bims-cagime 2025-11-16 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2025–11–16
thirty-one papers selected by
Kıvanç Görgülü, Technical University of Munich

Reawakening cAMP signalling in cancer cachexia.
Impaired cAMP-PKA-CREB1 signalling drives mitochondrial dysfunction in skeletal muscle during cancer cachexia.
ALDOA-Mediated Metabolic Reprogramming is a Targetable Vulnerability for Ferroptosis Sensitization in Cancer.
Lipidome Plasticity Preserves Membrane Function in Sphingolipid-Depleted HAP1 Cells.
Universal consensus 3D segmentation of cells from 2D segmented stacks.
A dynamic feedback loop between retrograde sterol transport and TORC2 controls adaptation of the plasma membrane to stress.
Deep-Learning Tool ScVital Enables Species-Agnostic Integration of Cancer Cell States.
Autophagy-dependent modulation of ER calcium release drives KCNMA1/BKCa signaling and seizure susceptibility.
Forward genetic screening in engineered colorectal cancer organoids identifies regulators of metastasis.
Reframing cancer cachexia: the vagal brain-liver axis as a novel neuro-metabolic target.
Antibodies unleashed against pancreatic cancer.
StealTHY: An immunogen-free CRISPR platform to expose concealed metastasis regulators in immunocompetent models.
Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer.
Spatially organized cellular communities shape functional tissue architecture in the pancreas.
SIGLEC12 mediates plasma membrane rupture during necroptotic cell death.
Autophagy Reprogramming in Cancer.
Ibrutinib and PD-1 blockade potentiate mesothelin-targeting CAR-T cell therapy in preclinical models of pancreatic cancer.
Protocol to quantify mechanical properties of cells using optical tweezers.
Different diabetes types and pancreatic ductal adenocarcinoma: a Mendelian randomization and pathway/gene-set analysis.
Cytosolic acetyl-coenzyme A is a signalling metabolite to control mitophagy.
Slc26a9 promotes the perineural invasion of pancreatic cancer in mice.
An engineered cysteine sensor optimized for high-throughput screening identifies regulators of intracellular thiol levels.
Bidirectional quantitative scattering microscopy.
Ist2 promotes lipid transfer by Osh6 via its membrane tethering and lipid scramblase activities.
The bottleneck for maternal transmission of mtDNA is linked to purifying selection by autophagy.
QuiCAT: A Scalable and Flexible Framework for Mapping Synthetic Sequences.
Inducing ferroptosis to impede metastasis by inhibiting the calcium channel TRPC6.
iGlucoSnFR2: A genetically encoded fluorescent sensor for measuring intracellular or extracellular glucose in vivo in mouse brain.
iPEX enables micrometre-resolution deep spatial proteomics via tissue expansion.
Developing a therapeutic elastase that stimulates anti-tumor immunity by selectively killing cancer cells.
Quantitative Mapping of Fibrotic Tissue Mechanics via Brillouin Spectroscopy.

Nat Metab. 2025 Nov 12.

Reawakening cAMP signalling in cancer cachexia.

Honglei Ji, Maria Rohm.

DOI: https://doi.org/10.1038/s42255-025-01417-4
Nat Metab. 2025 Nov 12.

Impaired cAMP-PKA-CREB1 signalling drives mitochondrial dysfunction in skeletal muscle during cancer cachexia.

Elia Angelino, Lorenza Bodo, Roberta Sartori, Valeria Malacarne, Beatrice D'Anna, Nicolò Formaggio, Suvham Barua, Tommaso Raiteri, Andrea Lauria, Simone Reano, Alessandra Murabito, Monica Nicolau, Fabiana Ferrero, Camilla Pezzini, Giulia Rossino, Francesco Favero, Michele Valmasoni, Nicoletta Filigheddu, Alessio Menga, Davide Corà, Emilio Hirsch, Salvatore Oliviero, Vittorio Sartorelli, Valentina Proserpio, Alessandra Ghigo, Marco Sandri, Paolo E Porporato, Daniela Talarico, Giuseppina Caretti, Andrea Graziani.

Skeletal muscle wasting is a defining feature of cancer cachexia, a multifactorial syndrome that drastically compromises patient quality of life and treatment outcomes. Mitochondrial dysfunction is a major contributor to skeletal muscle wasting in cancer cachexia, yet the upstream molecular drivers remain elusive. Here we show that cancer impairs the activity of cAMP-dependent protein kinase A (PKA) and of its transcriptional effector CREB1 in skeletal muscle, ultimately contributing to the downregulation of a core transcriptional network that supports mitochondrial integrity and function. The restoration of cAMP-PKA-CREB1 signalling through pharmacological inhibition of the cAMP-hydrolysing phosphodiesterase 4 (PDE4) rescues the expression of mitochondrial-related genes, improves mitochondrial function and mitigates skeletal muscle wasting in male mice. Altogether, our data identify tumour-induced suppression of the cAMP-PKA-CREB1 axis as a central mechanism contributing to mitochondrial dysfunction in skeletal muscle during cancer cachexia. Furthermore, these findings highlight PDE4, particularly the PDE4D isoform, as a potential therapeutic target to preserve muscle mitochondrial function and counteract muscle wasting in cancer cachexia.

DOI: https://doi.org/10.1038/s42255-025-01397-5
Adv Sci (Weinh). 2025 Nov 11. e11880

ALDOA-Mediated Metabolic Reprogramming is a Targetable Vulnerability for Ferroptosis Sensitization in Cancer.

Pengqi Wang, Kezhang He, Bowen Wang, Wei Zhou, Ying Zhang, Tianhua Ma, Sheng Ding.

  Ferroptosis presents great potential for cancer therapy, either alone or in combination with classical therapy. However, inducing ferroptosis by targeting canonical ferroptosis suppressors that directly inhibit lipid peroxidation non-selectively induces ferroptosis in both cancerous and normal cells, thereby limiting its therapeutic potential. In this study, it is revealed that aldolase A (ALDOA) reprograms lipid metabolism to resist ferroptosis in cancer cells and identifies ALDOA as a targetable vulnerability for ferroptosis sensitization. Cancer cells with ALDOA suppression exhibit increased susceptibility to ferroptosis-a response less obvious in normal cells. Mechanistically, ALDOA depletion induces significant accumulation of fructose 1,6-bisphosphate in cancer cells, thereby enhancing autophagy-dependent degradation of phospholipid-modifying enzymes. These alterations increase the ratio of phospholipids containing pro-ferroptotic polyunsaturated fatty acids over anti-ferroptotic monounsaturated fatty acids, culminating in heightened ferroptosis sensitivity. Moreover, ALDOA inhibitors selectively promote ferroptosis in cancer cells, both in vitro and in vivo. Collectively, the findings reveal that ALDOA-mediated metabolic reprogramming is a targetable vulnerability for ferroptosis sensitization in cancer.

