revealed that cancer metabolism in vivo was shaped by bioenergetic adaptations to tumor acidosis. Mechanistically, acidosis suppressed cytoplasmic activity of extracellular signal-regulated kinase (ERK), thereby preventing oncogene-induced mitochondrial fragmentation and promoting fused mitochondria. The resulting boost in mitochondrial respiration supported cancer cell adaptations to various metabolic stresses. Thus, acidosis is an environmental factor that alters energy metabolism to promote stress resilience in cancer.

DOI: https://doi.org/10.1126/science.adp7603
Nat Protoc. 2025 Oct 08.

Inducible CRISPR-Cas9 screening platform to interrogate non-proliferative cellular states.

Gabriele Casagrande Raffi, Hendrik J Kuiken, Cor Lieftink, Rene Bernards, Roderick L Beijersbergen, Liqin Wang.

CRISPR screens have revolutionized the study of diverse biological processes, particularly in cancer research. Both pooled and arrayed CRISPR screens have facilitated the identification of essential genes for cell survival and proliferation, drivers of drug resistance and synthetic lethal interactions. However, applying loss-of-function CRISPR screening to non-proliferative states remains challenging, largely because of slower editing and the poor sensitivity of identifying guide RNAs that 'drop out' in a population of non-dividing cells. Here, we present a detailed protocol to accomplish this, using an inducible Cas9 system that offers precise temporal control over Cas9 expression. This inducible system allows gene editing to occur only after the non-proliferative state is fully established. We describe the complete procedure for generating an inducible Cas9-expressing model and for measuring editing efficiency by using flow cytometry. In addition, we discuss how to optimize key parameters for performing successful CRISPR screens in various non-proliferative states. We describe a detailed workflow for performing a screen in senescent cells to identify senolytic targets. This protocol is accessible to researchers with experience in molecular biology techniques and can be completed in 8-12 weeks, from the generation of an inducible Cas9 cell line clone to the analysis of a CRISPR screen for hit identification. These techniques can be applied by researchers across different fields, including stem cell differentiation, immune cell development, aging and cancer research.

DOI: https://doi.org/10.1038/s41596-025-01251-8
Nat Rev Cancer. 2025 Oct 10.

Decoding ferroptosis for cancer therapy.

Adam Wahida, Marcus Conrad.

Resisting cell death is a pivotal hallmark of cancer and one of several increasingly actionable functional capabilities acquired by cancer cells to sustain their malignant state. Since the early 2000s, the discovery of multiple regulated cell death programmes has intensified interest in targeting these maladaptive traits that cancer cells employ to resist cellular demise. Among these, ferroptosis - the lethal outcome of iron-dependent (phospho)lipid peroxidation - stands apart from other regulated cell death mechanisms, as it is persistently suppressed while lacking an activating signal. In cancer research, ferroptosis has garnered considerable attention, with growing evidence suggesting that its deregulation intersects with other hallmarks of malignancy, thus positioning it as a pleiotropic target. However, in the absence of approved ferroptosis-based drugs and despite substantial advances in understanding the metabolic manoeuvres of cancer cells to evade ferroptosis, its heralded translational value remains somewhat speculative at this stage. This Review reconciles the biochemical foundation of ferroptosis, the evidence supporting its role in cancer biology and the potential strategies for rationalizing targeted therapies to induce ferroptosis-prone states in malignancies. Building on this foundation, we explore contentious issues surrounding ferroptosis, including its implications for immunogenicity and redox imbalances in cancer. Finally, we address critical considerations such as therapeutic windows and biomarkers of ferroptosis, which are prerequisites for successful translation into clinical oncology.

DOI: https://doi.org/10.1038/s41568-025-00864-1
Nat Rev Drug Discov. 2025 Oct 10.

Cancer cachexia contender enters first pivotal trial.

Asher Mullard.

DOI: https://doi.org/10.1038/d41573-025-00168-x
Npj Imaging. 2025 Oct 06. 3(1): 49

Enhanced maximum intensity projection (eMIP) for improving the fidelity of optoacoustic images.

Manuel Gehmeyr, María Begoña Rojas López, Suhanyaa Nitkunanantharajah, Hubert Preißl, Andreas Vosseler, Reiner Jumpertz von Schwartzenberg, Andreas L Birkenfeld, Nikoletta Katsouli, Nikolina-Alexia Fasoula, Angelos Karlas, Michael Kallmayer, Anette-Gabriele Ziegler, Dominik Jüstel, Vasilis Ntziachristos.

Three-dimensional (3D) image reconstructions are often rendered as two-dimensional images, using maximum intensity projections (MIPs). However, MIP's rendering fidelity depends on the alignment of the individual slices along the projection direction. Also, the presence of noise and artifacts affects the contrast and the projected image elements. We introduce enhanced MIP (eMIP), a methodology that aligns the boundaries (e.g., skin boundary) of adjacent slices of the 3D volume onto the same coordinate system assumed by MIP (e.g., same depth) and applies robust contrast adjustment to normalize the intensities of the projected slices. We benchmark eMIP on 1725 clinical scans of human skin, using raster-scan optoacoustic mesoscopy (RSOM) that were assessed by 8 experts. Our results show that eMIP facilitates interpretability compared to conventional MIP and increases consistently the perceived image quality. The improved diagnostic ability of eMIP has the potential to replace MIP in RSOM and similar modalities.

DOI: https://doi.org/10.1038/s44303-025-00112-z
J Cell Sci. 2025 Oct 09. pii: jcs.264154. [Epub ahead of print]

Toggle-Untoggle: A cell segmentation tool with an interactive user verification interface.

Nina Grishchenko, Margarita Byrsan, Matthew Craig Drummond-Stoyles, Michael F Olson.

  Accurate cell segmentation is an essential step in the quantitative analysis of fluorescence microscopy images. Pre-trained deep learning models for automatic cell segmentation such as those offered by Cellpose perform well across a variety of biological datasets but may still introduce segmentation errors. While training custom models can improve accuracy, it often requires programming expertise and significant time, limiting the accessibility of automatic cell segmentation for many wet lab researchers. To address this gap, we developed "Toggle-Untoggle", a standalone desktop application that enables intuitive, code-free quality control of automated cell segmentation. Our tool integrates the latest Cellpose "cyto3" model, known for its robust performance across diverse cell types, while also supporting the "nuclei" model and user-specified custom models to provide flexibility for a range of segmentation tasks. Through a user-friendly graphical interface, users can interactively toggle individual segmented cells on or off, merge or draw cell masks, and export morphological features and cell outlines for downstream analysis. Here we demonstrate the utility of "Toggle-Untoggle" in enabling accurate, efficient single-cell analysis on real-world fluorescence microscopy data, with no coding skills required.

