bims-cagime 2025-09-21 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2025–09–21
37 papers selected by
Kıvanç Görgülü, Technical University of Munich

KRAS Inhibition Activates an Actionable CD24 "Don't Eat Me" Signal in Pancreatic Cancer.
Syndecan-1 is a Key Mediator of Entosis and Cellular Competition in Pancreatic Cancer.
Comparative Analysis of Primary and Liver Fibroblasts Reveals MET as a Potent Target in Pancreatic Cancer Metastasis.
Leaflet-specific phospholipid imaging using genetically encoded proximity sensors.
Tumor nutrient stress gives rise to a drug tolerant cell state in pancreatic cancer.
Advancing biological understanding of cellular senescence with computational multiomics.
Tumor Genotype Dictates Mitochondrial and Immune Vulnerabilities in Liver Cancer.
Processing bodies promote lysosomal quality control and cell survival during recovery from lysosomal damage.
ATG16L strikes again! New findings link lysosome stress and physiology.
Covariation MS uncovers a protein that controls cysteine catabolism.
Pancreatic cells are resistant to KRAS(Q61L) expression due to hyperactive ERK/MAPK signaling and apoptosis induction.
An Alkyne-Directed Cleavage Approach for Activity-Based Cu(I) Sensing Reveals Manganese-Promoted Sensitization of Cuproptosis.
Beyond the tumor: towards a cachexia-based host phenotype through body composition analysis in patients with resectable lung cancer.
Mapping the genetic landscape of iron metabolism uncovers the SETD2 methyltransferase as a modulator of iron flux.
Tumor microenvironment subtyping in pancreatic ductal adenocarcinoma: New avenues for personalized therapeutic strategies.
Micron-scale, liquid-liquid phase separation in ternary lipid membranes containing DPPE.
BDH2-driven lysosome-to-mitochondria iron transfer shapes ferroptosis vulnerability of the melanoma cell states.
Surgery-Induced Neutrophil Extracellular Traps Promote Tumor Metastasis by Reprogramming Cancer Cell Lipid Metabolism.
The Prolyl Isomerase PIN1 Impacts Fibroblast Differentiation States and Crosstalk in Pancreatic Cancer.
Basal cell of origin resolves neuroendocrine-tuft lineage plasticity in cancer.
Spotlight on membrane fluidity of normal and cancer cells: Implications for cancer diagnosis and treatment.
The muscle specific MEF2Dα2 isoform promotes muscle ketolysis and running capacity in mice.
Neoadjuvant FOLFIRINOX versus neoadjuvant gemcitabine-based chemoradiotherapy in resectable and borderline resectable pancreatic cancer (PREOPANC-2): a multicentre, open-label, phase 3 randomised trial.
Homeocurvature: A new dimension of membrane adaptation to extreme environments.
Astrocytes mobilize a broader repertoire of lysosomal repair mechanisms than neurons.
Network-driven discovery of repurposable drugs targeting hallmarks of aging.
A mesothelial differentiation gateway drives fibrosis.
Fructose and glucose from sugary drinks enhance colorectal cancer metastasis via SORD.
The lipid phosphatase INPP4B controls pancreatic cancer cell migration and invasion by regulating fibronectin exocytosis.
Transcriptome and microRNAome profiling of human skeletal muscle in pancreatic cancer cachexia.
Low-GPX4 drives a sustained drug-tolerant persister state in TNBC by a targetable adaptive FSP1 upregulation.
In vivo CRISPR screening protocol to identify metastasis mediators using iteratively selected mouse models.
Survival Benefit of Surgery versus Oncology-Only Therapy in Artery-Involving Borderline Resectable and Locally Advanced Pancreatic Cancer.
Phase separation promotes Atg8 lipidation and vesicle condensation for autophagy progression.
Restraint of cancer cell plasticity by spatial homotypic clustering.
AVID mouse: A versatile platform for real-time, multiscale ATP imaging and spatial systems metabolism analysis in living mice.
Innovative Method for Fully Automated, Enzyme-Free Tissue Dissociation and Preparation for Single-Cell Analysis.

Cancer Res. 2025 Sep 18.

KRAS Inhibition Activates an Actionable CD24 "Don't Eat Me" Signal in Pancreatic Cancer.

Yongkun Wei, Minghui Liu, Er-Yen Yen, Jun Yao, Zhenzhen Xun, Phuoc T Nguyen, Xiaofei Wang, Zecheng Yang, Abdelrahman Yousef, Dean Pan, Yanqing Jin, Ching-Fei Li, Madelaine S Theardy, Jangho Park, Yiming Cai, Mitsunobu Takeda, Matthew Vasquez, Elizabeth M Park, David H Peng, Yong Zhou, Hong Zhao, Timothy P Heffernan, Andrea Viale, Huamin Wang, Stephanie S Watowich, Han Liang, Dan Zhao, Ronald A DePinho, Wantong Yao, Haoqiang Ying.

KRASG12C inhibitors (G12Ci) have produced encouraging, albeit modest and transient, clinical benefit in pancreatic ductal adenocarcinoma (PDAC). Identifying and targeting resistance mechanisms to G12Ci treatment is therefore crucial. To better understand the function of KRASG12C and possible G12Ci bypass mechanisms, we developed an autochthonous KRASG12C-driven PDAC model. Compared to the classical KRASG12D PDAC model, the G12C model exhibits slower tumor growth, yet similar histopathological and molecular features. Aligned with clinical experience, G12Ci treatment of KRASG12C tumors produced modest impact despite stimulating a 'hot' tumor immune microenvironment. Immunoprofiling revealed that CD24, a 'don't eat me' signal, is significantly upregulated on cancer cells upon G12Ci treatment. Blocking CD24 enhanced macrophage phagocytosis of cancer cells and significantly sensitized tumors to G12Ci treatment. Similar findings were observed in KRASG12D-driven PDAC. Together, this study reveals common and distinct oncogenic KRAS allele-specific biology and identifies a clinically actionable adaptive mechanism that may improve the efficacy of oncogenic KRAS inhibitor therapy in PDAC.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-2024
Pancreas. 2025 Sep 16.

Syndecan-1 is a Key Mediator of Entosis and Cellular Competition in Pancreatic Cancer.

Kara Li, Chenyang Li, Shigeaki Umeda, Rajya L Kappagantula, Masakatsu Paku, Yue Zeng, Christine Iacobuzio-Donahue, Wantong Yao.

  Entosis, a form of cell-in-cell (CIC) structure formation where one cell invades and becomes internalized by another, has long been observed in various malignancies and is considered a critical cellular process in cancer progression, with potential impacts on tumor heterogeneity, survival, and metastasis. Syndecan-1 (SDC1), a transmembrane proteoglycan involved in cell adhesion and communication, plays a pivotal role in these processes, yet its specific function in entosis within pancreatic ductal adenocarcinoma (PDAC) remains underexplored. This study aimed to investigate whether SDC1 facilitates entosis in PDAC cells and to assess its impact on tumor aggressiveness and patient outcomes. Using immunohistochemistry, flow cytometry, and entosis assays, our findings reveal that SDC1 prominently localizes at cell-cell contact points, facilitating stable intercellular adhesion and promoting entotic activity. Knockdown experiments reveal that reduced SDC1 expression significantly diminishes CIC formation, implicating SDC1 as a critical mediator of this process. Analysis of clinical samples revealed that high SDC1 expression correlates with increased entotic activity in PDAC tumors and is associated with decreased patient survival. These results suggest that SDC1-mediated entosis enhances tumor aggressiveness by contributing to cellular competition and heterogeneity. Our study sheds light on the critical role of SDC1 in promoting CIC formation and cancer progression, highlighting its potential as a therapeutic target to disrupt entotic mechanisms in PDAC.

Keywords:  cell competition; entosis; pancreatic cancer; syndecan1

DOI:  https://doi.org/10.1097/MPA.0000000000002542
bioRxiv. 2025 Sep 11. pii: 2025.09.06.674373. [Epub ahead of print]

Comparative Analysis of Primary and Liver Fibroblasts Reveals MET as a Potent Target in Pancreatic Cancer Metastasis.

Rima Singh, Natalie Yousefian, Walker M Allen, Cecily Anaraki, Alica K Beutel, Sabrina Calderon, Ian M Loveless, Oliver G McDonald, Jennifer P Morton, David Imagawa, Zeljka Jutric, Thomas F Martinez, Nina G Steele, Christopher J Halbrook.

The tumor microenvironment drives many malignant features of pancreatic ductal adenocarcinoma (PDAC). The fibroblasts within pancreatic tumors promote tissue remodeling, immune suppression, and resistance to therapy. However, the interactions between stromal populations and pancreatic cancer cells are less understood in the liver, the most frequent site of PDAC metastasis. To address this, we employ single cell transcriptomics to compare primary pancreatic vs. liver PDAC lesions. Here, we identify the expression of hepatocyte growth factor ( HGF ) in fibroblasts and its receptor MET in cancer cells are both markedly increased in the PDAC liver niche. Using functional assays, we validate that mitogenic MET signaling is activated in PDAC cells by liver-derived fibroblasts. Importantly, the inhibition of MET signaling leads to reduced tumor growth in immune competent mouse models. Collectively, our data demonstrates that liver stromal-epithelial crosstalk networks engage in signaling pathways distinct from primary pancreatic tumors, highlighting opportunities to develop new treatments for metastatic disease.