Keywords:  ALDOA; autophagy; cancer; ferroptosis; lipid metabolism; metabolic reprogramming

DOI:  https://doi.org/10.1002/advs.202511880
FASEB J. 2025 Nov 30. 39(22): e71238

Lipidome Plasticity Preserves Membrane Function in Sphingolipid-Depleted HAP1 Cells.

Bingen G Monasterio, Aritz B García-Arribas, Howard Riezman, Félix M Goñi, Alicia Alonso, Noemi Jiménez-Rojo.

  Sphingolipids (SL) are minor but essential component of mammalian membranes, known for their distinctive biophysical properties and their involvement in disease. In this study, we challenged human cells to grow under extreme SL depletion and uncovered their remarkable capacity for lipidome-driven adaptation. Using a serine palmitoyltransferase-deficient (SPTLC1-) near-haploid HAP1 cell line, we combined comprehensive lipidomic profiling with laurdan fluorescence generalized polarization (GP) imaging, and AFM-based force spectroscopy to assess the biophysical consequences of SL depletion. As expected, SL levels were markedly reduced in both whole-cell extracts and plasma membrane (PM) preparations of HAP1-SPT cells grown under SL-limiting conditions. However, laurdan GP and AFM breakthrough force values in PM preparations remained unchanged across different SL conditions, indicating a robust homeostatic adaptation of the membrane. Clear differences could be detected only after 48 h of SL restriction. Our findings underscore the resilience of membrane architecture-and highlight lipidome plasticity as a powerful compensatory strategy under metabolic stress.

Keywords:  AFM; CHO; HAP1; Laurdan; lipidomics; mass‐spectroscopy; membrane fluidity; plasma membrane; sphingolipids; sphingomyelin

DOI:  https://doi.org/10.1096/fj.202502545R
Nat Methods. 2025 Nov;22(11): 2386-2399

Universal consensus 3D segmentation of cells from 2D segmented stacks.

Felix Y Zhou, Zach Marin, Clarence Yapp, Qiongjing Zou, Benjamin A Nanes, Stephan Daetwyler, Andrew R Jamieson, Md Torikul Islam, Edward Jenkins, Gabriel M Gihana, Jinlong Lin, Hazel M Borges, Bo-Jui Chang, Andrew Weems, Sean J Morrison, Peter K Sorger, Reto Fiolka, Kevin M Dean, Gaudenz Danuser.

Cell segmentation is the foundation of a wide range of microscopy-based biological studies. Deep learning has revolutionized two-dimensional (2D) cell segmentation, enabling generalized solutions across cell types and imaging modalities. This has been driven by the ease of scaling up image acquisition, annotation and computation. However, three-dimensional (3D) cell segmentation, requiring dense annotation of 2D slices, still poses substantial challenges. Manual labeling of 3D cells to train broadly applicable segmentation models is prohibitive. Even in high-contrast images annotation is ambiguous and time-consuming. Here we develop a theory and toolbox, u-Segment3D, for 2D-to-3D segmentation, compatible with any 2D method generating pixel-based instance cell masks. u-Segment3D translates and enhances 2D instance segmentations to a 3D consensus instance segmentation without training data, as demonstrated on 11 real-life datasets, comprising >70,000 cells, spanning single cells, cell aggregates and tissue. Moreover, u-Segment3D is competitive with native 3D segmentation, even exceeding when cells are crowded and have complex morphologies.

DOI: https://doi.org/10.1038/s41592-025-02887-w
EMBO J. 2025 Nov 13.

A dynamic feedback loop between retrograde sterol transport and TORC2 controls adaptation of the plasma membrane to stress.

Maria G Tettamanti, Paulina Nowak, Beata Kusmider, Jennifer M Kefauver, Vincent Mercier, Aurélien Roux, Robbie Loewith.

  Cells monitor and dynamically regulate the lipid composition and biophysical properties of their plasma membrane (PM). The Target Of Rapamycin complex 2 (TORC2) is a protein kinase that acts as a central regulator of plasma membrane homeostasis, but the mechanisms by which it detects and reacts to membrane stresses are poorly understood. To address this knowledge gap, we characterized a family of amphiphilic molecules that physically perturb plasma membrane organization and in doing so inhibit TORC2 in yeast and mammalian cells. Using fluorescent reporters of various lipids in budding yeast, we show that exposure to these small molecules causes mobilization of PM ergosterol as well as inhibition of TORC2. TORC2 inhibition results in activation of the PM-ER sterol transporters Lam2 and Lam4 and the subsequent rapid removal of accessible ergosterol from the plasma membrane via PM-ER contact sites. This sequence of events, culminating in the reactivation of TORC2, is also observed with several other PM stresses, suggesting that TORC2 acts in a feedback loop to control active sterol levels at the plasma membrane to maintain its homeostasis.

Keywords:  Membrane Tension; Plasma Membrane Stress; Small Amphipaths; Sterol Transport; TOR Complex 2

DOI:  https://doi.org/10.1038/s44318-025-00618-7
Cancer Res. 2025 Nov 12.

Deep-Learning Tool ScVital Enables Species-Agnostic Integration of Cancer Cell States.

Jonathan Rub, Jason E Chan, Carleigh Sussman, Gary Guzman, William D Tap, Cristina R Antonescu, Samuel Singer, Tuomas Tammela, Doron Betel.

Genetically engineered mouse models (GEMM) of cancer are useful for exploring the development and biological composition of human tumors. Single-cell RNA-sequencing (scRNA-seq) provides a transcriptomic snapshot of cancer to explore heterogeneity of cell states in an immunocompetent context. However, cross-species comparison often suffers from biological batch effect and inherent differences between species decrease the signal of biological insights that can be gleaned from these models. Here, we developed scVital, a computational tool that uses a variational autoencoder and discriminator to embed scRNA-seq data into a species-agnostic latent space to overcome batch effect and identify cell states shared between species. In addition, latent space similarity (LSS) score was concurrently developed as a new metric to evaluate batch correction accuracy by leveraging pre-labeled clusters for scoring instead of the current method of creating new clusters. Using LSS for quantification, scVital performed comparably well relative to other deep learning algorithms and rapidly integrated scRNA-seq data of normal tissues across species with high fidelity. When scVital was applied to pancreatic ductal adenocarcinoma or lung adenocarcinoma data from GEMMs and primary patient samples, scVital accurately aligned biologically similar cell states. In undifferentiated pleomorphic sarcoma, a test case with no a priori knowledge of cell state concordance between mouse and human, scVital identified a previously unknown cell state that persisted after chemotherapy and is shared by a GEMM and human patient-derived xenografts. These findings establish the utility of scVital in identifying conserved cell states across species to enhance the translational capabilities of mouse models.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-4889
Autophagy. 2025 Nov 10. 1-3

Autophagy-dependent modulation of ER calcium release drives KCNMA1/BKCa signaling and seizure susceptibility.