Keywords:  Cell morphology; Cytoskeleton; Fluorescence microscopy; Image analysis

DOI:  https://doi.org/10.1242/jcs.264154
Nature. 2025 Oct 08.

Clues to why the weight-loss condition cachexia arises when cancer occurs.

Kerstin Haase, Mariam Jamal-Hanjani.



Keywords:  Cancer; Medical research

DOI:  https://doi.org/10.1038/d41586-025-02594-8
ACS Nano. 2025 Oct 08.

Modular Nanoassemblies Mimicking p62 Aggregates for Targeted Organelle Sequestration and Degradation against Breast Cancer.

Yuai Li, Yunting Zhang, Jingwen Wang, Yujie Che, Tao Gong, Zhirong Zhang, Renhe Liu, Yao Fu.

  Selective autophagy relies on multivalent recognition by receptors like SQSTM1/p62 to form aggregates that cluster disperse organelles, undergoing liquid-liquid phase separation to facilitate their clearance and maintain cellular homeostasis. Inspired by this, we present the multivalent nanoparticle-based organelle targeting chimera (NanoTACOrg) to efficiently degrade organelles by flexibly clustering organelles for sequestration and facilitating targeted recruitment of autophagosomes. NanoTACOrg, assembled with a PLGA core, lysosomal escape modules, organelle-targeting modules, and LC3B binding modules, is programmed to selectively degrade various organelles, including mitochondria, endoplasmic reticulum, and Golgi apparatus. After endocytosis and lysosomal escape, NanoTACOrg targets subcellular compartments and mimics p62 aggregate-driven organelle clustering and degradation, without exhibiting the "hook effect". Specifically, NanoTACMito-mediated mitochondrial degradation disrupts oxidative phosphorylation (OXPHOS) while enhancing compensatory glycolysis, thus sensitizing tumor cells to the glucose transporter 1 (GLUT1) inhibitor BAY-876. BAY-876 loaded NanoTACMito potently inhibits tumor growth, recurrence, and metastasis, demonstrating superior therapeutic efficacy by simultaneously targeting OXPHOS and glycolysis. These findings highlight the potential of NanoTACOrg as a versatile and effective platform for cancer therapy, particularly through organelle-specific degradation and metabolic reprogramming.

Keywords:  metabolic plasticity; multivalent binding; nanoparticle-mediated targeted degradation; organelle; tumor metastasis

DOI:  https://doi.org/10.1021/acsnano.5c10801
Cold Spring Harb Perspect Biol. 2025 Oct 06. pii: a041744. [Epub ahead of print]

Guiding Cell Migration with Electric Fields: Mechanisms and Applications of Galvanotaxis.

Min Zhao, Yan Zhang, Kan Zhu, Brian Reid.

Electric field-guided cell migration, known as galvanotaxis or electrotaxis, has garnered great interest as an engineering manipulation but has not been widely considered physiologically relevant. Here we provide experimental evidence proving galvanotaxis is a fundamental biological process, like chemotaxis, and show that the application of electric fields provides a powerful engineering approach. We will review our understanding of (1) endogenous electric fields naturally found in biological systems; (2) galvanotaxis of different cell types; and (3) sensing and signaling mechanisms of galvanotaxis. We reason that the bioelectrical mechanism is likely to be part of the environmental cues that cells and tissues integrate to make motility decisions.

DOI: https://doi.org/10.1101/cshperspect.a041744
J R Soc Interface. 2025 Oct;22(231): 20250638

Physical traits of supercompetitors in cell competition.

Logan C Carpenter, Shiladitya Banerjee.

  Cell competition is a fitness control mechanism in tissues, where less fit cells are eliminated to maintain tissue homeostasis. Two primary mechanisms of cell competition have been identified: contact-dependent apoptosis and mechanical stress-induced competition. While both operate in tissues, their combined impact on population dynamics is unclear. Here, we present a cell-based computational model that integrates cellular mechanics with proliferation, contact-induced apoptosis and mechanically triggered apoptosis to investigate competition between two distinct cell types. Using this framework, we systematically examine how differences in physical traits-such as stiffness, adhesion and crowding sensitivity-govern competitive outcomes. Our results show that apoptosis rates alone are insufficient to predict cell fate; differences in proliferation and contact inhibition play equally important, context-dependent roles. Notably, we find that increased cell stiffness can confer a fitness advantage, enabling stiffer cells to outcompete softer neighbours. However, cells with reduced stiffness can become 'soft' supercompetitors if they exhibit faster growth and lower sensitivity to crowding. We also demonstrate that colony size critically influences competition: a minimum size is required for mutant expansion, below which elimination becomes stochastic. This stochastic clearance is driven by a protrusive instability in the interface between two cells that promotes invasion of the supercompetitors.

Keywords:  apoptosis; cancer; cell competition; cell growth; cellular Potts model; tissue homeostasis

DOI:  https://doi.org/10.1098/rsif.2025.0638
Cell Metab. 2025 Oct 06. pii: S1550-4131(25)00387-0. [Epub ahead of print]

The energy resistance principle.

Martin Picard, Nirosha J Murugan.

  Living organisms are physical-energetic systems that must obey simple principles guiding energy transformation across physical and temporal scales. The energy resistance principle (ERP) describes behavior and transformation of energy in the carbon-based circuitry of biology. We show how energy resistance (éR) is the fundamental property that enables transformation, converting into useful work the unformed energy potential of food-derived electrons fluxing toward oxygen. Although éR is required to sustain life, excess éR directly causes reductive and oxidative stress, heat, inflammation, molecular damage, and information loss-all hallmarks of disease and aging. We discuss how disease-causing stressors elevate éR and circulating growth differentiation factor 15 (GDF15) levels, whereas sleep, physical activity, and restorative interventions that promote healing minimize éR. The ERP is a testable general framework for discovering the modifiable bioenergetic forces that shape development, aging, and the dynamic health-disease continuum.

Keywords:  GDF15; biological circuits; biomarkers; cytokines; disease; energy; exercise; healing; inflammation; mitochondria; oxygen; physical laws; transformation

DOI:  https://doi.org/10.1016/j.cmet.2025.09.002
Nat Commun. 2025 Oct 10. 16(1): 9030

A model for membrane curvature generation by caveolin discs driven by differential contact interaction.

Avishai Barnoy, Nicholas Ariotti, Robert G Parton, Michael M Kozlov.