DOI: https://doi.org/10.1101/2025.09.06.674373
Nat Chem Biol. 2025 Sep 15.

Leaflet-specific phospholipid imaging using genetically encoded proximity sensors.

William M Moore, Roberto J Brea, Caroline H Knittel, Ellen Wrightsman, Brandon Hui, Jinchao Lou, Christelle F Ancajas, Michael D Best, Christopher J Obara, Neal K Devaraj, Itay Budin.

The lipid composition of cells varies widely across organelles and between individual membrane leaflets. Transport proteins are thought to generate this heterogeneity, but measuring their functions in vivo has been hampered by limited tools for imaging lipids at relevant spatial resolutions. Here we present fluorogen-activating coincidence encounter sensing (FACES), a chemogenetic tool capable of quantitatively imaging subcellular lipid pools and reporting their transbilayer orientation in living cells. FACES combines bioorthogonal chemistry with genetically encoded fluorogen-activating proteins (FAPs) for reversible proximity sensing of conjugated molecules. We first apply this approach to identify roles for lipid transfer proteins that traffic phosphatidylcholine pools between the ER and mitochondria. We then show that transmembrane domain-containing FAPs can reveal the membrane asymmetry of multiple lipid classes in the trans-Golgi network and be used to investigate the mechanisms that generate it. Finally, we present that FACES can be applied to measure glycans and other molecule classes.

DOI: https://doi.org/10.1038/s41589-025-02021-z
bioRxiv. 2025 Sep 08. pii: 2025.09.04.673818. [Epub ahead of print]

Tumor nutrient stress gives rise to a drug tolerant cell state in pancreatic cancer.

Colin Sheehan, Lyndon Hu, Guillaume Cognet, Grace Croley, Thao Trang Nguyen, Anika Thomas-Toth, Darby Agovino, Patrick B Jonker, Mumina Sadullozoda, Leah M Ziolkowski, James K Martin, Alica K Beutel, Ranya Dano, Mohammed A Khan, Christopher J Halbrook, Kay F Macleod, Christopher R Weber, James L LaBelle, Alexander Muir.

Cytotoxic chemotherapy remains the standard-of-care treatment for patients with pancreatic ductal adenocarcinoma (PDAC). However, chemotherapy only has modest effects at improving patient survival due to primary or rapidly acquired chemoresistance. The biological underpinnings of PDAC therapy resistance are incompletely defined, but the tumor microenvironment is known to be a major contributor to chemoresistance. We have found chemoresistance is imprinted on PDAC cells by the tumor microenvironment and persists for a period of days after PDAC cells are removed from tumors. However, PDAC chemoresistance is lost upon long term culture in standard laboratory conditions. Interestingly, culture of PDAC cells in Tumor Interstitial Fluid Medium (TIFM), a culture medium we developed to recapitulate the nutrient availability of the tumor microenvironment, maintains PDAC cells in a chemo- and targeted therapy resistant state even after long term culture ex vivo . These findings suggest that microenvironmental metabolic stress keeps PDAC cells in a physiologically relevant, therapy resistant cell state that standard culture models fail to maintain. Using TIFM culture, we sought to understand how PDAC cells in this state resist therapeutic challenge. We found that chemo- and targeted therapies largely retain on-target activity within TIFM medium but fail to activate cell death, enabling a "chemotolerant" cell state, which is also observed in PDAC tumors. This chemotolerant state is driven by suppression of apoptotic priming and can be overcome by targeting the anti-apoptotic regulator BCL-XL. Taken together, these findings suggest that reprogramming of cell death mechanisms by the PDAC nutrient microenvironment is a key contributor to therapy resistance in this disease.

DOI: https://doi.org/10.1101/2025.09.04.673818
Nat Genet. 2025 Sep 15.

Advancing biological understanding of cellular senescence with computational multiomics.

SenNet Consortium

Cellular senescence is a complex biological process that plays a pathophysiological role in aging and age-related diseases. The biological understanding of senescence at the cellular and tissue levels remains incomplete due to the lack of specific biomarkers as well as the relative rarity of senescent cells, their phenotypic heterogeneity and dynamic features. This Review provides a comprehensive overview of multiomic approaches for the characterization and biological understanding of cellular senescence. The technical capability and challenges of each approach are discussed, and practical guidelines are provided for selecting tools for identifying, characterizing and spatially mapping senescent cells. The importance of computational analyses in multiomics research, including senescent cell identification, signature detection and interactions of senescent cells with microenvironments, is highlighted. Moreover, tissue-specific case studies and experimental design considerations for individual organs are presented. Finally, future directions and the potential impact of multiomic approaches on the biological understanding of cellular senescence are discussed.

DOI: https://doi.org/10.1038/s41588-025-02314-y
bioRxiv. 2025 Sep 11. pii: 2025.09.10.675369. [Epub ahead of print]

Tumor Genotype Dictates Mitochondrial and Immune Vulnerabilities in Liver Cancer.

Gokhan Unlu, Alon Millet, Khando Wangdu, Romain Donné, Ranya Erdal, Nicole L DelGaudio, Beste Uygur, Vyom Shah, Kevin Cho, Antonia Fecke, Feyza Cansiz, Zeynep Cagla Tarcan, Michael Isay-Del Viscio, Ece Kilic, Isabel Kurth, Henrik Molina, Albert Sickmann, Olca Basturk, Gary Patti, Semir Beyaz, Karl W Smith, Amaia Lujambio, Alpaslan Tasdogan, Sohail F Tavazoie, Kıvanç Birsoy.

Although oncogenic alterations influence tumor metabolism, how they impose distinct metabolic programs within a shared tissue context remains poorly defined. Here, we developed a rapid mitochondrial profiling platform to compare metabolites and proteins in genetic models of primary liver cancer (PLC). Analyses of six genetically distinct PLCs revealed that mitochondrial energy metabolism is largely dictated by oncogene identity. Kras -driven tumors required creatine metabolism to buffer energy demands during early tumorigenesis, whereas c-MYC -driven tumors relied on oxidative phosphorylation. Among c-MYC -driven PLCs, Pten -deficient tumors accumulated mitochondrial phosphoethanolamine, a precursor for phosphatidylethanolamine (PE) synthesis. Inhibition of PE synthesis selectively impaired the growth of Pten -deficient tumors and extended survival, in part through enhanced infiltration of CD8⁺ T cells and sensitization to TNFα-mediated cytotoxicity. Mechanistically, loss of PE elevated surface TNF receptor 2 (TNFR2), promoting TNFα signaling and pro-inflammatory response. These findings uncover genotype-specific mitochondrial metabolic liabilities and establish PE synthesis as a tumor-intrinsic mechanism of immune evasion in PLC.

DOI: https://doi.org/10.1101/2025.09.10.675369
Res Sq. 2025 Sep 09. pii: rs.3.rs-7474186. [Epub ahead of print]

Processing bodies promote lysosomal quality control and cell survival during recovery from lysosomal damage.

Jingyue Cassano, Jacob Duran, Li Chen, Jing Pu, Pavel Ivanov.

Lysosomes are essential for cell survival but are highly susceptible to diverse physical and pathological stressors. Thus, the ability to initiate an acute damage response and promote recovery after stressor resolution is critical for maintaining cellular homeostasis and viability. Although recent studies have advanced our understanding of acute responses to lysosomal injury, the molecular mechanisms governing the recovery stage and distinguishing it from the acute phase remain poorly defined. Here, we delineate a key difference between these two stages in translational regulation and uncover lysosomal recovery from acute damage as a novel trigger for processing body (PB) formation. PBs are membraneless biomolecular condensates involved in RNA metabolism and translational reprogramming. We provide the first evidence that PBs are critical for lysosomal quality control and cell survival during recovery. Mechanistically, PBs are induced selectively during the recovery phase, but not during the acute damage response, through interactions with stress granules (SGs), distinct membraneless biomolecular condensates formed upon acute injury to stabilize damaged lysosomal membranes for repair. Functional analyses reveal that PBs promote lysosomal quality control by collaborating with SG-mediated membrane stabilization, while independently recruiting released cathepsins, thereby collectively supporting cell survival. Together, these findings establish PBs as central effectors of the lysosomal recovery program and underscore the broader relevance of biomolecular condensates in cellular responses to lysosomal damage and related disease processes.

DOI: https://doi.org/10.21203/rs.3.rs-7474186/v1
J Cell Biol. 2025 Oct 06. pii: e202509030. [Epub ahead of print]224(10):

ATG16L strikes again! New findings link lysosome stress and physiology.