Gaga Kochlamazashvili, Marijn Kuijpers.

  Macroautophagy/autophagy is best known for its role in maintaining cellular homeostasis through degradation of damaged proteins and organelles. In neurons, autophagy also contributes to the regulation of activity by adjusting the availability of cellular components to physiological demand. In a recent study, we show that autophagy shapes neuronal excitability by restraining a calcium-dependent pathway that couples endoplasmic reticulum calcium release to KCNMA1/BKCa activity at the plasma membrane. When autophagy is lost, this pathway is enhanced, and seizure susceptibility increases.

Keywords:  Autophagy; BKCa; ERphagy; axon; calcium; endoplasmic reticulum; epilepsy; excitability; neuron; ryanodine receptor

DOI:  https://doi.org/10.1080/15548627.2025.2580436
Proc Natl Acad Sci U S A. 2025 Nov 18. 122(46): e2510910122

Forward genetic screening in engineered colorectal cancer organoids identifies regulators of metastasis.

Xin Wang, Zvi Cramer, Nicolae Adrian Leu, Keara Monaghan, Kayla Durning, Stephanie Adams-Tzivelekidis, Joshua H Rhoades, Jonathan Heintz, Yuhua Tian, Joshua Rico, Diego Mendez, Ricardo Petroni, Austin C King, Melissa S Kim, Rina Matsuda, Olivia Hanselman, Alice E Shin, María F Carrera Rodríguez, Igor E Brodsky, Anil Rustgi, Ning Li, Christopher J Lengner, M Andrés Blanco.

  Metastatic outgrowth requires that cancer cells delaminate from the primary tumor, intravasate, survive in circulation, extravasate, migrate to, and proliferate at a distal site. Recurrent genetic drivers of metastasis remain elusive, suggesting that unlike the early steps of oncogenesis, metastasis drivers may be variable. We develop a framework for identifying metastasis regulators using CRISPR/Cas9-based screening in a genetically defined organoid model of colorectal adenocarcinoma. We conduct in vitro screens for invasion and migration alongside orthotopic, in vivo screens for gain of metastasis in a syngeneic mouse model. We identify CTNNA1 and BCL2L13 as bona fide metastasis-specific suppressors which do not confer any selective advantage in primary tumors. CTNNA1 loss promotes cell invasion and migration, and BCL2L13 loss promotes anchorage-independent survival and non-cell-autonomous changes to macrophage polarization. This study demonstrates proof of principle that large-scale genetic screening can be performed in tumor-organoid models in vivo and identifies novel regulators of metastasis.

Keywords:  CRISPR screen; colorectal cancer; metastasis; organoid

DOI:  https://doi.org/10.1073/pnas.2510910122
Signal Transduct Target Ther. 2025 Nov 11. 10(1): 370

Reframing cancer cachexia: the vagal brain-liver axis as a novel neuro-metabolic target.

Daoyan Wei, Xinwen Lin, Robert S Bresalier.

DOI: https://doi.org/10.1038/s41392-025-02483-6
Nature. 2025 Nov;647(8089): 293

Antibodies unleashed against pancreatic cancer.



Keywords:  Cancer

DOI:  https://doi.org/10.1038/d41586-025-03517-3
Cell. 2025 Nov 07. pii: S0092-8674(25)01136-5. [Epub ahead of print]

StealTHY: An immunogen-free CRISPR platform to expose concealed metastasis regulators in immunocompetent models.

Massimo Saini, Francesc Castro-Giner, Adriana Hotz, Magdalena K Sznurkowska, Manuel Nüesch, François M Cuenot, Selina Budinjas, Gilles Bilfeld, Ece Su Ildız, Karin Strittmatter, Ilona Krol, Zoi Diamantopoulou, Aino Paasinen-Sohns, Maria Waldmeier, Rafaela Cássio, Susanne Kreutzer, Zacharias Kontarakis, Ana Gvozdenovic, Nicola Aceto.

  CRISPR screens have become standard gene discovery platforms in various contexts, including cancer. Yet commonly available CRISPR-Cas9 tools are increasingly recognized as unfit for in vivo investigations in immunocompetent contexts, due to broad immunogenicity of bacterial nucleases and reporters. Here, we show how conventional CRISPR screens in tumor grafts are systematically jeopardized by immunoediting in syngeneic and humanized immunocompetent hosts, resulting in iatrogenic clonal dropouts and ultimately compromising target identification. To resolve this, we present StealTHY, an immunogen-free CRISPR platform compatible with virtually all immunocompetent designs, enabling preservation of clonal architecture and exposing previously concealed cancer vulnerabilities. Among these, we identify the AMH-AMHR2 axis as a formerly unappreciated metastasis target. Thus, with StealTHY, we provide a new resource to expand the applicability of CRISPR screens to immunocompetent models, including humanized tumor grafts, revealing metastasis regulators of therapeutic relevance.

Keywords:  CRISPR; Cas9; anti-tumor immunity; cancer; cancer immunogenicity; humanized mice; metastasis; patient-derived xenografts; preclinical models of cancer

DOI:  https://doi.org/10.1016/j.cell.2025.10.007
Cancer Cell. 2025 Nov 13. pii: S1535-6108(25)00451-9. [Epub ahead of print]

Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer.

Yuetong Zhang, Jiaying Chen, Yong She, Zhaoyuan Fang, Yaxin Zhang, Danyun Ruan, Wenjun Guo, Jianping Liao, Weiping Zhou, Jianpei Lao, Weicheng Fang, Xingyan Pan, Wenfei Kang, Zifeng Wang, Yuanzhong Wu, Rong Deng, Lin Tian, Liqin Wang, Huilin Huang, Jian Zheng, Yan Yan, Hezhe Lu, Ruiping Wang, Rona Yaeger, Qi Zhao, Wenting Liao, Feng Wang, Yijun Gao.