The recent discovery of the flat, disc-like structure of caveolin oligomers, predicted to be embedded in one membrane leaflet, has challenged earlier models of membrane curvature generation by caveolins during caveola biogenesis. Here, we provide a mechanism for this phenomenon. We propose that the central factor behind the membrane shaping by caveolin discs is a difference in interaction energies of the membrane leaflets with each other and with the hydrophobic faces of the caveolin discs. We demonstrate, through computational analysis, that the caveolin disc embedding induces elastic stresses of tilt and splay in the membrane leaflets, which, in turn, drive membrane kinking along the disc boundaries. The predicted resulting membrane shapes have an overall curved and faceted appearance in agreement with observations. Our model also provides a mechanistic understanding of the role of the negative intrinsic curvatures of lipids such as cholesterol and diacylglycerols, in caveola assembly.

DOI: https://doi.org/10.1038/s41467-025-64084-9
BMC Cancer. 2025 Oct 08. 25(1): 1530

Lifetime stressor exposure and depression among patients with pancreatic cancer: insights from the Florida Pancreas Collaborative.

Anthony DeSomma, Sebastian Maletz, Toni L Basinski, Raiza Morales, Tiago Biachi de Castria, Mark Bloomston, Dung-Tsa Chen, Wade G Douglas, Kevin L Huguet, Daniel Jeong, Kun Jiang, Dae Won Kim, Anjuli Luthra, Jose M Pimiento, Sahana Rajasekhara, Vic Velanovich, Margaret A Park, Grant S Shields, George M Slavich, Jennifer B Permuth.

   BACKGROUND: Although depression is reported to be higher among patients with pancreatic cancer than in the general population, research on depression and stress levels in this population is limited.
METHODS: To address this gap, we investigated the prevalence of self-reported depression and lifetime stressor exposure in a cohort of treatment-naïve patients with pancreatic ductal adenocarcinoma (PDAC) or other types of pancreatic tumors such as pancreatic neuroendocrine tumors and intraductal papillary mucinous neoplasms who received care at one of 15 institutions participating in the multi-institutional study Florida Pancreas Collaborative. Depression severity was assessed using the Edmonton Symptom Assessment System-revised (ESAS-r) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC), and acute and chronic stressor exposure was assessed with the Stress and Adversity Inventory (STRAIN).
RESULTS: PDAC patients reported higher average depression symptom severity at the time of diagnosis and after 6 months compared to non-PDAC patients (p = 0.027 and p = 0.063, respectively). On the other hand, non-PDAC patients experienced a higher mean number and severity of lifetime stressors (p = 0.021 and p = 0.039, respectively) than PDAC patients. Across the sample, greater stressor exposure (measured by stressor count, severity, and event type) was associated with higher odds of clinically significant depressive symptoms. We also observed that chronic stressors were significantly associated with lower odds of advanced disease (OR = 0.896, p = 0.002). Among PDAC patients who completed both STRAIN and ESAS-r (n = 52), greater severity of acute life events was associated with a significant increase in ESAS-r depression scores between baseline and 6-month follow-up (p = 0.015).
CONCLUSIONS: These findings highlight distinct patterns of depression and stress across pancreatic tumor types and reveal a robust association between lifetime stress exposure and depressive symptoms. Together, they underscore the need for systematic screening and integrated psychosocial support for patients with pancreatic cancer.

Keywords:  Adversity; Depression; Lifetime stress; Pancreatic cancer

DOI:  https://doi.org/10.1186/s12885-025-15007-w
Cell Rep Med. 2025 Oct 07. pii: S2666-3791(25)00480-X. [Epub ahead of print] 102407

CD40 agonist mitazalimab with mFOLFIRINOX in untreated metastatic pancreatic cancer: Biomarkers associated with outcomes from OPTIMIZE-1.

Jean-Luc Van Laethem, Karen Geboes, Ivan Borbath, Teresa Macarulla Mercade, Aurélien Lambert, Philippe Cassier, Hans Prenen, Emmanuel Mitry, Jean-Frédéric Blanc, Lorenzo Pilla, Jaime Feliu, Mercedes Rodriguez Garrote, Roberto Antonio Pazo-Cid, Inmaculada Gallego, Karin Enell Smith, Karin Nordbladh, David Gomez Jimenez, Peter Ellmark, Yago Pico de Coaña, Sumeet Vijay Ambarkhane, Gregory L Beatty, Eileen M O'Reilly.

  Response determinants to immunotherapy in metastatic pancreatic ductal adenocarcinoma (mPDAC) remain unclear, limiting treatment advancements. We report a single-arm phase 1b/2 study (OPTIMIZE-1) evaluating the safety and efficacy of the cluster of differentiation 40 (CD40) agonist mitazalimab combined with modified FOLFIRINOX (mFOLFIRINOX), in chemotherapy-naive patients with mPDAC. Patients receive an initial dose of mitazalimab one week before starting biweekly cycles of mFOLFIRINOX plus mitazalimab. The study meets its pre-specified primary endpoint, achieving a confirmed objective response rate (ORR) of 42.1%. Median duration of response, progression-free survival, and overall survival was 12.6 months, 7.7 months, and 14.9 months, respectively. Multi-omic analyses of tumor and blood specimens identify a baseline tumor-intrinsic gene signature related to fibrosis associated with improved survival. Additionally, mitazalimab-induced increases in activated circulating myeloid, B cell, and T cell frequencies correlate with better outcomes. These results may inform future patient stratification strategies supporting a planned randomized confirmatory trial of mitazalimab with mFOLFIRINOX in mPDAC. This study was registered at ClinicalTrials.gov (NCT04888312).

Keywords:  CD40 agonist; biomarker; chemotherapy; classical mPDAC; ctKRAS; immunotherapy; mFOLFIRINOX; mPDAC; mitazalimab; tumor microenvironment

DOI:  https://doi.org/10.1016/j.xcrm.2025.102407
Am J Physiol Cell Physiol. 2025 Oct 06.

Unravelling the Diversity Observed in Cancer Cachexia.

Thomas J Hawke, Tyrone A Washington, Yusuke Nishimura, Nicholas P Greene.



Keywords:  cachexia; fat loss; muscle loss; skeletal muscle; wasting

DOI:  https://doi.org/10.1152/ajpcell.00731.2025
Nat Cancer. 2025 Oct 07.

A cellular and spatial atlas of TP53-associated tissue remodeling defines a multicellular tumor ecosystem in lung adenocarcinoma.