Alison D Klein, Michael Overholtzer.

Lysosome stress responses are emerging, but their connections to normal physiology are not well understood. In this issue, Duque et al. (https://doi.org/10.1083/jcb.202503166) discover that the autophagy protein ATG16L, a mediator of a stress response called CASM, also regulates normal lysosome function.

DOI: https://doi.org/10.1083/jcb.202509030
Nature. 2025 Sep 17.

Covariation MS uncovers a protein that controls cysteine catabolism.

Haopeng Xiao, Martha Ordonez, Emma C Fink, Taylor A Covington, Hilina B Woldemichael, Junyi Chen, Mika Sarkin Jain, Milan H Rohatgi, Shelley M Wei, Nils Burger, Muneeb A Sharif, Julius Jan, Yaoyu Wang, Jonathan J Petrocelli, Katherine Blackmore, Amanda L Smythers, Bingsen Zhang, Matthew Gilbert, Hakyung Cheong, Sumeet A Khetarpal, Arianne Smith, Dina Bogoslavski, Yu Lei, Laura Pontano Vaites, Fiona E McAllister, Nick Van Bruggen, Katherine A Donovan, Edward L Huttlin, Evanna L Mills, Eric S Fischer, Edward T Chouchani.

The regulation of metabolic processes by proteins is fundamental to biology and yet is incompletely understood. Here we develop a mass spectrometry (MS)-based approach that leverages genetic diversity to nominate functional relationships between 285 metabolites and 11,868 proteins in living tissues. This method recapitulates protein-metabolite functional relationships mediated by direct physical interactions and local metabolic pathway regulation while nominating 3,542 previously undescribed relationships. With this foundation, we identify a mechanism of regulation over liver cysteine utilization and cholesterol handling, regulated by the poorly characterized protein LRRC58. We show that LRRC58 is the substrate adaptor of an E3 ubiquitin ligase that mediates proteasomal degradation of CDO1, the rate-limiting enzyme of the catabolic shunt of cysteine to taurine1. Cysteine abundance regulates LRRC58-mediated CDO1 degradation, and depletion of LRRC58 is sufficient to stabilize CDO1 to drive consumption of cysteine to produce taurine. Taurine has a central role in cholesterol handling, promoting its excretion from the liver2, and we show that depletion of LRRC58 in hepatocytes increases cysteine flux to taurine and lowers hepatic cholesterol in mice. Uncovering the mechanism of LRRC58 control over cysteine catabolism exemplifies the utility of covariation MS to identify modes of protein regulation of metabolic processes.

DOI: https://doi.org/10.1038/s41586-025-09535-5
Cancer Res Commun. 2025 Sep 15.

Pancreatic cells are resistant to KRAS(Q61L) expression due to hyperactive ERK/MAPK signaling and apoptosis induction.

Rachel A Burge, Lucas Bialousow, Thomas McFall, Logan Bamonte, Grayson Johnson, Merissa Smith, Silvia G Vaena, Susana Comte-Walters, Lauren E Ball, Stefano Berto, John P O'Bryan, G Aaron Hobbs.

The RAS family of small GTPases is among the most frequently mutated gene families in human cancer. In pancreatic ductal adenocarcinoma (PDAC), ~95% of cases harbor an activating KRAS mutation, primarily at codon 12, 13, or 61, with G12D the most common overall (40%). In contrast, the KRASQ61L mutation, though constitutively active, is virtually absent in PDAC patient tumors. This suggests that KRASQ61L may engage in distinct, allele-specific signaling that limits its ability to drive tumorigenesis. Determining the mechanisms that limit the occurrence of this mutation will aid in our understanding of the critical KRAS effectors and pathways that drive tumorigenesis. To investigate these mechanisms, we utilized a tightly controlled doxycycline-inducible KRAS expression system in an isogenic, immortalized pancreatic cell line, enabling direct comparison of KRASQ61L to the common PDAC mutant KRASG12D. Using TurboID proximity labeling alongside RNA sequencing, we mapped early effector interactions and transcriptional responses, revealing that KRASQ61L induces greater hyperactivation of the ERK/MAPK pathway, resulting in increased nuclear translocation of ERK1/2. Finally, pancreatic cells are highly tolerant to overexpression of KRASG12D, but KRASQ61L overexpression leads to impaired proliferation and increased apoptosis. These findings provide experimental support for the long-standing "Goldilocks" model of oncogenic signaling, where too much ERK/MAPK pathway activation is detrimental to tumorigenesis. Our work offers a mechanistic explanation for the relative absence of KRASQ61L in PDAC and contributes to our understanding of KRAS allele-specific vulnerabilities, which can inform future therapeutic strategies targeting KRAS-driven pancreatic cancer.

DOI: https://doi.org/10.1158/2767-9764.CRC-25-0281
J Am Chem Soc. 2025 Sep 14.

An Alkyne-Directed Cleavage Approach for Activity-Based Cu(I) Sensing Reveals Manganese-Promoted Sensitization of Cuproptosis.

Xiao Xie, Gen Li, Aidan T Pezacki, Jiaying Gao, Miku Oi, Christopher J Chang.

Copper is an essential element for sustaining life. However, disruptions in copper homeostasis underpin disease, as illustrated by cuproptosis, an emerging form of cell death resulting from aberrant accumulation of copper pools in loosely bound, labile forms. Along these lines, activity-based sensing (ABS) offers a powerful strategy for tracking labile copper fluxes with metal and oxidation state selectivity by exploiting analyte reactivity for analyte detection. Traditional ABS probes for Cu(I), the major oxidation state of copper in cells, are selective but require O2 as a coadditive, thus limiting their temporal resolution and sensitivity. Here, we present the design, synthesis, and biological evaluation of a first-generation ABS strategy for direct Cu(I) sensing by leveraging alkyne-directed cleavage reactivity. Copper Alkyne Probe-1 (CAP-1) features a rapid response to changes in intracellular Cu(I) pools with over 400-fold selectivity for Cu(I) over competing biological metals. We apply this probe to identify novel metal-metal crosstalk in cuproptosis, where we observe that Mn(II) exposure sensitizes cells to cuproptosis through upregulating the mitochondrial reductase FDX1 and depleting reduced glutathione, thus synergistically elevating labile Cu(I) levels. By revealing an interplay between copper and manganese in regulating cell death, this work provides a starting point for broader investigations of metal-metal nutrient crosstalk in biology and medicine.

DOI: https://doi.org/10.1021/jacs.5c09297
Transl Lung Cancer Res. 2025 Aug 31. 14(8): 3183-3195

Beyond the tumor: towards a cachexia-based host phenotype through body composition analysis in patients with resectable lung cancer.

Koen C H A Verkoulen, Lars Geenen, Aimée J P M Franssen, Anne M A Verzijl, Yvonne L J Vissers, Karel W E Hulsewé, Juliette H R J Degens, David P J van Dijk, Erik R de Loos.

  Cancer cachexia, characterized by involuntary weight loss and extensive muscle and adipose tissue wasting, is a major contributor to morbidity and mortality in cancer patients. To date, no effective medical intervention can completely reverse this multifactorial syndrome, which is driven by different metabolic changes. Identification of cachectic patients is primarily based on alterations in body composition and the assessment of systemic metabolic and inflammatory changes. While these changes have been thoroughly described in patients with more advanced stages of lung cancer, their role in resectable lung cancer remains less explored. In this review, we summarize the different methods to assess body composition metrics such as skeletal muscle (SM) mass, fat distribution and overall body composition. As the dominant driver of cancer cachexia, we also describe the two most widely accepted acute phase proteins. Furthermore, we discuss the short and long-term clinical implications of cancer cachexia and the corresponding body composition and inflammatory changes in resectable lung cancer patients. Finally, we explore the possibility of identifying a specific host phenotype of cachectic lung cancer patients that predisposes to adverse outcomes of lung cancer surgery, which might enhance the predictive value for overall survival and aid in treatment decision-making in lung cancer patients in the future.

Keywords:  Cancer cachexia; body composition; inflammation; lung cancer surgery; survival

DOI:  https://doi.org/10.21037/tlcr-2025-511
Sci Adv. 2025 Sep 19. 11(38): eadw9095

Mapping the genetic landscape of iron metabolism uncovers the SETD2 methyltransferase as a modulator of iron flux.

Anthony W Martinelli, Chun-Pei Wu, Tristan Vornbäumen, Hudson W Coates, Louise H Jordon, Niek Wit, Jia J Sia, Anneliese O Speak, James A Nathan.

