bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2025–09–07
fifty-two papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. PI5P4Kα promotes glucose and iron acquisition to support metabolic fitness in pancreatic cancer.
  2. Targeting Methylglyoxal Metabolism to Enhance Ferroptosis Sensitivity in Tumor Therapy.
  3. Compression causes cancer cells to start spreading.
  4. An allele-agnostic mutant-KRAS inhibitor suppresses tumor maintenance signals and reprograms tumor immunity in pancreatic cancer.
  5. Hypoxia-induced metastatic heterogeneity in pancreatic cancer.
  6. Plasma membrane accessible cholesterol is regulated by ACC1 and lipid droplets.
  7. Organelle bridges and nanodomain partitioning govern targeting of membrane-embedded proteins to lipid droplets.
  8. A redundant system of thioredoxin and glutathione is essential for pancreatic acinar integrity.
  9. The Pdgfd-Pdgfrb axis orchestrates tumor-nerve crosstalk in pancreatic cancer.
  10. Lipid Composition Alters Ferroptosis Sensitivity.
  11. Cardiac wasting is not cardiac cachexia: the problem of the subjective/objective genitive in matters of the heart.
  12. Entangled cellular and molecular relationships at the sensory neuron-cancer interface.
  13. Fluid shear stress activates a targetable mechano-metastatic cascade to promote medulloblastoma metastasis.
  14. MIRO2-mediated mitochondrial transfer from cancer cells induces cancer-associated fibroblast differentiation.
  15. MYC-Driven Activation of USP39 Enhances SRSF1 Stability and Promotes PDAC Progression.
  16. Proximity-specific ribosome profiling reveals the logic of localized mitochondrial translation.
  17. Tumors hijack macrophages for iron supply to promote bone metastasis and anemia.
  18. Nuclear Symmetric Dimethylarginine Staining is Indicative of Pancreatic Ductal Adenocarcinoma.
  19. Aryl hydrocarbon receptor ligands drive pancreatic cancer initiation and progression through pro-tumorigenic T cell polarization.
  20. Inflammation awakens dormant cancer cells by modulating the epithelial-mesenchymal phenotypic state.
  21. Targeting RAS-mutant cancer cells using a synthetic RAS-activated cancer killing system.
  22. Protocol for plasma membrane enrichment by ultracentrifugation for mass spectrometry of cell lines, xenografts, and patient tumors.
  23. Targeting dormant tumor cells to prevent recurrent breast cancer: a randomized phase 2 trial.
  24. Nerve-associated macrophages control adipose homeostasis across lifespan and restrain age-related inflammation.
  25. MYC and p53 Alterations Cooperate through VEGF Signaling to Repress Cytotoxic T Cell and Immunotherapy Responses in Prostate Cancer.
  26. FSP1 and histone deacetylases suppress cancer persister cell ferroptosis.
  27. Differential cell survival outcomes in response to diverse amino acid stress.
  28. Processing bodies promote lysosomal quality control and cell survival during recovery from lysosomal damage.
  29. Hypoxia-Induced PRMT1 Lactylation Drives Vimentin Arginine Asymmetric Dimethylation in Tumor Metastasis.
  30. Open-Label, Phase II Trial of Extracellular Regulated Kinase Inhibition Alone and in Combination With Autophagy Inhibition in Patients With Metastatic Pancreatic Cancer.
  31. Feature-driven whole-tissue imaging with subcellular resolution.
  32. Muscle Proteome Dynamics.
  33. Capillary constrictions prime cancer cell tumorigenicity through PIEZO1.
  34. MYADM Activates RhoA-Mediated Amoeboid Migration to Drive Metastasis.
  35. Lysosomal reduced thiols are essential for mouse embryonic development.
  36. Molecular Magnetic Resonance Imaging of Dysregulated Zinc Secretion Detects Pancreatic Ductal Adenocarcinoma Lesions and Response to KRASG12D Inhibitor Treatment.
  37. Cancer cell and microenvironmental rewiring by ADAR1 loss impairs glioblastoma tumor growth and extends survival.
  38. Genetically encoded tool for manipulation of ATP/ADP ratio in human cells.
  39. TS2CG as a Membrane Builder.
  40. β-hydroxybutyrate dehydrogenase promotes pancreatic cancer cell proliferation through regulation of the NAD+/NADH balance and mitochondrial acetylation.