William Zhao, Thinh T Nguyen, Atharva Bhagwat, Akhil Kumar, Bruno Giotti, Benjamin Kepecs, Jason L Weirather, Navin R Mahadevan, Asa Segerstolpe, Komal Dolasia, Jamshid Abdul-Ghafar, Naomi R Besson, Stephanie M Jones, Brian Y Soong, Chendi Li, Sebastien Vigneau, Michal Slyper, Isaac Wakiro, Mei-Ju Su, Karla Helvie, Allison Frangieh, Judit Jane-Valbuena, Orr Ashenberg, Mark Awad, Asaf Rotem, Raphael Bueno, Orit Rozenblatt-Rosen, Kathleen Pfaff, Scott Rodig, Aaron N Hata, Aviv Regev, Bruce E Johnson, Alexander M Tsankov.

Tumor protein p53 (TP53) is the most frequently mutated gene across many cancers and is associated with shorter overall survival in lung adenocarcinoma (LUAD). Here, to define how TP53 mutations affect the LUAD tumor microenvironment (TME), we constructed a multiomic cellular and spatial atlas of 23 treatment-naive human lung tumors. We found that TP53-mutant malignant cells lose alveolar identity and upregulate highly proliferative and entropic gene expression programs consistently across LUAD tumors from resectable clinical samples, genetically engineered mouse models, and cell lines harboring a wide spectrum of TP53 mutations. We further identified a multicellular tumor niche composed of SPP1+ macrophages and collagen-expressing fibroblasts that coincides with hypoxic, prometastatic expression programs in TP53-mutant tumors. Spatially correlated angiostatic and immune checkpoint interactions, including CD274-PDCD1 and PVR-TIGIT, are also enriched in TP53-mutant LUAD tumors and likely engender a more favorable response to checkpoint blockade therapy. Our systematic approach can be used to investigate genotype-associated TMEs in other cancers.

DOI: https://doi.org/10.1038/s43018-025-01053-7
Mol Biol Cell. 2025 Oct 08. mbcE25060302

The biophysical mechanism of mitochondrial pearling.

Gabriel Sturm, Kayley Hake, Austin E Y T Lefebvre, Caleb J Rux, Daria Ivanova, Alfred Millett-Sikking, Kevin M Tharp, Beiduo Rao, Michael Closser, Adam James Waite, Magdalena Precido-Lopez, Alex T Ritter, Sophie Dumont, Wen Lu, Suliana Manley, Juan C Landoni, Wallace F Marshall.

Mitochondrial networks exhibit remarkable dynamics that are driven in part by fission and fusion events. However, there are other reorganizations of the network that do not involve fission and fusion. One such exception is the elusive, "beads-on-a-string" morphological transition of mitochondria. During such transitions, the cylindrical tubes of the mitochondrial membrane transiently undergo shape changes to a string of "pearls" connected along thin tubes. These dynamics have been observed in many contexts and given disparate explanations. Here we unify these observations by proposing a common underlying mechanism based on the biophysical properties of tubular fluid membranes for which it is known that, under particular regimes of tension and pressure, membranes reach an instability and undergo a shape transition to a string of connected pearls. First, we use high-speed light-sheet microscopy to show that transient, short-lived pearling events occur spontaneously in the mitochondrial network in every cell type we have examined, including during T cell activation, neuronal firing, and replicative senescence. This high-temporal data reveals two distinct classes of spontaneous pearling, triggered either by ionic flux or cytoskeleton tension. We then induce pearling with chemical, genetic, and mechanical perturbations and establish three main physical causes of mitochondrial pearling, i) ionic flux producing internal osmotic pressure, ii) membrane packing lowering bending elasticity, and iii) external mechanical force increasing membrane tension. Pearling dynamics thereby reveal a fundamental biophysical facet of mitochondrial biology. We suggest that pearling should take its place beside fission and fusion as a key process of mitochondrial dynamics, with implications for physiology, disease, and aging.

DOI: https://doi.org/10.1091/mbc.E25-06-0302
Biophys J. 2025 Oct 08. pii: S0006-3495(25)00660-5. [Epub ahead of print]

Mechanical Regulation And Activity of Nuclear Condensates.

Jessica Z Zhao, Jing Xia, Clifford P Brangwynne.

The cell nucleus is constantly subjected to forces under many fundamental biological processes, including confined cell migration, osmoregulation, and large-scale stresses across tissues during development. Biomolecular condensates, a class of subcellular structures without surrounding membranes, are responsive to external force perturbation, as seen in early work on germline p-granules nearly two decades ago. However, how external forces on cells impact physiological condensation at the subcellular level, and how condensates themselves can be mechanically active, is still an emerging area of research. Here we discuss recent advances in mechanochemical regulation of phase separation events, focusing primarily within the cell nucleus. We also discuss open questions about how biomolecular condensates may play a role in cell mechanics and function in response to external forces.

DOI: https://doi.org/10.1016/j.bpj.2025.10.009
BMC Biol. 2025 Oct 06. 23(1): 296

Bending the rules: curvature's impact on cell biology.

Carole Arnold, Ismail Tahmaz, Marie-Ly Chapon, Hasna Maayouf, Valeriy Luchnikov, Jean-Louis Milan, Fabricio Borghi, Laurent Pieuchot.

  Curvature is a ubiquitous feature in biology, shaping structures at every scale and playing diverse roles in processes ranging from membrane dynamics to tissue organization. In this review, we first introduce briefly the fundamental concepts and mathematical principles of curvature. The second section explores how membrane curvature is perceived by molecular sensors and integrated into cellular responses. The third section examines the effects of curvature on cellular processes and behaviors at the cell-scale, providing a detailed discussion of the underlying mechanisms. Finally, we offer insights into emerging perspectives and highlight the future challenges in unraveling the multifaceted roles of curvature in biology.

Keywords:  Cell migration; Curvature; Curvotaxis; Mechanosensing; Substrate topography

DOI:  https://doi.org/10.1186/s12915-025-02416-3
Nucleic Acids Res. 2025 Oct 08. pii: gkaf973. [Epub ahead of print]

PhaSepDB 3.0: a comprehensive knowledgebase of phase separation-related proteins from AI-assisted curation.

Kaiqiang You, Runyu Li, Ruixin Lian, Yuxuan Li, Hongzhining Yang, Yiran Zhou, Yangsheng Chen, Likun Wang, Zhaoqing Fan, Liwei Ma, Tingting Li.