Cellular iron levels must be tightly regulated to ensure sufficient iron for essential enzymatic functions while avoiding the harmful generation of toxic species. Here, to better understand how iron levels are controlled, we carry out genome-wide mutagenesis screens in human cells. Alongside mapping known components of iron sensing, we determine the relative contributions of iron uptake, iron recycling, ferritin breakdown, and mitochondrial flux in controlling the labile iron pool. We also identify SETD2, a histone methyltransferase, as a chromatin modifying enzyme that controls intracellular iron availability through ferritin breakdown. Functionally, we show that SETD2 inhibition or cancer-associated SETD2 mutations render cells iron deficient, thereby driving resistance to ferroptosis and potentially explaining how some tumors evade antitumoral immunity.

DOI: https://doi.org/10.1126/sciadv.adw9095
Adv Drug Deliv Rev. 2025 Sep 12. pii: S0169-409X(25)00182-6. [Epub ahead of print]226 115697

Tumor microenvironment subtyping in pancreatic ductal adenocarcinoma: New avenues for personalized therapeutic strategies.

Dharini Srinivasan, Johann Gout, Alexander Kleger, Elodie Roger.

  In the past decade, single-cell-resolved approaches have uncovered the extensive heterogeneity of pancreatic ductal adenocarcinoma (PDAC), reshaping our understanding of this complex solid tumor. PDAC entities exhibit both intra- and inter-tumor heterogeneity at the tumor and stromal levels, translating into distinct ecosystems and functions, ultimately impacting disease progression and treatment response. Increasing evidence highlights how specific genetic alterations drive unique tumor microenvironment landscapes, affecting fibroblast programming, immune cell contexture and extracellular matrix remodeling. In this review, we emphasize the importance of deciphering and stratifying heterogeneous tumor-stroma networks and provide an overview on the intricate crosstalk linking tumor identity and stromal phenotype. We further discuss the concept of multicellular subtyping and the role of spatial organization in shaping patient outcomes to refine prognostic and therapeutic stratification. Lastly, we explore existing and potential therapeutic strategies aimed at targeting both tumor-intrinsic and stromal-extrinsic vulnerabilities, offering insights into approaches that could enhance the efficacy of tailored treatment schemes. By integrating these perspectives, we aim to provide a comprehensive framework for advancing precision medicine in PDAC.

Keywords:  Pancreatic cancer; Precision medicine; Stromal subtypes; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.addr.2025.115697
Biophys J. 2025 Sep 12. pii: S0006-3495(25)00596-X. [Epub ahead of print]

Micron-scale, liquid-liquid phase separation in ternary lipid membranes containing DPPE.

Gunnar J Goetz, Sasha Naomi, Angelique M Madrigal, Catherine L A Chang, Caitlin E Cornell, Sarah L Keller.

  Micron-scale, liquid-liquid phase separation occurs in membranes of living cells, with physiological consequences. To discover which lipids might support phase separation in cell membranes and how lipids might partition between phases, miscibility phase diagrams have been mapped for model membranes. Typically, model membranes are composed of ternary mixtures of a lipid with a high melting temperature, a lipid with a low melting temperature, and cholesterol. Phospholipids in ternary mixtures are chosen primarily to favor stable membranes (phosphatidylcholines and sphingomyelins) or add charge (phosphatidylglycerols and phosphatidylserines). A major class of phospholipids missing from experimental ternary diagrams has been the phosphatidylethanolamines (PEs). PE-lipids constitute up to 20 mol% of common biological membranes, where they influence protein function and facilitate membrane fusion. These biological effects are often attributed to PE's smaller headgroup, which leads to higher monolayer spontaneous curvatures and higher melting temperatures. Taken alone, the higher melting points of saturated PE-lipids imply that liquid-liquid phase separation should persist to higher temperatures in membranes containing PE-lipids. Here, we tested that hypothesis by substituting a saturated PE-lipid (DPPE) for its corresponding PC-lipid (DPPC) in two well-studied ternary membranes (DOPC/DPPC/cholesterol and DiphyPC/DPPC/cholesterol). We used fluorescence microscopy to map full ternary phase diagrams for giant vesicles over a range of temperatures. Surprisingly, we found no micron-scale, liquid-liquid phase separation in vesicles of the first mixture (DOPC/DPPE/cholesterol), and only a small region of liquid-liquid phase separation in the second mixture (DiphyPC/DPPE/cholesterol). Instead, coexisting solid and liquid phases were widespread, with the solid phase enriched in DPPE. An unusual feature of these ternary membranes is that solid and liquid-ordered phases can be distinguished by fluorescence microscopy, so tie-line directions can be estimated throughout the phase diagram, and transition temperatures to the 3-phase region (containing a liquid-disordered phase, a liquid-ordered phase, and a solid phase) can be accurately measured.

Keywords:  lipid; liposome; phase separation; three-phase coexistence; vesicle

DOI:  https://doi.org/10.1016/j.bpj.2025.09.016
Nat Metab. 2025 Sep 16.

BDH2-driven lysosome-to-mitochondria iron transfer shapes ferroptosis vulnerability of the melanoma cell states.

Francesca Rizzollo, Abril Escamilla-Ayala, Nicola Fattorelli, Natalia Barbara Lysiak, Sanket More, Pablo Hernández Varas, Lucia Barazzuol, Chris Van den Haute, Joris Van Asselberghs, David Nittner, Jonathan Coene, Vivek Venkataramani, Bernhard Michalke, Christine Gaillet, Tatiana Cañeque, Irwin Davidson, Steven H L Verhelst, Peter Vangheluwe, Tito Calì, Jean-Christophe Marine, Raphaël Rodriguez, Julie Bonnereau, Patrizia Agostinis.

Iron sustains cancer cell plasticity, yet it also sensitizes the mesenchymal, drug-tolerant phenotype to ferroptosis. This posits that iron compartmentalization must be tightly regulated. However, the molecular machinery governing organelle Fe(II) compartmentalization remains elusive. Here, we show that BDH2 is a key effector of inter-organelle Fe(II) redistribution and ferroptosis vulnerability during melanoma transition from a melanocytic (MEL) to a mesenchymal-like (MES) phenotype. In MEL cells, BDH2 localizes at the mitochondria-lysosome contacts (MLCs) to generate the siderophore 2,5-dihydroxybenzoic acid (2,5-DHBA), which ferries iron into the mitochondria. Fe(II) transfer by BDH2 supports mitochondrial bioenergetics, which is required to maintain lysosomal acidification and MLC formation. Loss of BDH2 alters lysosomal pH and MLC tethering dynamics, causing lysosomal iron sequestration, which primes MES cells for ferroptosis. Rescuing BDH2 expression, or supplementing 2,5-DHBA, rectifies lysosomal pH and MLCs, protecting MES cells from ferroptosis and enhancing their ability to metastasize. Thus, we unveil a BDH2-dependent mechanism that orchestrates inter-organelle Fe(II) transfer, linking metabolic regulation of lysosomal pH to the ferroptosis vulnerability of the mesenchymal, drug-tolerant cancer cells.

DOI: https://doi.org/10.1038/s42255-025-01352-4
Cancer Res. 2025 Sep 18.

Surgery-Induced Neutrophil Extracellular Traps Promote Tumor Metastasis by Reprogramming Cancer Cell Lipid Metabolism.

Tony Haykal, Ruiqi Yang, Celine Tohme, Zhengyi He, Silvia Liu, David A Geller, Christof Kaltenmeier, Stacy L Gelhaus, Richard L Simmons, Hamza O Yazdani, Samer Tohme.

Cancer surgery is a double-edged sword, as it can induce an inflammatory response that promotes tumor recurrence and progression. In this study, we explored the effects of surgery-induced neutrophil extracellular traps (NETs) in reprogramming cancer metabolism to foster metastatic tumor growth. To model the effect of surgery on tumor progression, mice bearing subcutaneous tumors underwent a midline laparotomy with mesenteric exploration for 30 mins. Mice subjected to surgery showed accelerated primary subcutaneous and lung metastatic tumor growth. Perioperative inhibition of NET formation utilizing DNAse, GSK484, or PAD4 knockout mice prevented surgically induced tumor growth, whereas pre-treating cancer cells with NETs in vitro before inoculation increased tumor burden. Cancer cells exposed to surgical stress in vivo or treated with NETs in vitro showed activation of the MYC oncogenic pathway and fatty acid oxidation (FAO). NETs also stimulated uptake of long-chain fatty acids (LCFA) and upregulation of CD36, the main LCFA transporter. Blocking FAO with etomoxir, a CPT1α inhibitor, prevented metastatic tumor growth induced by surgical NETs. FA metabolism was crucial for cancer cells under anoikis stress, allowing survival of circulating cancer cells exposed to NETs. Analysis of patient data substantiated the correlation between NET abundance and lipid metabolism, and plasma from post-operative patients upregulated CD36 expression and promoted the proliferation of colorectal cancer cells. Together, these findings show that the systemic NETosis response triggered by surgery promotes tumor progression by activating the MYC transcriptional program and reprogramming FAO metabolism in cancer cells.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-3393
Cancer Res. 2025 Sep 18.

The Prolyl Isomerase PIN1 Impacts Fibroblast Differentiation States and Crosstalk in Pancreatic Cancer.