  While dual KRAS and epidermal growth factor receptor (EGFR) inhibition shows promise in treating KRAS-mutant colorectal cancer (CRC), resistance remains a major challenge. Using genetically engineered mouse models, patient-derived organoids and xenografts, as well as clinical specimens, we discover that colorectal tumors surviving combined KRAS and EGFR inhibition acquire a Paneth-like cell state-a secretory lineage typically confined to the intestinal crypt. Lineage tracing reveals that CRC cells evade dual therapy by transitioning into a Paneth-like state. Through integrated transcriptomic analysis and CRISPR genetic screening, we identify SMAD1 as a key regulator of this lineage plasticity, promoting resistance by directly activating FGFR3. Genetic or pharmacological inhibition of FGFR3 prevents the Paneth-like transition, restores drug sensitivity, and synergizes with KRAS-EGFR inhibition across multiple preclinical models. These findings reveal that the SMAD1-FGFR3 axis triggers Paneth-like plasticity to drive KRAS-EGFR dual therapy resistance in CRC and highlight FGFR3 blockade as a promising strategy to overcome plasticity-driven drug tolerance.

Keywords:  KRAS mutant colorectal cancer; Paneth-like cell state; drug resistance; dual KRAS and EGFR-targeted therapy; lineage plasticity; trans-differentiation

DOI:  https://doi.org/10.1016/j.ccell.2025.10.010
Sci Adv. 2025 Nov 14. 11(46): eadx5791

Spatially organized cellular communities shape functional tissue architecture in the pancreas.

Alejo Torres-Cano, Jean-Francois Darrigrand, Gabriel Herrera-Oropeza, Georgina Goss, David Willnow, Anna Salowka, Siwanart Ma, Debashish Chitnis, Morgane Rouault, Alessandra Vigilante, Francesca M Spagnoli.

Organ function depends on the precise spatial organization of cells across multiple scales, from individual units to cellular communities that form local niches and, ultimately, higher-order structures. Although cell identities are increasingly well defined, the spatial arrangement and interactions among diverse cell types remain poorly understood. Here, we combine single-cell and spatial transcriptomics to map pancreatic cell populations across space and time, from embryonic development to adult homeostasis in mice. Using these maps, we resolve spatial heterogeneity among pancreatic cell types and uncover epithelial-mesenchymal units as basic tissue niches, which we functionally characterize in both mouse and human models. We also demonstrate that the mesenchymal lineage diversifies into various specialized subtypes during development, but this complexity diminishes over time, ultimately converging into a few fibroblast subtypes in adulthood. Together, our findings reveal how different progenitor lineages codevelop and organize into structured communities that establish a functional pancreas, providing a framework to guide in vitro organogenesis and tissue engineering for pancreatic diseases.

DOI: https://doi.org/10.1126/sciadv.adx5791
Nature. 2025 Nov 12.

SIGLEC12 mediates plasma membrane rupture during necroptotic cell death.

Hyunjin Noh, Zeena Hashem, Elena Boms, Ayaz Najafov.

Necroptosis is a form of lytic cell death that is overactivated during infections and in inflammatory pathologies1. NINJ1 was recently found to be a mediator of plasma membrane rupture (PMR) during pyroptosis, toxin-induced necrosis, apoptosis, and ferroptosis2,3, but the mediator of PMR during necroptotic cell death remained unknown. Here, using a CRISPR-Cas9-based genome-wide knockout approach, we identify SIGLEC12 as a key mediator of necroptosis downstream of MLKL at the PMR step. Cells with knockdown or knockout of SIGLEC12 are defective in necroptosis-induced PMR and demonstrate ballooning morphology. During necroptosis, SIGLEC12 undergoes dephosphorylation, interacts with MLKL, forms cytosolic puncta and assembles into fibrils. Notably, SIGLEC12 is cleaved by TMPRSS4 during necroptosis to produce a 20-kDa fragment highly homologous to NINJ1, and this cleavage event is required and sufficient to induce PMR during necroptosis. A SIGLEC12 variant associated with cancer (Ser458Phe) and a variant found in the general human population (Arg528Trp) attenuate SIGLEC12 cleavage by TMPRSS4. Knockout of Siglec12 in mouse cells does not affect PMR, suggesting a species-specific role. Our identification of SIGLEC12 as a mediator of PMR expands our understanding of how programmed necrosis is executed and offers new approaches for targeting this proinflammatory form of cell death in human diseases.

DOI: https://doi.org/10.1038/s41586-025-09741-1
J Cell Physiol. 2025 Nov;240(11): e70107

Autophagy Reprogramming in Cancer.

Annie D Fuller, Travis H Bordner, Abigail J Staub, Jazmyne L Jackson, No'ad Shanas, John M Crespo, William A Nazario-Lugo, Mazen Rukhsar, Alex Tufano, Courtney Worrell, Zachary Wilmer Reichenbach, Kelly A Whelan.

  During malignancy, metabolic reprogramming is critical for cancer cells to survive and thrive in nutrient- and oxygen-poor conditions. Autophagy is a catabolic process through which intracellular components are degraded to support cells upon exposure to stressful conditions. While autophagy is protective during early cancer initiation, tumor cells may initiate cell-intrinsic and cell-extrinsic autophagy to support their survival in later stages of cancer. As autophagy is present at low levels in most tissues under homeostasis and upregulated in malignancy, there has been great interest in targeting the autophagy pathway for cancer therapy. Here, we discuss the mechanisms through which autophagy and autophagy-related proteins act to limit carcinogenesis. We then review pro-tumor roles for autophagy in tumor cells as well as in components of the tumor microenvironment. Finally, we discuss autophagy-targeted approaches for cancer therapy. This review article highlights autophagy as a key player in cell metabolism that is often leveraged to support cancer progression and as a potential therapeutic target in a variety of cancer types.

Keywords:  autophagy; cancer; metabolism

DOI:  https://doi.org/10.1002/jcp.70107
Clin Cancer Res. 2025 Nov 13.

Ibrutinib and PD-1 blockade potentiate mesothelin-targeting CAR-T cell therapy in preclinical models of pancreatic cancer.