Phase separation (PS) is a fundamental principle driving the formation of membraneless organelles (MLOs), which are critical for various cellular functions and pathological conditions. We present PhaSepDB 3.0 (https://db.phasep.pro/), a significantly updated knowledgebase of proteins related to PS. To address the challenges of curating a vast body of literature, we have implemented a novel human-AI collaborative workflow that integrates a large language model (LLM)-based agentic system with expert verification, enabling a major expansion and enrichment of the database. PhaSepDB 3.0 now contains 3,484 expert-curated entries for 1849 PS-related proteins, more than doubling the content of the previous version. The annotation framework has been restructured to capture deeper insights, including functional relevance, experimental evidence, and the intrinsic and extrinsic regulations of PS. A key new feature is the protein-wise summary page, which synthesizes data from multiple publications to provide a comprehensive overview of each protein's PS behaviour and functional relevance. With redesigned, user-friendly web interfaces, PhaSepDB 3.0 serves as a critical resource for the community, supporting researchers to explore the intricate basis of PS and its biological implications in greater detail.

DOI: https://doi.org/10.1093/nar/gkaf973
Genome Biol. 2025 Oct 09. 26(1): 347

A molecular census to elucidate the demixing mechanism of membraneless organelles.

Cheryn Ali, Fernando Muzzopappa, Fabian Erdel.

   BACKGROUND: Cells contain membraneless organelles that have been proposed to form via phase separation involving dense networks of multivalent intermolecular interactions. As it is notoriously difficult to experimentally distinguish punctate structures formed by phase separation from those formed by other mechanisms, this issue is controversial. To complement experimental assays, we present a computational by-the-numbers approach to phase separation. We mine publicly available datasets to perform a molecular census of prominent subnuclear organelles in mouse embryonic stem cells: nucleoli, transcriptional condensates, heterochromatin foci, and Polycomb bodies. We estimate copy numbers and intermolecular distances and compare the latter to the Debye length, which is the characteristic distance over which intermolecular interactions typically occur.
RESULTS: We find that none of the organelles studied here contain any protein species that shows intermolecular distances below the estimated Debye length if molecules in the organelles are randomly distributed, which disfavors the classical one-component phase separation scenario. Considering multiple species based on databases of phase-separating proteins, we find that nucleoli and transcriptional condensates are compatible with multi-component phase separation driven by proteins and RNAs, while heterochromatin foci and Polycomb bodies are better explained by a model in which proteins bind to chromatin without phase-separating via dense multivalent interaction networks. We also provide an interactive tool that allows testing of alternative multi-component scenarios.
CONCLUSION: We introduce a computational by-the-numbers approach to benchmark different demixing models that may explain the assembly of membraneless organelles. Our results suggest that cells use different mechanisms to form subnuclear organelles with different biophysical properties.

Keywords:  Biology by the numbers; Condensates; Debye length; Demixing mechanisms; Membraneless organelles; Network fluid; Percolation; Phase separation

DOI:  https://doi.org/10.1186/s13059-025-03806-0
Nat Protoc. 2025 Oct 09.

Filter-aided expansion proteomics for the spatial analysis of single cells and organelles in FFPE tissue samples.

Zhen Dong, Chunlong Wu, Jiayi Chen, Wenhao Jiang, Kiryl D Piatkevich, Yi Zhu, Tiannan Guo.

Filter-aided expansion proteomics (FAXP) is a spatial proteomics approach designed for high-resolution analysis of formalin-fixed, paraffin-embedded (FFPE) tissues. Here we describe the integration of hydrogel-based tissue expansion with mass spectrometry, enabling isotropic expansion and robust protein retention while preserving spatial features. The FAXP workflow consists of several sequential steps, including tissue section dewaxing, in situ protein anchoring, hydrogel embedding, homogenization, staining, isotropic expansion, microdissection and filter-aided in-gel digestion to maximize peptide recovery. The Protocol integrates laser capture microdissection, enabling the precise isolation of single cells and subcellular components for subcellular spatial proteomics analysis. The approach achieves up to a fivefold linear expansion factor of FFPE tissue, including extracellular matrix-rich samples such as colorectal cancer, with less than 6% distortion, enabling the identification of an average of 2,368 proteins from single mouse liver nucleus shape and 3,312 proteins from single mouse liver cell shape using an Astral mass spectrometer. The method is compatible with diverse tissue types, including extracellular matrix-rich specimens, and integrates seamlessly with imaging workflows, such as immunostaining, for spatially resolved proteomic analysis. FAXP enables researchers to obtain comprehensive proteomic profiles with strong reproducibility and high sensitivity. The entire workflow takes ~27 h and requires only commercially available reagents and supplies and is thus accessible for researchers with intermediate expertise in tissue processing, microscopy and proteomics. FAXP can advance spatial proteomics-based studies, in particular of cancer heterogeneity, neurodegenerative diseases and cellular microenvironments within FFPE tissues, including archival clinical samples.

DOI: https://doi.org/10.1038/s41596-025-01256-3
J Phys Chem Lett. 2025 Oct 06. 10647-10654

Distinct Structural Responses of Lipid Bilayers to Horizontal and Vertical Electric Fields.

Hironori Kageyama, Maki Komiya, Eiji Yamamoto, Ayumi Hirano-Iwata.

Electric fields modulate the structure and mechanical properties of biological membranes, influencing diverse cellular processes. While the effects of vertical electric fields (EVert) across the membranes have been extensively studied, the influence of horizontal (in-plane) electric fields (EHorz) remains poorly understood. Here, using molecular dynamics (MD) simulations and bright-field imaging of planar lipid bilayers (PLBs), fundamental components of biological membranes, we investigate how EHorz and EVert affect lipid bilayer properties. Simulations revealed that EHorz induces greater structural changes than EVert, such as membrane area reduction and increases in lipid tail ordering, even at high cholesterol concentrations. Consistently, bright-field imaging shows that the DC horizontal membrane voltage (VHorz) causes membrane area contraction, whereas the vertical voltage (VVert) has no effect under the tested conditions. These results demonstrate that in-plane electric fields elicit distinct structural responses in lipid bilayers, highlighting its potential physiological relevance and importance in membrane biophysics.

DOI: https://doi.org/10.1021/acs.jpclett.5c02764
J Am Chem Soc. 2025 Oct 10.

An Inverse Electron-Demand Diels-Alder Approach to Selective Activity-Based Sensing of Acetaldehyde in Living Cells.

Yuxuan Li, Gen Li, Erin L Li, Jaehee Kim, Christopher J Chang.