Chloe L Bowman, Colin J Daniel, Eric J Carlson, Vidhi M Shah, Amy S Farrell, Kayleigh M Kresse, Xiaoyan Wang, Kyra A Lindley, Madeline R Kuhn, Kevin MacPherson-Hawthorne, Brittany L Allen-Petersen, Jennifer Eng, Motoyuki Tsuda, Isabel A English, Carl Pelz, Arslan Amer, Aaron R Doe, Megan A Turnidge, Zina P Jenny, Trent Waugh, Zinab O Doha, Nicholas D Kendsersky, Kristof Torkenczy, Katherine R Pelz, Andrew J Fields, Gabriel M Cohn, Gabrielle S Dewson, Mary C Thoma, Taylor S Amery, Mara H Sherman, Koei Chin, Anupriya Agarwal, Jason M Link, Brett C Sheppard, Andrew C Adey, Rosalie C Sears, Ellen M Langer.

The prolyl isomerase PIN1 is overexpressed in cancer and contributes to cancer cell-intrinsic phenotypes including proliferation and migration. However, PIN1 may also function in stromal cells within the tumor microenvironment (TME). Here, we showed that PIN1 is a critical regulator of pancreatic stellate cell (PSC) state at baseline and in response to the myofibroblast activating factor TGF-β. Loss or inhibition of PIN1 altered the epigenetic and transcriptional response of PSCs to TGF-β, preventing PSC differentiation to a myofibroblast state and altering expression of secreted matrix proteins and signaling molecules. Consistent with inhibition of the TGF-β response, low fibroblast PIN1 expression in mouse and human pancreatic ductal adenocarcinoma (PDAC) correlated with low expression of α-SMA, a marker of myofibroblast activation. Decreased PIN1 expression at baseline also altered paracrine HGF signaling from fibroblasts to tumor cells. PSCs with low PIN1 expression displayed reduced expression and secretion of HGF, resulting in an attenuation of c-MET receptor phosphorylation and signaling in nearby cancer cells. In allograft models, host PIN1 was critical for normal growth of a subset of pancreatic cancer cell lines that are responsive to HGF signaling. Through the identification of changes to fibroblast activation state and crosstalk following PIN1 loss or inhibition, these data suggest that systemic targeting of PIN1 will suppress the pro-tumorigenic PDAC microenvironment and may differentially affect heterogeneous patient populations.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-3437
Nature. 2025 Sep 17.

Basal cell of origin resolves neuroendocrine-tuft lineage plasticity in cancer.

Abbie S Ireland, Daniel A Xie, Sarah B Hawgood, Margaret W Barbier, Lisa Y Zuo, Benjamin E Hanna, Scarlett Lucas-Randolph, Darren R Tyson, Benjamin L Witt, Ramaswamy Govindan, Afshin Dowlati, Justin C Moser, Anish Thomas, Sonam Puri, Charles M Rudin, Joseph M Chan, Andrew Elliott, Trudy G Oliver.

Neuroendocrine and tuft cells are rare chemosensory epithelial lineages defined by the expression of ASCL1 and POU2F3 transcription factors, respectively. Neuroendocrine cancers, including small cell lung cancer (SCLC), frequently display tuft-like subsets, a feature linked to poor patient outcomes1-9. The mechanisms driving neuroendocrine-tuft tumour heterogeneity and the origins of tuft-like cancers are unknown. Using multiple genetically engineered animal models of SCLC, we demonstrate that a basal cell of origin (but not the accepted neuroendocrine origin) generates neuroendocrine-tuft-like tumours that highly recapitulate human SCLC. Single-cell clonal analyses of basal-derived SCLC further uncovered unexpected transcriptional states, including an Atoh1+ state, and lineage trajectories underlying neuroendocrine-tuft plasticity. Uniquely in basal cells, the introduction of genetic alterations enriched in human tuft-like SCLC, including high MYC, PTEN loss and ASCL1 suppression, cooperates to promote tuft-like tumours. Transcriptomics of 944 human SCLCs revealed a basal-like subset and a tuft-ionocyte-like state that altogether demonstrate notable conservation between cancer states and normal basal cell injury response mechanisms10-13. Together, these data indicate that the basal cell is a probable origin for SCLC and other neuroendocrine-tuft cancers that can explain neuroendocrine-tuft heterogeneity, offering new insights for targeting lineage plasticity.

DOI: https://doi.org/10.1038/s41586-025-09503-z
Eur J Pharmacol. 2025 Sep 12. pii: S0014-2999(25)00906-9. [Epub ahead of print]1006 178152

Spotlight on membrane fluidity of normal and cancer cells: Implications for cancer diagnosis and treatment.

Roberto Canaparo, Federica Foglietta, Carlo Della Pepa, Loredana Serpe.

  Membrane fluidity is crucial for cellular function, signalling, and adaptation. Healthy cells maintain strict control over membrane fluidity through homeostatic mechanisms such as lipid-protein interactions, phospholipid asymmetry and cholesterol distribution. In contrast, cancer cells exhibit profound dysregulation. Altered lipid metabolism, increased incorporation of unsaturated fatty acids and disrupted cholesterol homeostasis create a more fluid and dynamic membrane environment, thereby enhancing oncogenic signalling, mechanotransduction and immune evasion. These changes are key drivers of cancer behaviours, including enhanced proliferation, resistance to apoptosis and metastasis. This review explores the biophysical basis of membrane fluidity, examining its dual role as a diagnostic biomarker and a therapeutic target in cancer. Advanced imaging techniques, such as fluorescence recovery after photobleaching (FRAP), fluorescence lifetime imaging microscopy (FLIM) and electron spin resonance (ESR), enable precise measurement of membrane fluidity, revealing cancer-specific alterations. These tools provide high-resolution insights into lipid organization and protein mobility, facilitating improved cancer diagnostics and therapeutic response monitoring. Emerging therapeutic strategies exploit membrane fluidity to selectively induce cancer cell death. These strategies include modulating cholesterol levels, using lipid metabolism inhibitors, and activating sonosensitisers, intracellular responsive chemical agents that generate reactive oxygen species, using ultrasound by sonodynamic therapy. Despite these advances, there are still challenges in translating membrane-targeted strategies into clinical practice, primarily due to tumour heterogeneity and the complex relationship between lipid dynamics and protein function. Future research must integrate lipidomics, biophysics, and oncology to exploit membrane fluidity as a biomarker and therapeutic target, paving the way for more precise cancer treatments.

Keywords:  Cancer cells; Cell membrane fluidity; Cholesterol modulation; Lipid metabolism inhibitors; Sonodynamic therapy

DOI:  https://doi.org/10.1016/j.ejphar.2025.178152
EMBO Rep. 2025 Sep 16.

The muscle specific MEF2Dα2 isoform promotes muscle ketolysis and running capacity in mice.

Sushil Kumar, Xuan Ji, Hina Iqbal, Xiangnan Guan, Brittany Mis, Devanshi Dave, Suresh Kumar, Jacob Besler, Ranjan Dash, Zheng Xia, Ravi K Singh.

  During prolonged starvation and exhaustive exercise, when there is low availability of carbohydrates, the liver breaks down fatty acids to generate ketone bodies, which are utilized by peripheral tissues as an alternative fuel source. The transcription factor MEF2D undergoes regulated alternative splicing in the postnatal period to produce a highly conserved, muscle specific MEF2Dα2 protein isoform. Here, we discover that compared to WT mice, MEF2Dα2 exon knockout (Eko) mice display reduced running capacity and muscle expression of all three ketolytic enzymes: BDH1, OXCT1, and ACAT1. MEF2Dα2 Eko mice consistently show increased blood ketone body levels in a tolerance test, after exercise, and when fed a ketogenic diet. Lastly, using mitochondria isolated from skeletal muscle, Eko mice show reduced ketone body utilization compared to WT mice. Collectively, our findings identify a new role for the MEF2Dα2 protein isoform in regulating skeletal muscle ketone body oxidation, exercise capacity, and systemic ketone body levels.

Keywords:  Alternative Splicing; Ketone Body; MEF2 Transcription Factors; MExercise Metabolism

DOI:  https://doi.org/10.1038/s44319-025-00578-3
Lancet Oncol. 2025 Sep 10. pii: S1470-2045(25)00363-8. [Epub ahead of print]

Neoadjuvant FOLFIRINOX versus neoadjuvant gemcitabine-based chemoradiotherapy in resectable and borderline resectable pancreatic cancer (PREOPANC-2): a multicentre, open-label, phase 3 randomised trial.