  41. A single fluorescent probe for simultaneous detection of polarity, viscosity, and esterase.
  42. Organic Fluorophores for Studying Lipid Membrane Structures and Dynamics.
  43. L1CAM signaling through planar cell polarity generates SOX2 + metastatic progenitors in lung adenocarcinoma.
  44. Cancer Cachexia.
  45. Liver-specific loss of Atg9a perturbs lipid metabolism and hepatocyte integrity.
  46. Cytosolic DNA crosstalk in senescence: a new axis of inflammatory signaling?
  47. Chemoselective Characterization of New Extracellular Matrix Deposition in Bioengineered Tumor Tissues.
  48. Reconstitution of autophagic-like membrane tethering reveals that Atg11 can bind and cluster vesicles on cargo mimetics.
  49. Fusion oncoproteins acquire condensate propensity to initiate tumour formation.
  50. Liver metastases license neutrophils through IL-1 to potentiate cancer progression.
  51. Asparaginase and Autophagy Inhibitors Effectively Remove Senescent Cells by Synergistically Limiting Asparagine Supply.
  52. Local photocrosslinking of native tissue matrix regulates lung epithelial cell mechanosensing and function.
  1. Cell Rep. 2025 Aug 29. pii: S2211-1247(25)00970-2. [Epub ahead of print]44(9): 116199
    PI5P4Kα promotes glucose and iron acquisition to support metabolic fitness in pancreatic cancer.
    Gurpreet K Arora, Ryan M Loughran, Kyanh Ly, Cheska Marie Galapate, Alicia Llorente, Taylor R Anderson, Cynthia Y Zhang, Shea F Grenier, Li Ling, Sophia Crabtree, Guillem Lambies, Chantal Pauli, David A Scott, Yoav Altman, Benji Portillo, Rabi Murad, Cosimo Commisso, Brooke M Emerling.
      Phosphoinositide kinases generate distinct phosphoinositides that regulate pathways to support tumorigenesis. Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) have garnered interest for their role in cancer metabolism; however, their function in pancreatic ductal adenocarcinoma (PDAC) remains unexplored. We identify PI5P4Kα as a critical dependency to support the unique metabolic demands of PDAC cells through its key role in the acquisition of essential metabolic substrates, including glucose and iron. Our data show that inhibition of PI5P4Kα creates a metabolic bottleneck that PDAC cells cannot overcome through adaptive shifts, leading to cancer-specific apoptotic cell death that is reversible by iron supplementation. Notably, we find that PI5P4Kα knockdown suppresses tumor growth in a xenograft mouse model of PDAC. These results not only illuminate the mechanistic underpinnings of PI5P4Kα function in PDAC but also position it as a promising therapeutic target for this disease.
    Keywords:  CP: Cancer; CP: Metabolism; PI5P4K; PIP4K; apoptosis; autophagy; glucose; iron; metabolism; nutrient stress; pancreatic cancer; phosphoinositide kinase
    DOI:  https://doi.org/10.1016/j.celrep.2025.116199
  2. Adv Sci (Weinh). 2025 Sep 04. e05356
    Targeting Methylglyoxal Metabolism to Enhance Ferroptosis Sensitivity in Tumor Therapy.
    Xinyue Zhang, Leng Han, Zimu Wang, Hanghui Yu, Jiao Liu, Rui Kang, Daolin Tang, Zhengjia Liu, Xianlong Du, Enyong Dai.
      Ferroptosis, characterized by iron-dependent lipid peroxidation, is a form of oxidative cell death increasingly recognized for its role in cancer therapy. The susceptibility of cancer cells to ferroptosis varies, highlighting the need to elucidate its underlying metabolic mechanisms. This study identifies a novel pathway in which the E3 ubiquitin ligase, praja ring finger ubiquitin ligase 1 (PJA1), mediates the proteasomal degradation of glyoxalase I (GLO1) exclusively in ferroptosis-sensitive cancer cells. This degradation pathway is absent in ferroptosis-resistant cells, resulting in differing management of methylglyoxal (MGO). The accumulation of MGO, as opposed to its clearance, facilitates ferroptosis by promoting the autophagic degradation of key anti-ferroptotic proteins, specifically ferritin and glutathione peroxidase 4 (GPX4). Targeting the PJA1-GLO1 axis through genetic and pharmacological means enhances the sensitivity of tumors to ferroptosis inducers across various preclinical models, including xenografts, orthotopic, and patient-derived models. Additionally, clinical data demonstrate that elevated GLO1 expression is associated with poorer survival outcomes in pancreatic cancer patients. These findings suggest that modulating the MGO metabolism pathway, particularly through targeting the PJA1-GLO1 axis, can amplify the effectiveness of ferroptosis-inducing agents in cancer therapy.