Acetaldehyde (AA) is a reactive aldehyde primarily produced in cells as a metabolic intermediate during ethanol oxidation. Excess AA, often resulting from impaired AA detoxification, leads to aberrant DNA, protein, and/or lipid damage and increases risk of diseases such as cancer, hepatitis, and cirrhosis. Traditional methods for detecting biological AA often require sample destruction or extensive processing, which compromise spatiotemporal resolution, or do not exhibit sufficient selectivity for this two-carbon metabolite over other competing aldehydes and reactive carbon species in living systems. To overcome these limitations, we now report the design, synthesis, and biological applications of a fluorescent probe platform for acetaldehyde-specific activity-based sensing. The first-generation reagent Acetaldehyde Probe-1 (AAP-1) utilizes an AA-triggered inverse electron-demand Diels-Alder (IEDDA) reaction to enable selective detection of physiologically relevant levels of this two-carbon aldehyde in aqueous solution and in live cells, with minimal interference from competing biological analytes, including highly similar aldehydes like formaldehyde (FA) and methylglyoxal (MGO). Furthermore, AAP-1 enables visualization of endogenous AA pools generated during ethanol metabolism in a human liver cancer cell line, highlighting the potential of this chemical activity-based sensing strategy for studying two-carbon biology in living systems.

DOI: https://doi.org/10.1021/jacs.5c14058
Oncogene. 2025 Oct 04.

Targeting SREBP-dependent lipogenesis potentiates the anti-tumor activity of docetaxel by increasing membrane permeability and intracellular drug accumulation.

Jiaqi Chen, Mu-En Wang, Alyssa R Bawcom, Yi Lu, John M Asara, Lei Li, Ming Chen.

Lipid metabolism is among the most frequently dysregulated metabolic processes in human cancer, yet how cellular lipids, the end products of lipogenesis, and their composition are altered to support various aspects of cancer remains poorly understood. Here, we show that targeting SREBP-dependent lipogenesis via FGH10019, an orally available SREBP inhibitor, enhances docetaxel-induced cytotoxicity in human prostate cancer cells in vitro and in vivo. Mechanistically, suppression of lipid biosynthesis leads to a shift in cellular lipid composition toward polyunsaturated lipids, resulting in increased membrane permeability and intracellular docetaxel accumulation. Thus, our findings reveal a critical role of de novo lipogenesis in protecting cancer cells from chemotherapeutics and suggest that treatment with lipogenesis inhibitors could improve the efficacy of chemotherapy against human prostate cancer.

DOI: https://doi.org/10.1038/s41388-025-03588-6
Transl Oncol. 2025 Oct 03. pii: S1936-5233(25)00281-5. [Epub ahead of print]62 102550

A central research portal for mining pancreatic clinical and molecular datasets and accessing biobanked samples.

Jorge Oscanoa, Helen Ross-Adams, Abu Z M Dayem Ullah, Trupti S Kolvekar, Lavanya Sivapalan, Emanuela Gadaleta, Graeme J Thorn, Maryam Abdollahyan, Ahmet Imrali, Amina Saad, Rhiannon Roberts, Christine S Hughes, Pcrftb Hemant M Kocher, Claude Chelala.

   OBJECTIVES: We present Pancreas Genome Phenome Atlas (PGPA) as a resource for the mining and analysis of pancreatic -omics datasets, and demonstrate the biological interpretations possible due to this dynamic analytics hub accommodating an extensive range of publicly available datasets.
METHODS: Clinical and molecular datasets from four primary sources are included (The Cancer Genome Atlas, International Cancer Genome Consortium, Cancer Cell Line Encyclopaedia, Genomics Evidence Neoplasia Information Exchange), which form the foundation of -omics profiling of pancreatic malignancies and related lesions (n = 7760 specimens). Several user-friendly analytical tools to integrate and explore molecular data derived from these primary specimens and cell lines are available. Crucially, PGPA is positioned as the data access point for Pancreatic Cancer Research Fund Tissue Bank - the only national pancreatic cancer biobank in the UK. This will pioneer a new era of biobanking to promote collaborative studies and effective sharing of multi-modal molecular, histopathology and imaging data (>125 000 specimens from >3980 cases and controls; >2700 radiology images, and >2630 digitised H&Es from 401 donors) to accelerate validation of in silico findings in patient-derived material.
RESULTS: We demonstrate the practical utility of PGPA by investigating somatic variants associated with established transcriptomic subtypes and disease prognosis: several patient-specific variants are clinically actionable and may be leveraged for precision medicine.
CONCLUSIONS: This places PGPA at the analytical forefront of pancreatic biomarker-based research, providing the user community with a distinct resource to facilitate hypothesis-testing on public data, validate novel research findings, and access curated, high-quality patient tissues for translational research.

Keywords:  Biomarkers; Genomics; Pancreas biobank; Transcriptomics; Translational

DOI:  https://doi.org/10.1016/j.tranon.2025.102550
Cancer Sci. 2025 Oct 11.

Heterogeneity of Cellular Senescence: Subtype-Specific Mechanisms and the Emerging Role of Plasma Membrane Damage.

Enaam Alghamdi, Keiko Kono.

  Cellular senescence is a state of stable cell cycle arrest accompanied by heightened immune activity, contributing to aging and age-related diseases. Although once regarded as a terminal and static condition, cellular senescence is now recognized as a dynamic and highly regulated process controlled by complex molecular networks. In vitro, it can be triggered by a variety of stimuli, including telomere attrition, DNA damage, oncogene activation, mitochondrial dysfunction, and others. However, the precise in vivo triggers of cellular senescence remain unclear. Recent findings from our group demonstrate that plasma membrane damage can induce cellular senescence in cultured normal human fibroblasts. Notably, the gene expression profile of these cells shares key characteristics with the cells localized near fibrotic cutaneous wounds in humans. In this review, we highlight recent advances in understanding the diverse subtypes of cellular senescence and their underlying regulatory networks, their context-dependent roles in tumorigenesis, and the therapeutic potential and challenges associated with targeting senescent cells. Unraveling the heterogeneity of cellular senescence holds promise for harnessing the beneficial roles of cellular senescence while mitigating its pro-tumorigenic and pro-aging effects.

Keywords:  cellular senescence; oncogene‐induced senescence; p16; p53; plasma membrane damage

DOI:  https://doi.org/10.1111/cas.70223
iScience. 2025 Sep 19. 28(9): 113275

Bioelectric characterization of senescing human keratinocytes.

Hamid Sediqi, Michael Levin.

  Aging disrupts tissue integrity through the accumulation of senescent cells that impair morphology, signaling, and regeneration. We investigated how bioelectric signaling, specifically resting membrane potential (Vmem), guides the transition to senescence in human keratinocytes. Using voltage-sensitive dyes, we tracked Vmem alongside senescence markers, chromatin state, and senescence-associated secretory phenotype (SASP) cytokines. Senescence was marked by depolarization, increased inter-culture heterogeneity, reduced intra-culture variability, and loss of spatial Vmem organization. SASP activation was partial: depolarization selectively enhanced interleukin-6 (IL-6) but not IL-1α or IL-8, indicating Vmem shapes the senescent secretome. Senescent cells showed reduced responsiveness to hyperpolarizing drug pinacidil and impaired bioelectric resilience. Hyperpolarization attenuated, and depolarization exacerbated, senescence-associated phenotypes. These findings support the morphostatic information loss theory, which posits that aging results from breakdown of bioelectrically encoded cues that preserve tissue structure. Vmem emerges as a low-dimensional integrator of cell state and spatial order, offering a biophysical target to delay senescence and maintain tissue coordination.