Alexander Armstrong, Graziella van der Plancke, Sae Nishiguchi, Diego Salas-Benito, Amanda A Bouffard, Sadie Goncalves, Ashlyn T Merce, Christopher Kelly, Filippo Birocchi, Sangwoo Park, Mark B Leick, Nora Horick, Trisha R Berger, Marcela V Maus, Giulia Escobar.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) remains refractory to chimeric antigen receptor (CAR) T cell therapies due to its immunosuppressive microenvironment and a dense extracellular matrix deposited by cancer-associated fibroblasts (CAFs), which impair CAR-T cell infiltration. To address these barriers, we previously developed a dual-targeting CAR-TEAM platform in which mesothelin-specific CAR-T cells secrete a FAP-targeting T cell engager antibody molecule (TEAM) to simultaneously kill tumor cells and CAFs. Here, we leveraged mesothelin-targeting CAR-T cells and tested rational drug combinations and optimal delivery strategies to enhance therapeutic efficacy and guide potential combinations that could be incorporated into a clinical study.
EXPERIMENTAL DESIGN: Tumor mesothelin shedding by proteases and CAR-T cell dysfunction remain key obstacles to CAR-T cell efficacy. Using pre-clinical PDAC models, we tested mesothelin-targeting CAR-T cells in combination with agents that increase tumor mesothelin expression, promote T cell polarization and persistence, and support T cell function. Furthermore, we compared intravenous versus intraperitoneal delivery routes to treat peritoneal metastases.
RESULTS: We demonstrated that ibrutinib enhanced CAR-T cell expansion, Th1 skewing, and anti-tumor activity in PDAC. PD-1 blockade synergistically improved CAR-T cell anti-tumor function in a patient-derived PDAC xenograft and intraperitoneal delivery proved superior against peritoneal disease. Conversely, while an ADAM10/17 inhibitor prevented mesothelin shedding and improved tumor killing in vitro, it did not enhance efficacy in vivo.
CONCLUSION: These findings identify clinically actionable strategies to optimize CAR-T cell therapy against PDAC. A phase-I clinical trial testing meso-FAP CAR-TEAM T cells, alone or in combination with ibrutinib or PD-1 blockade is in development.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-2907
STAR Protoc. 2025 Nov 11. pii: S2666-1667(25)00595-7. [Epub ahead of print]6(4): 104189

Protocol to quantify mechanical properties of cells using optical tweezers.

Wessel S Rodenburg, Jorine M Eeftens.

  Mechanical properties of cells determine their ability to deform when subjected to force, which is crucial in many biological processes. Here, we present a protocol to quantify these properties on living cells by applying piconewton-range forces with optically trapped microspheres. We describe steps for sample preparation of both adherent and suspended cells, calibration of optical trap stiffness, and generation of force-deformation curves. We next detail how to quantify cellular mechanical properties from the resulting data. For complete details on the use and execution of this protocol, please refer to Rodenburg et al.1.

Keywords:  Biophysics; Cell biology; Single cell; Single-molecule assays

DOI:  https://doi.org/10.1016/j.xpro.2025.104189
J Natl Cancer Inst. 2025 Nov 09. pii: djaf308. [Epub ahead of print]

Different diabetes types and pancreatic ductal adenocarcinoma: a Mendelian randomization and pathway/gene-set analysis.

Ting Zhang, Xing Hua, Chirayu Mohindroo, Xiaoyu Wang, Diptavo Dutta, Jia Liu, Shilpa Katta, Shengchao A Li, Jiahui Wang, Samuel O Antwi, Alan A Arslan, Laura E Beane Freeman, Paige M Bracci, Federico Canzian, Mengmeng Du, Steven Gallinger, Phyllis J Goodman, Verena Katzke, Charles Kooperberg, Loic Le Marchand, Rachel E Neale, Alpa V Patel, Sandra Perdomo, Xiao-Ou Shu, Kala Visvanathan, Stephen K Van Den Eeden, Emily White, Wei Zheng, Demetrius Albanes, Gabriella Andreotti, William R Bamlet, Paul Brennan, Julie E Buring, Stephen J Chanock, Yu Chen, Burcu Darst, Pietro Ferrari, Edward L Giovannucci, Michael Goggins, Christopher Haiman, Manal Hassan, Elizabeth A Holly, Rayjean J Hung, Miranda R Jones, Peter Kraft, Robert C Kurtz, Núria Malats, Steven C Moore, Kimmie Ng, Ann L Oberg, Irene Orlow, Ulrike Peters, Miquel Porta, Kari G Rabe, Nathaniel Rothman, Maria-José Sánchez, Howard D Sesso, Debra T Silverman, Melissa C Southey, Caroline Y Um, James Yarmolinsky, Herbert Yu, Chen Yuan, Jun Zhong, Brian M Wolpin, Harvey A Risch, Laufey T Amundadottir, Alison P Klein, Kai Yu, Haoyu Zhang, Rachael Z Stolzenberg-Solomon.

   BACKGROUND: The associations between different types of diabetes, characterized by distinct pathophysiology and genetic architecture, and pancreatic ductal adenocarcinoma (PDAC) risk are not understood.
METHODS: We investigated associations of genetic susceptibility to type 2 diabetes (T2D), eight T2D mechanistic clusters, type 1 diabetes (T1D), and maturity-onset diabetes of the young (MODY) with PDAC risk. We used genome-wide association study (GWAS) summary-level statistics for T2D (242,283 cases, 1,569,734 controls), T1D (18,942 cases, 501,638 controls), and PDAC (10,244 cases and 360,535 controls) in individuals of European ancestry.
RESULTS: Two-sample Mendelian randomization (MR) using the Robust Adjusted Profile Score (MR-RAPS) method indicated that genetically predicted T2D was associated with PDAC risk (OR = 1.10; 95% CI 1.05-1.15), particularly the T2D obesity (OR = 1.28; 95% CI 1.15-1.42) and lipodystrophy (OR = 1.25; 95% CI 1.03-1.51) clusters. No association was observed for T1D with PDAC risk (OR = 1.01; 95% CI 0.99-1.02). Pathway/gene-set analysis using the summary-based Adaptive Rank Truncated Product (sARTP) method revealed a significant association between the MODY gene-sets and PDAC risk (P = 1.5 × 10-8), which remained after excluding 20 known PDAC GWAS loci (P = 7.6 × 10-4). HNF1A, FOXA3, and HNF4A were the top contributing genes after excluding the previously identified GWAS loci regions.
CONCLUSIONS: Our results from this genetic association study support that T2D, particularly the obesity and lipodystrophy mechanistic clusters, and MODY genomic susceptibility regions play a role in the etiology of PDAC.

Keywords:  Maturity-onset diabetes of the young; Mendelian Randomization; Pancreatic ductal adenocarcinoma; Type 1 Diabetes; Type 2 Diabetes

DOI:  https://doi.org/10.1093/jnci/djaf308
Nature. 2025 Nov 12.

Cytosolic acetyl-coenzyme A is a signalling metabolite to control mitophagy.

Yifan Zhang, Xiao Shen, Yuan Shen, Chao Wang, Chengping Yu, Jiangxue Han, Siyi Cao, Lin Qian, Miaolian Ma, Shijing Huang, Wenyu Wen, Miao Yin, Qun-Ying Lei.