    Keywords:  autophagy; degradation; ferroptosis; methylglyoxal; pancreatic cancer
    DOI:  https://doi.org/10.1002/advs.202505356
  3. Nature. 2025 Sep 03.
    Compression causes cancer cells to start spreading.
      
    Keywords:  Cancer; Cell biology
    DOI:  https://doi.org/10.1038/d41586-025-02768-4
  4. Sci Transl Med. 2025 Sep 03. 17(814): eadt5511
    An allele-agnostic mutant-KRAS inhibitor suppresses tumor maintenance signals and reprograms tumor immunity in pancreatic cancer.
    Kathleen M McAndrews, Francesca Paradiso, Clint A Stalnecker, Benson S Chellakkan, Fredrik I Thege, David H Peng, Barbara A Moreno Diaz, Hikaru Sugimoto, Sarah I Patel, Krishnan K Mahadevan, Michelle L Kirtley, Danielle Wills, Amari M Sockwell, Andre Luis F Fonseca, Yunhe Liu, Kimal I Rajapakshe, Nathaniel G Yee, Phuong Thao Tran, Huda Alchikh Omar, Antonio Tedeschi, Fiorella Schischlik-Siegl, Andrew S Boghossian, Matthew G Rees, Melissa M Ronan, Jennifer A Roth, Dorothea Rudolph, Martin Aichinger, Florian Ebner, Artem V Artemov, Jesse Lipp, Laura Pisarsky, Valerie Laura Herrmann, John Park, Jörg F Rippmann, Otmar Schaaf, Vanessa Chandler, Mariah Williams, Charles E Deckard, Linghua Wang, Channing J Der, Christopher Vellano, Paola A Guerrero, Timothy P Heffernan, Raghu Kalluri, Anirban Maitra.
      KRAS is among the most frequently mutated oncogenes in cancer, and for decades, efforts at pharmacological blockade of its function in solid cancers have been unsuccessful. A notable advance in this endeavor is the recent development of small-molecule KRAS inhibitors, which enable direct targeting of the mutant oncoprotein. Here, we comprehensively evaluated the preclinical efficacy of BI-2493, a first-in-class allele-agnostic mutant-KRAS inhibitor (panKRASi), in pancreatic ductal adenocarcinoma (PDAC). We report effective tumor growth suppression across a broad range of models, including cell lines, patient-derived xenografts (PDXs), and syngeneic orthotopic models, and prolonged survival in genetically engineered mouse models. Overall, transcriptomic, proteomic, and phosphoproteomic profiling of panKRASi-treated models confirmed RAS pathway inhibition along with up-regulation of LKB1/AMPK (liver kinase B1/AMP-activated protein kinase) targets. In panKRASi-treated immune-replete models, we observed increased intratumoral CD8+ effector T cells and decreased infiltration of myeloid cells, along with remodeling of the tumor microenvironment (TME), enabling responses to immune checkpoint blockade. In the long term, emergence of resistance to panKRASi monotherapy was associated with increased YAP signaling within tumor cells and enhanced expression of immune checkpoints in the TME that impede effective T cell function. Our multifaceted approach identified potential combinatorial approaches for generating sustained responses to panKRASi.
    DOI:  https://doi.org/10.1126/scitranslmed.adt5511
  5. bioRxiv. 2025 Aug 29. pii: 2025.08.26.672389. [Epub ahead of print]
    Hypoxia-induced metastatic heterogeneity in pancreatic cancer.