Keywords:  Bioengineering; Biological sciences; Biotechnology

DOI:  https://doi.org/10.1016/j.isci.2025.113275
Nat Cancer. 2025 Oct 10.

Primary tumor chromatin landscape governs metastatic organotropism.

Amy C Gladstein, David M Feldser.

DOI: https://doi.org/10.1038/s43018-025-01048-4
Cancer Metastasis Rev. 2025 Oct 08. 44(4): 76

Spatial proteomics for investigating solid tumor resistance mechanisms.

Xin Ming M Zhou, Anjali J D'Amiano, Charles Lu, Vrinda Madan, Sara Khoshniyati, Jack Kollings, Noah E Sunshine, Sachin S Surwase, Joel C Sunshine.

  Spatial proteomics technologies have been pivotal in profiling tumor immune microenvironments at single-cell resolution, advancing our understanding of cancer biology, identifying key cell populations in solid tumors, and predicting treatment responses. Although immune checkpoint and molecular inhibitors have revolutionized cancer care, resistance mechanisms remain a major therapeutic challenge that hinder productive responses in a notable fraction of cancer patients. In this review, we outline current spatial proteomics and computational analysis tools for studying the tumor immune microenvironment and discuss how spatial proteomics techniques have helped elucidate cancer resistance mechanisms across multiple tumor types. In this process, we highlight the importance of investigating immunosuppressive cell populations that can mediate cancer resistance, specifically with regard to their localization, protein signatures, and surrounding interactions. Finally, we provide a look ahead at future applications of artificial intelligence/machine learning and multi-omics approaches that will help further propel our understanding of cancer resistance mechanisms through spatial biology research.

Keywords:  Cancer resistance; Immunotherapy; Proteomics; Spatial biology

DOI:  https://doi.org/10.1007/s10555-025-10292-0
Nat Rev Endocrinol. 2025 Oct 06.

Translating cellular senescence research into clinical practice for metabolic disease.

Selim Chaib, Allyson K Palmer, Saranya P Wyles, Nicolas Musi, James L Kirkland, Tamara Tchkonia.

Translational research on cellular senescence has led to numerous early-phase clinical trials targeting senescent cells to treat, prevent or alleviate multiple disorders and diseases, including metabolic diseases and their comorbidities. Cellular senescence is a cell fate that occurs in response to stressors, including metabolic disruptions, and is one of the hallmarks (or pillars) of ageing. In their senescent state, cells cease proliferation and can develop a senescence-associated secretory and metabolic phenotype that contributes to the pathogenesis of metabolic dysfunction associated with obesity and ageing. Metabolic stress, which is central to the development of metabolic diseases, can trigger cellular senescence, thereby enabling a vicious cycle that exacerbates metabolic dysfunction. Therapies targeting senescent cells (senotherapeutics), either alone or in combination with other gerotherapies or lifestyle interventions, hold great promise for addressing the ongoing obesity epidemic and the need for improved therapies to prevent and treat metabolic diseases and their complications and comorbidities. In this Review, we discuss novel senotherapeutics, including challenges related to the translation of these therapies and the need to establish gerodiagnostic biomarkers to track the elimination of senescent cells, define eligibility and measure efficacy, as well as considerations for clinical trial design and execution.

DOI: https://doi.org/10.1038/s41574-025-01187-9
Npj Imaging. 2025 Oct 06. 3(1): 48

Phosphatidylserine exposure and plasma membrane perforation as ferroptotic signatures for in vivo imaging.

Ali Yasin Sonay, Elana Apfelbaum, Benedict Edward Mc Larney, Jan Grimm.

Ferroptosis emerged as a cell death modality against cancer, but there are currently no available biomarkers for imaging ferroptosis-based therapies. To address this, we evaluated phosphatidylserine exposure and perforation of lipid membranes during ferroptosis to explore potential targeting opportunities. We demonstrated that nano-sized gaps at late stage ferroptosis can serve as entry points for dyes that can bind to intracellular structures. These changes were accompanied with cellular signaling components similar to platelet activation, with phosphatidylserine exposure on the cell surface as a potential target for imaging programed cell death, including ferroptosis. We employed a novel tumor-seeking dye CJ215 that can also label apoptotic cells and showed that CJ215 accumulates in ferroptotic cells both in vitro and in vivo by binding to phosphatidylserine, which can be prevented with ferroptosis inhibition. Since phosphatidylserine exposure also occurs during apoptosis, CJ215 can monitor both apoptosis and ferroptosis-based therapies.

DOI: https://doi.org/10.1038/s44303-025-00110-1
Mol Biol Cell. 2025 Oct 08. mbcE25070313

A Structured Framework of Cytoskeletal Proteins and Non-centrosomal Microtubules Promote the Initiation and Elongation of Invadopodia.

Mark Garewal, Pedro Ramos, Kenneth A Myers.

Cancer deaths are largely attributed to the dissemination of cancer cells from a primary tumor to a secondary metastatic site. The metastatic cascade is initiated by cancer cell invasion that is facilitated by cytoskeletal remodeling to produce ventral cell protrusions, termed invadopodia, that degrade the extracellular matrix to promote motility. Conventional invadopodia studies rely on techniques with embedded cells in 3D matrices to observe and determine protein behavior, which often utilize immunolabeling strategies and struggle to visualize individual invadopodia, thereby limiting investigations of protein and invadopodia dynamics. Here, the design and utilization of an Axial Invasion Chamber is described for live-cell imaging of elongating invadopodia in 3D. Results identify that cytoskeletal and microtubule associated proteins within invadopodia exist in an organized framework, and determine the functional contribution by which non-centrosomal microtubules promote cancer cell invasion and migration. [Media: see text].

DOI: https://doi.org/10.1091/mbc.E25-07-0313
Lab Chip. 2025 Oct 06.

Spatiotemporal temperature control by holographic heating microscopy unveils cellular thermosensitive calcium signalling.

Kotaro Oyama, Ayumi Ishii, Shuhei Matsumura, Tomoko G Oyama, Mitsumasa Taguchi, Madoka Suzuki.