Dutch Pancreatic Cancer Group

BACKGROUND: The PREOPANC-2 trial aimed to evaluate whether neoadjuvant FOLFIRINOX improved overall survival compared with neoadjuvant gemcitabine-based chemoradiotherapy followed by adjuvant gemcitabine in patients with resectable or borderline resectable pancreatic ductal adenocarcinoma (PDAC).
METHODS: In this investigator-initiated, open-label, nationwide, phase 3 randomised trial, patients aged 18 years or older with resectable or borderline resectable PDAC and a WHO performance status of 0 or 1 were enrolled across 19 Dutch centres. Patients in the FOLFIRINOX (FFX) group received FOLFIRINOX (85 mg/m2 intravenous oxaliplatin, 180 mg/m2 intravenous irinotecan, 400 mg/m2 intravenous leucovorin, followed by a 400 mg/m2 intravenous fluorouracil bolus and then continuous infusion at 2400 mg/m2 intravenously over 46 h every 14 days for eight cycles) followed by surgery without adjuvant treatment. Patients in the chemoradiotherapy (CRT) group received three cycles of neoadjuvant gemcitabine (1000 mg/m2 intravenously on days 1, 8, and 15 of each 28-day cycle and on days 1 and 8 only for cycles one and three) combined with hypofractionated radiotherapy (36 Gy in 15 fractions) during the second cycle only, followed by surgery and four cycles of adjuvant gemcitabine. Randomisation (1:1) was done using a minimisation technique and stratified by resectability status (resectable vs borderline resectable disease) and centre. The primary endpoint was overall survival in the modified intention-to-treat population, after excluding ineligible patients. Data on race and ethnicity were not collected. This trial is registered with EudraCT (2017-002036-17) and is complete.
FINDINGS: From June 5, 2018, to Jan 28, 2021, 375 patients were randomly assigned to the FFX group (n=188) or the CRT group (n=187). Six patients (three per group) were excluded due to ineligibility (n=4) or immediate withdrawal of informed consent after randomisation (n=2). 208 (56%) of 369 patients were male and 161 (44%) were female. After a median follow-up of 42·3 months (IQR 35·7-48·7), median overall survival was 21·9 months (95% CI 17·7-27·0) in the FFX group versus 21·3 months (16·8-25·5) in the CRT group (HR 0·88 [95% CI 0·69-1·13], p=0·32). The most common grade 3-4 adverse events were neutropenia (43 [25%] of 175 in the FFX group vs 38 [22%] of 176 in the CRT group), diarrhoea (41 [23%] vs two [1%]), and leukopenia (14 [8%] vs 26 [15%]). Serious adverse events occurred in 85 (49%) patients in the FFX group compared with 75 (43%) in the CRT group (p=0·26). Adverse events of grades 3 or worse occurred in 117 (67%) patients in the FFX group versus 106 (60%) patients in the CRT group (p=0·20). Treatment-related deaths occurred in two (1%) patients in the FFX group (multi-organ failure and intestinal mucositis) and one (1%) patient in the CRT group (upper gastrointestinal haemorrhage).
INTERPRETATION: This randomised trial did not show a difference in overall survival between neoadjuvant FOLFIRINOX and neoadjuvant gemcitabine-based chemoradiotherapy in patients with resectable or borderline resectable PDAC. Both neoadjuvant treatment regimens may be considered in these patients.
FUNDING: Dutch Cancer Society and ZonMw.

DOI: https://doi.org/10.1016/S1470-2045(25)00363-8
Prog Lipid Res. 2025 Sep 17. pii: S0163-7827(25)00037-2. [Epub ahead of print] 101355

Homeocurvature: A new dimension of membrane adaptation to extreme environments.

Jacob R Winnikoff, Itay Budin.

Adaptation to abiotic factors is essential for life's radiation across the planet. Lipids, particularly sensitive to pressure and temperature (P and T), play a critical role in biochemical adaptation. In oceanic depths, lower temperatures and increasing hydrostatic pressure influence lipid packing. The prevailing model for lipid response to P and T has been homeoviscosity, regulating membrane viscosity. However, our recent systematic analysis of lipid adaptation in ctenophores revealed an alternative homeocurvature model influenced by the spontaneous curvature of phospholipids. This model highlights pressure as a stronger modulator of lipid curvature than membrane fluidity, which is particularly relevant in deep-sea environments. This review aims to enhance understanding of lipidome responses by synthesizing the challenges posed by extreme P and T. We explore the interplay between homeocurvature and homeoviscosity, illustrating the unexpected genesis of the homeocurvature model through chemical and biophysical trends. We apply both models to four published lipidomic datasets from diverse marine taxa, proposing that broader environmental sampling is vital for assessing existing models and discovering new ones. Understanding membrane responses to environmental factors informs the function of cell membranes broadly and helps predict the evolutionary and ecological impacts of global change.

DOI: https://doi.org/10.1016/j.plipres.2025.101355
bioRxiv. 2025 Sep 08. pii: 2025.09.07.674666. [Epub ahead of print]

Astrocytes mobilize a broader repertoire of lysosomal repair mechanisms than neurons.

Erin M Smith, Natali L Chanaday, Sandra Maday.

Lysosomal damage impairs proteostasis and contributes to neurodegenerative diseases, yet cell-type-specific differences in lysosomal repair remain unclear. Using a neuron-astrocyte coculture system, we compared responses to lysosomal injury induced by a lysosomotropic methyl ester. Both neurons and astrocytes showed lysosomal damage, marked by galectin-3 recruitment to lumenal lysosomal β-galactosides, elevated lysosomal pH, and engagement of lysophagy receptors TAX1BP1 and p62. However, astrocytes showed a preferential recruitment of ESCRT repair machinery to damaged lysosomes. Additionally, the lysosomal membrane reformation pathway regulated by the RAB7-GAP, TBC1D15, was more robustly activated in astrocytes. By contrast, the PITT pathway, mediating lipid transfer between the ER and damaged lysosomes, was engaged in both cell types. Our data reveal a divergence in how neurons and astrocytes mobilize repair pathways to manage lysosomal damage. These data may reflect differences in lysosomal resilience between astrocytes and neurons and inform therapeutic strategies to correct lysosomal dysfunction in neurodegenerative diseases.

DOI: https://doi.org/10.1101/2025.09.07.674666
ArXiv. 2025 Sep 03. pii: arXiv:2509.03330v1. [Epub ahead of print]

Network-driven discovery of repurposable drugs targeting hallmarks of aging.

Bnaya Gross, Joseph Ehlert, Vadim N Gladyshev, Joseph Loscalzo, Albert-László Barabási.

Despite the thousands of genes implicated in age-related phenotypes, effective interventions for aging remain elusive, a lack of advance rooted in the multifactorial nature of longevity and the functional interconnectedness of the molecular components implicated in aging. Here, we introduce a network medicine framework that integrates 2,358 longevity-associated genes onto the human interactome to identify existing drugs that can modulate aging processes. We find that genes associated with each hallmark of aging form a connected subgraph, or hallmark module, a discovery enabling us to measure the proximity of 6,442 clinically approved or experimental compounds to each hallmark. We then introduce a transcription-based metric, pAGE, which evaluates whether the drug-induced expression shifts reinforce or counteract known age-related expression changes. By integrating network proximity and pAGE, we identify multiple drug repurposing candidate that not only target specific hallmarks but act to reverse their aging-associated transcriptional changes. Our findings are interpretable, revealing for each drug the molecular mechanisms through which it modulates the hallmark, offering an experimentally falsifiable framework to leverage genomic discoveries to accelerate drug repurposing for longevity.
Nat Commun. 2025 Sep 16. 16(1): 8295

A mesothelial differentiation gateway drives fibrosis.

Safwen Kadri, Adrian Fischer, Martin Mück-Häusl, Wei Han, Amal Kadri, Yue Lin, Lin Yang, Shaoping Hu, Haifeng Ye, Pushkar Ramesh, Meshal Ansari, Herbert B Schiller, Hans-Günther Machens, Yuval Rinkevich.

Internal organs are encased by a supportive epithelial monolayer of mesodermal origin, termed mesothelium. The nature, evolution and function of mesothelial cells, and their genetic regulation impacting disease development are insufficiently understood. Here, we generate a comprehensive organ-wide single-cell transcriptomic compendium of mesothelium across healthy and diseased mouse and human organs, delineating the evolution of conserved activated states of mesothelial cells in response to disease. We uncover genetic drives behind each cell state and reveal a conserved metabolic gate into multipotent proteolytic, inflammatory and fibrotic cell differentiation, in mouse and human. Using lung injury models in mice, in combination with mesothelial cell-specific viral approaches, we show that direct metabolic reprogramming using Ifi27l2a and Crip1 on organ surfaces, blocks multipotent differentiation and protects mouse lungs from fibrotic disease. These findings place mesothelial cells as cellular exemplars and gateway to fibrotic disease, opening translational approaches to subvert fibrosis across a range of clinical indications.

DOI: https://doi.org/10.1038/s41467-025-63990-2
Nat Metab. 2025 Sep 19.

Fructose and glucose from sugary drinks enhance colorectal cancer metastasis via SORD.