    Pradeep Moon Gunasekaran, Qianqian Wang, Yoke-Chen Chang, Polina Guseva, Rajika Chauhan, Alexander Kley, Gene Lee, Siddharth Ghosh Roy, Yousef Masoudpoor, Arthur Roberts, Kelly Watkins Walton, Lucyann Franciosa, Shafiq Bhat, Emmanuel Zachariah, Kishan Patel, Zhongren Zhou, Wenjin Chen, Julie Zhouli Ni, Sam Guoping Gu, Cristina Montagna, Shin-Heng Chiou.
      In most solid tumors, hypoxia constitutes a defining microenvironmental feature that reprograms malignant cells into a highly metastatic state by driving cellular plasticity and exacerbating chromosomal instability (CIN). However, the mechanisms by which cancer cells concurrently co-opt these elements of hypoxic adaptation to promote metastasis remains poorly understood. Here, we report that hypoxia promotes metastasis by suppressing the JmjC-containing histone lysine demethylase Kdm8. CRISPR/Cas9-mediated targeting of Kdm8 in a Kras ; Trp53 -driven mouse model of pancreatic ductal adenocarcinoma (PDA) robustly rewires the malignant cell transcriptomic programs, leading to a profound loss of the epithelial morphology and widespread metastatic disease. In PDA patients, a high KDM8-induced gene signature is associated with reduced metastatic burden and better survival in advanced disease. Notably, Kdm8 suppression in normoxia recapitulates key aspects of the global epigenetic and transcriptomic rewiring, mitotic spindle defects, and CIN induced by hypoxia. Moreover, disruption of Kdm8's demethylase activity phenocopies Kdm8 loss, whereas expression of hypermorphic Kdm8 variants resistant to hypoxic suppression markedly reduces metastasis beyond the levels achieved by the wildtype protein. Through the suppression of Kdm8 demethylase function, hypoxia unleashes a potent metastatic program by simultaneously advancing cellular plasticity and CIN.
    DOI:  https://doi.org/10.1101/2025.08.26.672389
  6. bioRxiv. 2025 Aug 26. pii: 2025.08.21.671640. [Epub ahead of print]
    Plasma membrane accessible cholesterol is regulated by ACC1 and lipid droplets.
    Kalani M Wijesinghe, Chai-Wan Kim, Emily O Schad, Shuo Li, Summer Chen, Erin Takeshima, Chandni B Khandwala, Desiree Tillo, Andres M Lebensohn, James A Olzmann, Rajat Rohatgi, Maia Kinnebrew.
      Proper maintenance of plasma membrane (PM) cholesterol is essential for diverse processes ranging from animal development to pathogen evasion. Despite decades of study, the mechanisms governing cellular cholesterol regulation are incomplete. Using genome-wide screens we find that ACC1, the rate-limiting enzyme in fatty acid biosynthesis, regulates PM cholesterol transport. ACC1 loss causes a ∼10-fold increase in PM accessible cholesterol in cells and mice. Mechanistically, we find that ACC1 regulates lipid droplet (LD) catabolism, and LDs are intimately tied to PM accessible cholesterol levels since reductions or elevations in their numbers block or promote cholesterol trafficking, respectively. Furthermore, LDs are required for cholesterol trafficking induced by 25-hydroxycholesterol, a modulator of inflammation and an interferon-stimulated second messenger that protects cells from pathogen invasion. This work identifies an unrecognized role for ACC1 and LDs in cholesterol regulation, which has implications for diseases where LD numbers are altered, from metabolic syndromes to neurodegeneration.
    DOI:  https://doi.org/10.1101/2025.08.21.671640
  7. bioRxiv. 2025 Aug 20. pii: 2024.08.27.610018. [Epub ahead of print]
    Organelle bridges and nanodomain partitioning govern targeting of membrane-embedded proteins to lipid droplets.
    Arda Mizrak, Jacob Kæstel-Hansen, Jessica Matthias, J Wade Harper, Nikos S Hatzakis, Robert V Farese, Tobias C Walther.