Optical microheating technologies have revealed how biological systems sense heating and cooling at the microscopic scale. Sensing is based on thermosensitive biochemical reactions that frequently engage membrane proteins, Ca2+ channels, and pumps to convert sensing information as the Ca2+ signalling in cells. These findings highlight the feasibility of thermally manipulating intracellular Ca2+ signalling. However, how the thermosensitive Ca2+ signalling would behave, particularly in multicellular systems, remains elusive. In this study, to extend the ability of the spatiotemporal temperature control by optical microheating technologies, we propose holographic heating microscopy. Water-absorbable infrared (IR) laser light is modulated by a reflective liquid crystal on a silicon spatial light modulator (LCOS-SLM). A computer-generated hologram displayed on the LCOS-SLM modulates the spatial phase pattern of the IR laser light to generate predesigned temperature gradients at the microscope focal plane. The holographic heating microscopy visualises how thermosensitive Ca2+ signalling is generated and propagated in MDCK cells, rat hippocampal neurons, and rat neonatal cardiomyocytes. Moreover, the optical control of the temporal temperature gradient reveals the cooling-rate dependency of Ca2+ signalling in HeLa cells. These findings demonstrate the extended ability of holographic heating microscopy in investigating cellular thermosensitivities and thermally manipulating cellular functions.

DOI: https://doi.org/10.1039/d5lc00675a
Nature. 2025 Oct 08.

A parabrachial hub for need-state control of enduring pain.

Nitsan Goldstein, Amadeus Maes, Heather N Allen, Tyler S Nelson, Kayla A Kruger, Morgan Kindel, Albert T M Yeung, Nicholas K Smith, Jamie R E Carty, Lavinia Boccia, Niklas Blank, Emily Lo, Rachael E Villari, Ella Cho, Erin L Marble, Michelle Awh, Yasmina Dumiaty, Melissa J Chee, Rajesh Khanna, Christoph A Thaiss, Bradley K Taylor, Ann Kennedy, J Nicholas Betley.

Long-term sustained pain following acute physical injury is a prominent feature of chronic pain conditions1. Populations of neurons that rapidly respond to noxious stimuli or tissue damage have been identified in the spinal cord and several nuclei in the brain2-4. Understanding the central mechanisms that signal ongoing sustained pain, including after tissue healing, remains a challenge5. Here we use spatial transcriptomics, neural manipulations, activity recordings and computational modelling to demonstrate that activity in an ensemble of anatomically and molecularly diverse parabrachial neurons that express the neuropeptide Y (NPY) receptor Y1 (Y1R neurons) is increased following injury and predicts functional coping behaviour. Hunger, thirst or predator cues suppressed sustained pain, regardless of the injury type, by inhibiting parabrachial Y1R neurons via the release of NPY. Together, our results demonstrate an endogenous analgesic hub at pain-responsive parabrachial Y1R neurons.

DOI: https://doi.org/10.1038/s41586-025-09602-x
Science. 2025 Oct 09. 390(6769): eadt4169

T cell cholesterol transport links intestinal immune responses to dietary lipid absorption.

Yajing Gao, John P Kennelly, Xu Xiao, Emily Whang, Alessandra Ferrari, Alexander H Bedard, Julia J Mack, Alexander Nguyen, Sonal Srikanth, Thomas Weston, Lauren F Uchiyama, Whitaker Cohn, Danielle H Cho, Min Sub Lee, Julian Whitelegge, Yousang Gwack, Stephen G Young, Steven J Bensinger, Peter Tontonoz.

The intrinsic pathways that control membrane organization in immune cells and their impact on cellular functions are poorly defined. We found that the nonvesicular cholesterol transporter Aster-A linked plasma membrane (PM) cholesterol availability in CD4 T cells to systemic metabolism. Aster-A was recruited to the PM during T cell receptor (TCR) activation, where it facilitated the removal of accessible cholesterol. Loss of Aster-A increased cholesterol accumulation in the PM, which enhanced TCR nanoclustering and signaling. Aster-A associated with stromal interaction molecule 1 (STIM1) and negatively regulated calcium (Ca2+) flux. Aster-A deficiency promoted CD4 T cells to acquire a T helper 17 (TH17) phenotype and stimulated interleukin-22 production, which reduced intestinal fat absorption and conferred resistance to diet-induced obesity. These findings delineate how immune cell membrane homeostasis links to systemic physiology.

DOI: https://doi.org/10.1126/science.adt4169
Biol Lett. 2025 Oct;21(10): 20250275

Why did Bob stop losing weight? We need to talk about energy expenditure compensation.

Lewis G Halsey.

  Repeatedly, intervention studies report that participants undertaking a new exercise regimen lose weight initially, but then their weight loss quickly plateaus. A careful look at the literature shows that plateauing happens even when participants' food intake does not increase and their exercise intensity is maintained. So how can we explain this, given that if the body is consistently in energy debt, surely weight loss must result. I argue that energy expenditure compensation-reductions in energy expended on some biological processes to counteract increases in energy expended on activity levels-is an under-recognized compensatory response to heightened exercise. We observe energy expenditure compensation 'in the field', for example, people in pre-industrialized nations expend a lot of energy each day on physical activity but nonetheless have a daily energy expenditure commensurate with that of relatively sedentary Westerners. But most researchers and practitioners have not connected the aforementioned laboratory and field observations-that is, if our activity levels are consistently heightened for long enough, our bodies adaptively compensate in terms of overall energy expenditure, such that if we undertake an exercise regimen, in the long run we only lose a fraction of the weight we aspire to. We need to raise awareness about energy expenditure compensation, how it can limit weight loss and how in light of this knowledge we might better prescribe 'weight loss regimens' to encourage additional weight reduction in those who aspire to it.

Keywords:  calories; energy compensation; energy expenditure; energy expenditure compensation; exercise; weight loss

DOI:  https://doi.org/10.1098/rsbl.2025.0275
Nat Cell Biol. 2025 Oct 07.

Translational regulation in stress biology.

Naomi R Genuth, Andrew Dillin.

Organisms must constantly respond to stress to maintain homeostasis, and the successful implementation of cellular stress responses is directly linked to lifespan regulation. In this Review we examine how three age-associated stressors-loss of proteostasis, oxidative damage and dysregulated nutrient sensing-alter protein synthesis. We describe how these stressors inflict cellular damage via their effects on translation and how translational changes can serve as both sensors and responses to the stressor. Finally, we compare stress-induced translational programmes to protein synthesis alterations that occur with age and discuss whether these changes are adaptive or deleterious to longevity and healthy ageing.

DOI: https://doi.org/10.1038/s41556-025-01765-z