Acetyl-coenzyme A (AcCoA) sits at the nexus of nutrient metabolism and shuttles between the canonical and non-canonical tricarboxylic acid cycle1,2, which is dynamically regulated by nutritional status, such as fasting3. Here we find that mitophagy is triggered after a reduction in cytosolic AcCoA levels through short-term fasting and through inhibition of ATP-citrate lyase (encoded by ACLY), mitochondrial citrate/malate antiporter (encoded by SLC25A1) or acyl-CoA synthetase short chain family member 2 (encoded by ACSS2), and the mitophagy can be counteracted by acetate supplementation. Notably, NOD-like receptor (NLR) family member X1 (NLRX1) mediates this effect. Disrupting NLRX1 abolishes cytosolic AcCoA reduction-induced mitophagy both in vitro and in vivo. Mechanically, the mitochondria outer-membrane-localized NLRX1 directly binds to cytosolic AcCoA within a conserved pocket on its leucine-rich repeat (LRR) domain. Moreover, AcCoA binds to the LRR domain and enhances its interaction with the nucleotide-binding and oligomerization (NACHT) domain, which helps to maintain NLRX1 in an autoinhibited state and prevents the association between NLRX1 and light chain 3 (LC3). Furthermore, we find that the AcCoA-NLRX1 axis underlies the KRAS-inhibitor-induced mitophagy response and promotes drug resistance, providing a metabolic mechanism of KRAS inhibitor resistance. Thus, cytosolic AcCoA is a signalling metabolite that connects metabolism to mitophagy through its receptor NLRX1.

DOI: https://doi.org/10.1038/s41586-025-09745-x
Biochem Biophys Res Commun. 2025 Nov 08. pii: S0006-291X(25)01668-7. [Epub ahead of print]791 152952

Slc26a9 promotes the perineural invasion of pancreatic cancer in mice.

Bohan Hua, Xiaogeng Huang, Liping Chen, Yuhua Li, Dashan Lu, Dongjie Wang, Yujing Chen, Huadong Ni, Ming Yao, Chaobo Ni.

  Perineural invasion (PNI) is a pivotal prognostic factor in pancreatic ductal adenocarcinoma (PDAC), associated with aggressive tumor behavior and poor patient outcomes. This study investigated the role of Slc26a9 in regulating peripheral nerve invasion in pancreatic cancer. Bioinformatic analysis of GEO datasets showed markedly higher Slc26a9 expression in PNI-positive patients than in those without PNI. A PDAC model was established by implanting Panc02-luc cells into C57BL/6 mice. Abdominal mechanical hyperalgesia, hunching behavior, and anxiety-like behaviors were assessed using von Frey, hunch-score, and open field tests. PNI in pancreatic tissue was evaluated by immunohistochemistry. On postoperative days 7, 14, and 21, PDAC mice exhibited significantly increased tumor volume and weight, and decreased spleen weight (days 14 and 21) compared to the sham group. By day 21, body weight was also significantly reduced. On day 7, there were no significant differences in mechanical sensitivity, hunch scores, or anxiety-like behaviors, and no PNI was observed. By day 14, PDAC mice showed marked increases in pain, hunch scores, and anxiety-like behaviors, accompanied by evidence of PNI. To further explore the mechanism, we engineered a Slc26a9-overexpressing Panc02 cell line. Transwell and scratch assays demonstrated that Slc26a9 overexpression promotes Panc02 cell migration in vitro. In vivo, mice implanted with Slc26a9-overexpressing cells exhibited pronounced abdominal mechanical hyperalgesia, elevated hunch scores, and anxiety-like behaviors as early as day 7, along with confirmed PNI in the pancreas. These results suggest that Slc26a9 facilitates PNI in pancreatic cancer and may serve as a promising therapeutic target.

Keywords:  Pain; Pancreatic cancer; Perineural invasion; Slc26a9; panc02

DOI:  https://doi.org/10.1016/j.bbrc.2025.152952
Cell Chem Biol. 2025 Nov 10. pii: S2451-9456(25)00343-5. [Epub ahead of print]

An engineered cysteine sensor optimized for high-throughput screening identifies regulators of intracellular thiol levels.

Rachel P M Abrams, Rebecca G Donahue, Jessica Ma, Ying Mao, Morgan E Diolaiti, Alan Ashworth.

  Dysregulation of cysteine-dependent processes is implicated in many diseases, including cancer. Despite the importance of cysteine in crucial cellular functions, including protein synthesis, redox balance, and glutathione production, a lack of efficient assays to measure cellular cysteine has limited efforts to identify agents that affect physiological cysteine levels. We employed circular permutation to engineer a fluorescent sensor that changes conformation upon cysteine binding. Biochemical experiments showed that this sensor is selective for cysteine, operating in the 10 μM-10 mM range. To demonstrate the sensor's applicability, we performed high-throughput screens for compounds that reduce cellular cysteine. Liquid chromatography of cell extracts validated the effect of two hit compounds, and mechanistic investigations showed that one was dependent on the anticancer target, xCT. Future application of this sensor in cell biology and drug discovery will advance understanding of cysteine metabolism and drive the development of therapeutics that restore cysteine homeostasis.

Keywords:  cellular sensor; cysteine; drug discovery; ferroptosis; high-throughput screening; oxidative stress; protein engineering

DOI:  https://doi.org/10.1016/j.chembiol.2025.10.006
Nat Commun. 2025 Nov 14. 16(1): 9712

Bidirectional quantitative scattering microscopy.

Kohki Horie, Keiichiro Toda, Takuma Nakamura, Takuro Ideguchi.

Quantitative phase microscopy (QPM) and interferometric scattering (iSCAT) microscopy are powerful label-free imaging techniques that are widely used in biomedical applications. Each method, however, possesses distinct limitations: QPM, which measures forward scattering (FS), excels at imaging microscale structures but struggles with rapidly moving nanoscale objects, whereas iSCAT, based on backward scattering (BS), is highly sensitive to nanoscale dynamics but lacks the ability to comprehensively image microscale structures. Here, we introduce bidirectional quantitative scattering microscopy (BiQSM), an approach that integrates FS and BS detection using off-axis digital holography with bidirectional illumination and spatial-frequency multiplexing. BiQSM achieves spatiotemporal consistency and a dynamic range 14 times wider than QPM, enabling simultaneous imaging of nanoscale and microscale cellular components. We demonstrate BiQSM's ability to reveal spatiotemporal behaviors of intracellular structures and small particles using FS and BS images. Time-lapse imaging of dying cells further highlights BiQSM's potential as a label-free tool for monitoring cellular vital states through structural and motion-related changes. By bridging the strengths of QPM and iSCAT, BiQSM advances quantitative cellular imaging, opening avenues for studying dynamic biological processes.