      Numerous metabolic enzymes translocate from the ER membrane bilayer to the lipid droplet (LD) monolayer, where they perform essential functions. Mislocalization of certain LD-targeted membrane proteins, including HSD17B13 and PNPLA3, is implicated in metabolic dysfunction-associated steatotic liver disease (MASLD). However, the mechanisms governing the trafficking and accumulation of ER proteins on LDs remain poorly understood. Here, using MINFLUX and HILO single-molecule tracking combined with machine learning, we show that HSD17B13, GPAT4, and the model cargo LiveDrop diffuse at comparable speeds in the ER and on LDs, but become nano-confined upon reaching the LD surface. Mechanistic dissection of LiveDrop targeting revealed that this confinement, along with protein accumulation on LDs, depends on specific residues within its targeting motif. These residues mediate preferential and repeated interactions with nanoscale membrane domains, suggesting that LD-targeted proteins selectively partition into distinct lipid-protein environments that transiently retain and concentrate them at the LD surface. Single-molecule trajectories further revealed bidirectional trafficking of LiveDrop across seipin-containing ER-LD bridges, providing direct evidence for lateral protein transfer across membrane contact sites. These findings establish nanodomain-based confinement as a key mechanism driving selective protein accumulation on LDs and reveal how membrane bridges between organelles facilitate protein sorting.
    DOI:  https://doi.org/10.1101/2024.08.27.610018
  8. Cell Mol Gastroenterol Hepatol. 2025 Sep 02. pii: S2352-345X(25)00168-7. [Epub ahead of print] 101627
    A redundant system of thioredoxin and glutathione is essential for pancreatic acinar integrity.
    Henrik Einwächter, Bailing Li, Michaela Aichler, Mariana Rickmann, Nirav Florian Chhabra, Rupert Oellinger, Markus Brielmeier, Roland M Schmid.
       BACKGROUND & AIMS: Oxidative stress and antioxidant defense mechanisms have long been implicated in the pathogenesis of acute pancreatitis (AP). However, there is a notable lack of in vivo experimental evidence clarifying their precise role.
    METHODS: We generated and analyzed mice with a pancreas-specific deletion of Txnrd1 (Txnrd1Δpanc). AP was induced in these mice using caerulein injections. Pancreatic tissue was subsequently analyzed using immunoblotting, histology, immunohistochemistry, RNA sequencing and biochemical assays.
    RESULTS: Txnrd1Δpanc mice exhibited normal growth, pancreatic weight, histology, and pancreatic function comparable to controls, though they experienced a slightly more severe course of AP. An increase in glutathione levels and upregulation of components within the glutathione system were observed in these mice. However, depletion of the glutathione pool led to pancreatic necrosis, followed by regeneration. When glutathione depletion was combined with AP, Txnrd1Δpanc mice suffered a profound and permanent loss of acinar tissue.
    CONCLUSIONS: These findings indicate that the response to AP is closely linked to alterations in antioxidant systems. The thioredoxin and the glutathione systems appear to perform overlapping protective roles in safeguarding acinar cells during AP. A simultaneous disruption of both systems proves detrimental to pancreatic integrity during acute pancreatitis.
    Keywords:  acute pancreatitis; glutathione; thioredoxin
    DOI:  https://doi.org/10.1016/j.jcmgh.2025.101627
  9. bioRxiv. 2025 Aug 31. pii: 2025.08.26.672505. [Epub ahead of print]
    The Pdgfd-Pdgfrb axis orchestrates tumor-nerve crosstalk in pancreatic cancer.
    Peter Wang, Nicole Lester, Ella Perrault, Jennifer Su, Dennis Gong, Carina Shiau, Jingyi Cao, Phuong Nguyen, Jung Woo Bae, Deniz Olgun, Hannah Hoffman, Ashley Lam, Jean Huang-Gao, Saifur Rahaman, Jimmy Guo, Jaimie Barth, Nicholas Caldwell, Prajan Divakar, Jason Reeves, Arya Bahrami, Shanshan He, Michael Patrick, Eric Miller, Maria Ganci, Grissel Cervantes-Jaramillo, Theodore Hong, Jennifer Wo, Hannah Roberts, Ralph Weissleder, Hongyoon Choi, Carlos Fernandez-Del-Castillo, Kathy Cormier, David T Ting, Tyler Jacks, Lei Zheng, Martin Hemberg, Mari Mino-Kenudson, William L Hwang.