Tianshi Feng, Qin Luo, Yanlin Liu, Zeyu Jin, David Skwarchuk, Rumi Lee, Miso Nam, John M Asara, Daya R Adye, Philip L Lorenzi, Lin Tan, Guangsheng Pei, Zhongming Zhao, Neda Zarrin-Khameh, Adriana Paulucci-Holthauzen, Brian W Simons, Ju-Seog Lee, Scott Kopetz, Jihye Yun.

The consumption of sugar-sweetened beverages (SSBs), which contain high levels of fructose and glucose, has been causally and mechanistically linked to an increased risk of colorectal cancer (CRC). However, the effects of SSB consumption on advanced stages of disease progression, including metastasis, remain poorly understood. Here we show that exposure of CRC cells to a glucose and fructose formulation-reflecting the composition of both high-fructose corn syrup and sucrose found in SSBs-enhances cellular motility and metastatic potential compared to glucose alone. Given that CRC cells grow poorly in fructose alone, and cells in vivo are not physiologically exposed to fructose without glucose, we excluded the fructose-only condition from our studies unless needed as a control. Mechanistically, the combination of glucose and fructose elevates the NAD⁺/NADH ratio by activation of the reverse reaction of sorbitol dehydrogenase in the polyol pathway. This redox shift relieves NAD⁺ limitations and accelerates glycolytic activity, which in turn fuels activation of the mevalonate pathway, ultimately promoting CRC cell motility and metastasis. Our findings highlight the detrimental impact of SSBs on CRC progression and suggest potential dietary and therapeutic strategies to mitigate metastasis in patients with CRC.

DOI: https://doi.org/10.1038/s42255-025-01368-w
J Biol Chem. 2025 Sep 15. pii: S0021-9258(25)02568-2. [Epub ahead of print] 110716

The lipid phosphatase INPP4B controls pancreatic cancer cell migration and invasion by regulating fibronectin exocytosis.

Golam T Saffi, Nicholas Kleine, Leonardo Salmena.

Increased expression of Inositol Polyphosphate 4-Phosphatase, Type II (INPP4B) correlates with aggressive phenotypes in pancreatic ductal adenocarcinoma (PDAC). Although prior studies have linked INPP4B to lysosome positioning, exocytosis, and enhanced cell migration and invasion in PDAC, the specific mechanisms underlying these processes remain unclear. In this study, we demonstrate that INPP4B promotes fibronectin 1 (FN1) secretion via TRPML1-dependent lysosomal exocytosis. Additionally, we show that INPP4B-mediated regulation of F-actin formation, focal adhesion kinase (FAK) activation, and increased cell migration and invasion depend on FN1 exocytosis. These findings underscore the INPP4B-TRPML1-FN1 axis as a critical contributor to PDAC aggressiveness and identify it as a promising candidate for the development of new therapeutic strategies.

DOI: https://doi.org/10.1016/j.jbc.2025.110716
medRxiv. 2025 Sep 04. pii: 2025.09.02.25334959. [Epub ahead of print]

Transcriptome and microRNAome profiling of human skeletal muscle in pancreatic cancer cachexia.

Ashok Narasimhan, Xiaoling Zhong, Brittany R Counts, Andrew Young, Sha Cao, Jun Wan, Sheng Liu, Leonidas G Koniaris, Teresa A Zimmers.

Background and Aims: Over 80% of patients with pancreatic cancer experience cachexia, characterized by severe muscle and fat loss. While all the mechanistic understanding comes from preclinical models, the translatable nature of these findings to humans remains a critical gap due to the limited knowledge of human cachexia biology.
Methods: We generated matched gene and microRNA profiles from rectus abdominis muscle of 55 pancreatic ductal adenocarcinoma and 18 control subjects. Differentially expressed genes and microRNAs were identified at 1.5-fold change and p<0.05.
Results: Gene expression results revealed a striking sex-specific difference at the expression and pathway levels. In both sexes, co-expression gene network analysis identified more significant modules and hub genes at 1-month of weight loss than the traditionally used six months, suggesting that gene alterations may be more dynamic in the early stages of the disease progression. When comparing hub genes from humans to experimental models of cachexia, genes such as RELA, DDX21, WDR75, PTPN1, and CRIP3 exhibited similar patterns of expression, suggesting their potential role in cachexia. microRNAs also exhibited sex-specific expression. Although several common miRNAs were identified between sexes, their gene targets differed, indicating that microRNAs may regulate gene targets in a sex-specific manner.
Conclusions: The dataset can serve as a resource for validating preclinical findings and exploring previously unexplored molecules in cachexia. Future studies will functionally characterize the role of the hub genes and microRNAs in cachexia. This is the first study to identify sex-specific genes and microRNAs from a single cancer type.

DOI: https://doi.org/10.1101/2025.09.02.25334959
Redox Biol. 2025 Sep 11. pii: S2213-2317(25)00377-5. [Epub ahead of print]87 103864

Low-GPX4 drives a sustained drug-tolerant persister state in TNBC by a targetable adaptive FSP1 upregulation.

Nazia Chaudhary, Dibita Mandal, Bhagya Shree Choudhary, Sushmita Patra, Darshan Jain, Pritam Poonia, Shagufa Shaikh, Siddhi Tekalkar, Shivani Malvankar, Anusha Shivashankar, Eeshrita Jog, Leena Pilankar, Rahul Thorat, Vaishali V Kailje, Sonal Khanna, Subhakankha Manna, Bushra K Khan, Anjana Jadhav, Kedar Sharma, Soundharya Ramu, Sarthak Sahoo, Mohit Kumar Jolly, Sorab N Dalal, Sanju Sinha, Nishanth Ulhas Nair, Eytan Ruppin, Fabienne Lamballe, Flavio Maina, Nandini Verma.

  Metastatic relapses in Triple-Negative Breast Cancer (TNBC) patients with residual disease pose a significant clinical challenge. In this study, we longitudinally modelled cellular state transition from dormant drug-tolerant persister (DDTP) to proliferative (PDTP) cell state across TNBC subtypes. We identified specific molecular and phenotypic alterations that characterize the DTP states in TNBC cells that are maintained upon re-gaining proliferation. We found that Basal-Like proliferative DTPs stably acquired mesenchymal traits, while luminal androgen receptor-positive TNBC DTPs undergo partial Epithelial-to-Mesenchymal Transition (EMT). TNBC DTP cells exhibit reduced expression of glutathione peroxidase-4 (GPX4), conferring susceptibility to ferroptosis inducers. Mechanistically, GPX4 downregulation promotes EMT in TNBC, supported by an inverse correlation between GPX4 and EMT marker vimentin (VIM) expression that also serves as a predictor of survival in TNBC patients undergoing chemotherapy. The genetic, pharmacological, or chemotherapy-induced suppression of GPX4 in TNBC cells leads to robust upregulation of ferroptosis suppressor protein-1 (FSP1). The clinical significance of these findings is established by a strong predictive value of FSP1high/VIMhigh signature for worst survival and incomplete pathological response in chemotherapy-treated TNBC patients. Further, targeting FSP1 re-sensitizes cells to chemotherapy, while combined inhibition of FSP1 and GPX4 is selectively lethal in proliferative DTP TNBC cells by inducing ferroptosis.

Keywords:  Combination therapy; Drug-tolerant persister cells; EMT; FSP1; GPX4; TNBC

DOI:  https://doi.org/10.1016/j.redox.2025.103864
STAR Protoc. 2025 Sep 17. pii: S2666-1667(25)00448-4. [Epub ahead of print]6(4): 104042

In vivo CRISPR screening protocol to identify metastasis mediators using iteratively selected mouse models.

Yuqi Wang, Mangze Hu, Yilong Zou, Xi Wang.

  In vivo CRISPR screens uncover metastasis genes in native contexts, surpassing in vitro model limitations. Here, we present a protocol to identify metastasis-driving genes in ovarian cancer using an in vivo CRISPR screening technique. Key steps include single-guide RNA (sgRNA) library design and validation, lentiviral transduction, establishment of metastatic mouse models, tissue collection, sgRNA amplification for sequencing, bioinformatics-based candidate gene identification, and functional validation. For complete details on the use and execution of this protocol, please refer to Wang et al.1.

Keywords:  CRISPR; Cancer; Metabolism

DOI:  https://doi.org/10.1016/j.xpro.2025.104042
Ann Surg Oncol. 2025 Sep 15.