DOI: https://doi.org/10.1038/s41467-025-65570-w
Sci Adv. 2025 Nov 14. 11(46): eadz2217

Ist2 promotes lipid transfer by Osh6 via its membrane tethering and lipid scramblase activities.

Alicia Fabbre, Camille Syska, Heitor Gobbi Sebinelli, Anna Cardinal, Maud Magdeleine, Noha Al-Qatabi, Juan Martín D'Ambrosio, Cédric Montigny, Guillaume Lenoir, Alenka Čopič, Guillaume Drin.

Lipid transfer proteins unevenly distribute lipids within the cell, which is crucial for its functioning. In yeast, Osh6 transfers phosphatidylserine (PS) from the endoplasmic reticulum (ER) to the plasma membrane (PM) by exchange with phosphatidylinositol 4-phosphate. We investigated why its activity depends on Ist2, an ER-resident lipid scramblase that connects the ER to the PM via an intrinsically disordered region (IDR). We found that Osh6, in a lipid-loaded state, binds the Ist2 IDR with micromolar affinity and functions at ER-PM contact sites only if its binding site within the IDR is sufficiently distant from the ER membrane. We determined, in reconstituted contact sites, that the association of Osh6 with the Ist2 IDR enables rapid, directed PS transfer. We identified the Ist2-binding site in Osh6 by molecular modeling and functional analyses. Last, we established that Ist2's scramblase activity sustains Osh6-mediated PS transfer between membranes. Identifying these functional partnerships highlights why lipid transport processes are organized in membrane contact sites.

DOI: https://doi.org/10.1126/sciadv.adz2217
Sci Adv. 2025 Nov 14. 11(46): eaea4660

The bottleneck for maternal transmission of mtDNA is linked to purifying selection by autophagy.

Laura S Kremer, Zoe Golder, Tom Barton-Owen, Polyxeni Papadea, Camilla Koolmeister, Patrick F Chinnery, Nils-Göran Larsson.

Mammalian mitochondrial DNA (mtDNA) inheritance differs fundamentally from nuclear inheritance owing to exclusive maternal transmission, high mutation rate, and lack of recombination. Two key mechanisms shape this inheritance: the bottleneck, which drives stochastic transmission of maternal mtDNA variants, and purifying selection, which actively removes mutant mtDNA. Whether these mechanisms interact has been unresolved. To address this question, we generated a series of mouse models with random mtDNA mutations alongside alleles altering mtDNA copy number or decreasing autophagy. We demonstrate that tightening the mtDNA bottleneck increases heteroplasmic variance between individuals, causing lower mutational burden and nonsynonymous-to-synonymous ratios. In contrast, reduced autophagy weakens purifying selection, leading to decreased interoffspring heteroplasmic variance and increased mutational burden with higher nonsynonymous-to-synonymous ratios. These findings provide experimental evidence that the mtDNA bottleneck size modulates the efficacy of purifying selection. Our findings yield fundamental insights into the processes governing mammalian mtDNA transmission with direct implications for the origin and propagation of mtDNA mutations causing human disease.

DOI: https://doi.org/10.1126/sciadv.aea4660
Bioinformatics. 2025 Nov 11. pii: btaf607. [Epub ahead of print]

QuiCAT: A Scalable and Flexible Framework for Mapping Synthetic Sequences.

D Lucarelli, T Kos, C Shull, S Jiménez, R Öllinger, R Rad, D Saur, F J Theis.

MOTIVATION: Synthetic cellular tagging technologies play a crucial role in cell fate and lineage-tracing studies. Their integration with single-cell and spatial transcriptomics assays has heightened the need for scalable software solutions to analyze such data. However, previous methods are either designed for a subset of tagging technologies, or lack the performance needed for large-scale applications.
RESULTS: To address these challenges, we developed Quick Clonal Analysis Toolkit (QuiCAT), an end-to-end Python-based package that streamlines the extraction, clustering, and analysis of synthetic tags from sequencing data. QuiCAT outperforms existing pipelines in both speed and accuracy. Its outputs are widely compatible with the Python ecosystem for single-cell and spatial transcriptomics data analysis packages allowing seamless integrations and downstream analyses. QuiCAT provides users with two workflows: a reference-free approach for extracting and mapping synthetic tags, and a reference-based approach for aligning tags against known sequences. We validate QuiCAT across diverse datasets, including population-level data, single-cell and spatially resolved transcriptomics, and benchmarked it against the two most recently published tools. Our computational optimizations enhance performance while improving accuracy..
AVAILABILITY: QuiCAT is available as a Python package to be installed. The source code is available at https://github.com/theislab/quicat.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

DOI: https://doi.org/10.1093/bioinformatics/btaf607
Cell Rep. 2025 Nov 08. pii: S2211-1247(25)01314-2. [Epub ahead of print]44(11): 116543

Inducing ferroptosis to impede metastasis by inhibiting the calcium channel TRPC6.

Boris S Dimitrov, Dimpi Mukhopadhyay, Hira Lal Goel, Emmet R Karner, Christi A Silva, Ayush Kumar, Cornelia Peterson, Mengdie Wang, Arthur M Mercurio.

  We investigated a potential function of transient receptor potential cation channel 6 (TRPC6) in enabling breast cancer cells to resist stimuli that induce ferroptosis. A minority population of quiescent cells was isolated from triple-negative breast cancer (TNBC) cell lines that exhibit increased TRPC6 expression and resistance to ferroptosis compared to proliferating cells. These quiescent cells are also more metastatic than the proliferating cells, supporting the hypothesis that metastasis requires the ability of cells to evade ferroptosis. In pursuit of the mechanism, we discovered that the ability of TRPC6 to repress c-Myc is essential because its repression sustains levels of glutathione that are sufficient to impede ferroptosis. Importantly, treatment of TNBC cells with a TRPC6 inhibitor reduces metastasis significantly, an effect that is mitigated by a ferroptosis inhibitor. These results indicate that a sub-population of TNBC cells characterized by TRPC6 expression has the potential to form metastases by evading ferroptosis.

Keywords:  CP: cancer; TRPC6; breast cancer; cancer; ferroptosis; glutathione; metastasis

DOI:  https://doi.org/10.1016/j.celrep.2025.116543
Sci Adv. 2025 Nov 14. 11(46): eadz3889

iGlucoSnFR2: A genetically encoded fluorescent sensor for measuring intracellular or extracellular glucose in vivo in mouse brain.