Survival Benefit of Surgery versus Oncology-Only Therapy in Artery-Involving Borderline Resectable and Locally Advanced Pancreatic Cancer.

and the Rediscover Study Group members

   BACKGROUND: Modern chemotherapy has redefined resectability of pancreatic ductal adenocarcinoma (PDAC), prioritizing tumor biology over anatomy. However, comparative outcomes of surgery versus continued oncologic therapy (COT) in borderline resectable (BR) or locally advanced (LA) PDAC remain unclear. This study addresses this gap.
PATIENTS AND METHODS: This retrospective, international, multicenter cohort study included patients with BR/LA-PDAC treated with neoadjuvant or primary chemotherapy between 2012 and 2024. All met guideline-based criteria for potential resection on the basis of anatomy, biology, and performance status. Treatment allocation (surgery versus COT) was based on institutional practice or surgeon preference, reflecting real-world decision-making. The primary endpoint was overall survival (OS), analyzed using unadjusted comparison, propensity score matching (PSM), and entropy balancing.
RESULTS: A total of 312 patients were included: 158 underwent resection and 154 received COT. Median OS was 39.0 months (IQR 14.3-42.6 months) with resection versus 16.7 months (IQR 8.8-22.5 months) with COT (p < 0.0001). After PSM (75 pairs), OS remained significantly longer with resection (42.6 months, IQR 12.9-42.1 months) versus COT (18.6 months, IQR 9.4-23.9 months; p < 0.0001). In the LA-PDAC subgroup, OS was 42.6 months (IQR 23.2-NA months) with resection versus 18.6 months (IQR 11.8-25.6 months; p < 0.0001) with COT. On multivariable analysis, resection (HR 0.34, 95% CI 0.21-0.54; p < 0.0001) and CA 19-9 (HR 1.0001; p = 0.0297) were independently associated with OS. Entropy-weighted models confirmed these findings. The survival benefit persisted when postoperative deaths were included.
CONCLUSIONS: In patients with BR/LA-PDAC with favorable response to chemotherapy, surgical resection significantly improves survival compared with COT.

Keywords:  Borderline resectable pancreatic ductal adenocarcinoma; Continued oncologic treatment; Locally advanced pancreatic ductal adenocarcinoma; Neoadjuvant chemotherapy; Primary chemotherapy; Resection; Survival

DOI:  https://doi.org/10.1245/s10434-025-18212-w
Nat Struct Mol Biol. 2025 Sep 16.

Phase separation promotes Atg8 lipidation and vesicle condensation for autophagy progression.

Yuko Fujioka, Takuma Tsuji, Tetsuya Kotani, Hiroyuki Kumeta, Chika Kakuta, Junko Shimasaki, Toyoshi Fujimoto, Hitoshi Nakatogawa, Nobuo N Noda.

Upon starvation, the autophagy-initiating Atg1 complex undergoes phase separation to organize the preautophagosomal structure (PAS) in Saccharomyces cerevisiae, from which autophagosome formation is considered to proceed. However, the physiological roles of the PAS droplet remain unclear. Here we show that core Atg proteins are recruited into early PAS droplets that are formed by phase separation of the Atg1 complex with different efficiencies in vitro. The Atg12-Atg5-Atg16 E3 ligase complex for Atg8 lipidation is the most efficiently condensed in the droplets through specific Atg12-Atg17 interaction, which is also important for the PAS targeting of the E3 complex in vivo. In vitro reconstitution demonstrates that E3-enriched early PAS droplets promote Atg8 lipidation and that Atg8 coating of the vesicle membrane is both necessary and sufficient for their condensation into the droplets. These data suggest that the PAS functions as an efficient production site for lipidated Atg8 and pools membrane seeds to drive autophagosome formation.

DOI: https://doi.org/10.1038/s41594-025-01678-3
Cancer Cell. 2025 Sep 18. pii: S1535-6108(25)00366-6. [Epub ahead of print]

Restraint of cancer cell plasticity by spatial homotypic clustering.

Simona Migliozzi, Bruno Adabbo, Luciano Garofano, Fan Wu, Pedro Davila, Ricardo J Komotar, Michael E Ivan, Ashish H Shah, Benjamin B Currall, Sion Williams, Daniel Bilbao Cortes, Melinda Minucci Boone, Macarena I de la Fuente, Sakir H Gultekin, Michele Ceccarelli, Antonio Iavarone, Anna Lasorella.

  Tumor heterogeneity fueled by plasticity of cancer cells is a key to therapy failure. Here, we define the role of proximal communications of malignant cells in glioblastoma plasticity. We find that tumor cell state coherence is maximal in cells organized in homotypic clusters with defined relationships with non-malignant cells, whereas randomly dispersed cells downregulate the original state, acquire alternative phenotypes and exhibit changes in the microenvironment. We demonstrate the intrinsic propensity of glioblastoma cells to develop into clustered and dispersed spatial patterns in orthotopic mouse models and experimentally validate the cell state-specific mechanisms of cell-cell adhesion that prevent phenotype deviation with pharmacologic perturbations in patients-derived glioblastoma models. We establish the generality of "homotypic clustered cell identity" in circulating clustered and single breast cancer cells and show that the glioblastoma glycolytic-plurimetabolic dispersed cellular state uniquely confers shorter survival, thus assigning clinical significance to the spatial patterning of cancer cells in human tumors.

Keywords:  cancer cell plasticity; glioblastoma; intratumor heterogeneity; single-cell spatial proteomics; single-cell spatial transciptomic; tumor ecosystem

DOI:  https://doi.org/10.1016/j.ccell.2025.08.009
Cell Rep. 2025 Sep 12. pii: S2211-1247(25)01017-4. [Epub ahead of print]44(9): 116246

AVID mouse: A versatile platform for real-time, multiscale ATP imaging and spatial systems metabolism analysis in living mice.

Yuichiro Ohnishi, Daiki Setoyama, Hideki Miwa, Norimichi Koitabashi, Riki Ogasawara, Seri Kitada, Naoki Matoba, Takahito Ayano, Kaoru Hiramoto, Ryuto Yasui, Yuki Sugiura, Takahisa Anada, Kosuke Ino, Hinako Matsuda, Takahiro Noma, Shigenori Nonaka, Takashi Izumi, Masahiko Kurabayashi, Makoto Suematsu, Yuya Kunisaki, Motoko Yanagita, Hiromi Imamura, Masamichi Yamamoto.

  We developed the AVID (ATP visualization in vivo directly) mouse, a genetically encoded biosensor mouse enabling real-time, multiscale imaging of ATP dynamics across the whole body, organs, and cellular compartments in living animals. AVID revealed previously undetectable localized ATP depletion near the central vein of the liver after myocardial infarction, spatially linked to kynurenic acid accumulation-a phenomenon invisible to conventional bulk metabolomics. By seamlessly integrating macroscopic organ-level imaging with microscopic spatial metabolomics, AVID establishes a new framework for spatial systems metabolism. Beyond myocardial infarction, this platform offers broad applicability to study organ-organ metabolic communication, spatial metabolic heterogeneity, and localized metabolic shifts across diverse physiological and pathological contexts, providing a transformative resource for metabolic research.

Keywords:  ATP dynamics; CP: Metabolism; FRET; GO-ATeam biosensor; disease progression; energy metabolism; in vivo imaging; multiscale imaging; myocardial infarction; organ-organ interaction; spatial systems metabolism

DOI:  https://doi.org/10.1016/j.celrep.2025.116246
Cell Mol Bioeng. 2025 Aug;18(3-4): 251-269

Innovative Method for Fully Automated, Enzyme-Free Tissue Dissociation and Preparation for Single-Cell Analysis.

Sarah Planchak, E Celeste Welch, Benjamin Phelps, Joshua Phelps, Alejandra Hernandez Moyers, Kathryn Whitehead, John Murphy, Nikos Tapinos, Anubhav Tripathi.

   Purpose: Tissue dissociation is a critical but often overlooked step in single-cell analysis, impacting data quality, reproducibility, and biological insights. Conventional enzymatic and mechanical dissociation methods introduce variability, damage cells, and alter transcriptomic profiles, compromising downstream applications. While the initial innovation in electrical dissociation was published, this work introduces expanded characterization, including bulk RNA sequencing, diverse tissue types, and improved flow cytometry.
Methods: Here, we present a fully automated, enzyme-free method that integrates electric field-based dissociation with purification and centrifugation, providing a standardized, scalable alternative. A square wave oscillating electric field at 100 V/cm was used for dissociating tissue samples in 5 minutes or less.
Results: The system rapidly and gently dissociated glioblastoma spheroids and mouse spleen tissue, achieving a 10 × increase in live cell yield compared to automated enzymatic and mechanical dissociation (gentleMACS) and a 96 ± 2% single-cell recovery rate in glioblastoma spheroids. Transcriptomic analysis revealed minimal gene expression changes post-dissociation, with an R2 value of 0.997 between conditions, indicating high consistency. Flow cytometry confirmed that key immune cell populations (B, T, NK cells) were preserved, with comparable distributions between manual and electrical dissociation.
Conclusions: By reducing operator variability, improving scalability, and maintaining cellular integrity, this technology offers a robust solution for high-throughput single-cell applications in diagnostics, drug discovery, and precision medicine.
Supplementary Information: The online version contains supplementary material available at 10.1007/s12195-025-00850-5.

Keywords:  Automation; Cell spheroid; Electric fields; RNA sequencing; Single-cell analysis; Tissue dissociation

DOI:  https://doi.org/10.1007/s12195-025-00850-5