Jonathan S Marvin, Philipp Mächler, Chengbo Meng, Tayfun Ates, Ronak H Patel, Raghabendra Adhikari, Monika A Makurath, Zaneta Ku, Daniel Feliciano, Deniz Atasoy, Guohong Cui, David Kleinfeld, Timothy A Brown.

Continuous glucose monitors have proven invaluable for monitoring blood glucose levels for diabetics, but they are of limited use for observing glucose dynamics at the cellular (or subcellular) level. We have developed a second generation, genetically encoded intensity-based glucose sensing fluorescent reporter (iGlucoSnFR2). We show that when it is targeted to the cytosol, it reports intracellular glucose consumption and gluconeogenesis in cell culture, along with efflux from the endoplasmic reticulum. It outperforms the original iGlucoSnFR in vivo when observed by fiber photometry in mouse brain and reports transient increase in glucose concentration when stimulated by noradrenaline or electrical stimulation. Last, we demonstrate that membrane localized iGlucoSnFR2 can be calibrated in vivo to indicate absolute changes in extracellular glucose concentration in awake mice. We anticipate iGlucoSnFR2 facilitating previously unobservable measurements of glucose dynamics with high spatial and temporal resolution in living mammals and other experimental organisms.

DOI: https://doi.org/10.1126/sciadv.adz3889
Nature. 2025 Nov 12.

iPEX enables micrometre-resolution deep spatial proteomics via tissue expansion.

Fengxiang Wang, Cuiji Sun, Tianshu William Wu, Yuting Fu, Yujing Fan, Shuchang Zhao, Kaiyin Huang, Zijian Pan, Yang Lu, Jingrong Regina Han, Shikai Jia, Lizhou Zeng, Sheng Zhang, Ting Chen, Shaowei An, Shuang Susie Meng, Xun Guo, Weizhe Li, Heyuan Lian, Xiaoting Sun, Jin Hu, Chuanzhen Yang, Shan Feng, Pengfei Li, Liyuan Du, Xiaodong Liu, Kiryl D Piatkevich, Yilong Zou.

The number of spatial omics technologies being developed is increasing1. However, a missing tool is one that can locate proteins in tissues in an untargeted manner at high spatial resolution and coverage. Here we present in situ imaging proteomics via expansion (iPEX), which integrates isotropic tissue magnification2 with matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging. iPEX provides scalable spatial resolution down to the micrometre scale and substantially increases the sensitivity of protein identification by 10-100-fold. Using the retina as a model, iPEX enabled the construction of spatial proteomic maps with high precision, the visualization of single-cell layers and extrasomatic structures and the identification of colocalized proteins. iPEX was readily applied to diverse tissues, including brain, intestine, liver and organoids, detecting 600-1,500 proteins at 1-5-µm effective pixel size. The application of iPEX to depict spatial proteomic maps in brains of mice with 5xFAD Alzheimer's disease revealed an early-onset mitochondrial aberrancy. Notably, in young mice, the peroxisomal acetyl-CoA acyltransferase ACAA1A-of which the N392S mutant is a monogenic risk factor in Alzheimer's disease3-was downregulated. ACAA1 depletion blocked the biosynthesis of long-chain polyunsaturated fatty acids, including docosahexaenoic acid, in multiple cellular contexts. These lipidome alterations were restored in cells overexpressing wild-type ACAA1 but not ACAA1(N392S), which suggests that the dysregulation of long-chain polyunsaturated fatty acids has an early role in neurodegeneration. Together, these results demonstrate that iPEX facilitates untargeted spatial proteomics at micrometre resolution for diverse applications.

DOI: https://doi.org/10.1038/s41586-025-09734-0
Cell Rep Med. 2025 Nov 07. pii: S2666-3791(25)00519-1. [Epub ahead of print] 102446

Developing a therapeutic elastase that stimulates anti-tumor immunity by selectively killing cancer cells.

Ravindra Gujar, Chang Cui, Maria Fumagalli, Nicole Martinez, Afshin Bahador, Alain Algazi, Kevin Harrington, Court Turner, Lev Becker.

  Recent clinical studies highlight the effectiveness of combining cytotoxic agents with immunotherapies, emphasizing the need for next-generation treatments that integrate both therapeutic approaches. Here, we use 30 cancer cell lines, 15 tumor models, and 45 patient samples to develop N17350, a therapeutic elastase that targets the "neutrophil elastase pathway" to induce tumor regression and stimulate anti-tumor immunity. N17350 leverages linker histone H1.0 and H1.2, proteins elevated in many cancers, to trigger immunogenic cancer cell death while preserving immune cells. Intra-tumoral N17350 administration induces rapid, genotype-independent tumor regression, triggering CD8+ T cell activation to promote durable responses and enable checkpoint inhibitor efficacy in refractory models. N17350 maintains potency with repeated dosing and across diverse treatment histories, including resistance to chemotherapies and checkpoint inhibitors. These findings support the advancement of N17350 to first-in-human clinical trials as a cytotoxic agent designed to stimulate anti-tumor immunity by selectively killing cancer cells.

Keywords:  ELANE pathway; N17350; abscopal effect; cytotoxic therapeutic; elastase; histone H1; immunogenic cell death; immunotherapy; pan-cancer; selective cancer killing

DOI:  https://doi.org/10.1016/j.xcrm.2025.102446
J Biophotonics. 2025 Nov 14. e202500489

Quantitative Mapping of Fibrotic Tissue Mechanics via Brillouin Spectroscopy.

Vsevolod Cheburkanov, Sujeong Jung, Mikhail Y Berezin, Vladislav V Yakovlev.

  Fibrosis is a pathological scarring process that disrupts tissue architecture, and is characterized by excessive extracellular matrix (ECM) deposition, leading to tissue stiffening and impaired organ function. Accurate quantification and spatial mapping of fibrotic tissue mechanics are critical for diagnosis, monitoring disease progression, and evaluating therapeutic responses. Here, we employ Brillouin microspectroscopy, a non-invasive, label-free optical technique, to quantify the mechanical properties of human fibrotic tissue in in situ. We show that Brillouin spectroscopy distinguishes fibrotic tissue from healthy tissue on the basis of localized differences in the complex longitudinal modulus and enables real-time monitoring of dynamic alterations in viscoelastic properties during fibrogenesis. To our knowledge, this is the first demonstration of Brillouin spectroscopy for in situ characterization of fibrosis and wound healing in a human model. These findings underscore Brillouin microspectroscopy's potential application as a promising diagnostic and monitoring tool for fibrotic diseases.

Keywords:  Brillouin spectroscopy; confocal microscopy; fibrosis; in situ imaging; tissue elasticity

DOI:  https://doi.org/10.1002/jbio.202500489