      Nerves are an integral component of the tumor microenvironment, contributing to cancer progression, metastasis, morbidity, and mortality. In pancreatic ductal adenocarcinoma (PDAC), worse clinical outcomes are associated with perineural invasion (PNI), a process by which cancer cells surround and invade nerves. Here, we employed whole-transcriptome and single-cell spatial transcriptomics to identify candidate tumor-nerve interactions that promote PNI. We discovered that Pdgfd signaling promotes key features of nerve invasion. Mechanistically, Pdgfd stimulated cancer cell invasiveness, neurite outgrowth, and direct physical engagement with glia. Pharmacological blockade of this axis reduced each of these processes in vitro as well as PNI in vivo. Thus, Pdgfd-Pdgfrb signaling mediates PNI by coordinating multifaceted cancer-neuron-glia interactions and represents a promising therapeutic strategy aimed at disrupting harmful cancer-nerve crosstalk.
    DOI:  https://doi.org/10.1101/2025.08.26.672505
  10. Cancer Res. 2025 Sep 05.
    Lipid Composition Alters Ferroptosis Sensitivity.
    Vivian S Park, Lauren E Pope, Justin P Ingram, Grace A Alchemy, Julie J Purkal, Magdalena B Murray, Sha Jin, Eli Y Andino-Frydman, Sanjana Singh, Anlu Chen, Priya Narayanan, Sarah Kongpachith, Darren C Phillips, Scott J Dixon, Relja Popovic.
      Ferroptosis is a regulated non-apoptotic cell death process characterized by iron-dependent lipid peroxidation. Peroxidation of polyunsaturated fatty acid-containing phospholipids (PUFA-PLs) is necessary for the execution of ferroptosis. Glutathione peroxidase 4 (GPX4) suppresses ferroptosis by reducing lipid hydroperoxides to lipid alcohols. GPX4 may be a useful target for drug development, highlighting the need to identify factors that govern GPX4 inhibitor sensitivity. Here, we found that reduced GPX4 expression was sufficient to induce ferroptosis in multiple adherent (2D) cancer cell cultures. However, lower GPX4 protein levels did not consistently affect tumor xenograft growth in mice. Culturing cells as spheroids (3D) was sufficient to reduce sensitivity to pharmacological GPX4 inhibition. Mechanistically, growth in 3D versus 2D conditions upregulated expression of the monounsaturated fatty acid (MUFA) biosynthetic gene stearoyl-CoA desaturase (SCD), altering the ratio of MUFA-PLs to PUFA-PLs in a direction favoring ferroptosis resistance. Similar shifts in MUFA-PL to PUFA-PL ratios were observed in xenograft tumors. Thus, lipidome remodeling in 3D growth conditions and in vivo may limit GPX4 inhibitor efficacy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-4207
  11. Eur J Transl Myol. 2025 Sep 02.
    Cardiac wasting is not cardiac cachexia: the problem of the subjective/objective genitive in matters of the heart.
    Anna Luisa Mazzotti, Medhi Hassani, Zhenlin Li, Denise Paulin, Onnik Agbulut, Dario Coletti.
      Tessitore, Costelli et al. were among the first to report a previously unnoticed loss of heart mass in cachectic mice suffering from a severe tumor burden. At the time both the general consensus definition of cachexia and the cancer cachexia classification did not exist. In particular, cancer cachexia is a syndrome characterized by muscle wasting leading to body weight loss in the presence of cancer. More recently, Zhou et al. highlighted once more the existence of a tumor-induced loss of heart mass in a murine model of cancer cachexia. This study generated a new line of research aimed at exploring the mechanisms underlying cardiac wasting in the presence of cancer. Cardiac wasting in the presence of cancer-induced cachexia is distinct from and other than cardiac cachexia, i.e. the atrophy of skeletal muscle induced by cardiac pathologies. However, over the years we have noticed that expressions such as "cardiac cachexia", "cardiac atrophy", and "muscle cachexia"  - that sound alike but are very different - are often mistakenly used. In particular, we are afraid that these misunderstandings may suggest to inexperienced readers that cardiac cachexia is a form of cardiac muscle atrophy, which is not. To add insult to injury, some authors use the expression "muscle cachexia" meaning muscle atrophy, which, as a consequence, may suggest to naive readers that cardiac cachexia is a form of cardiac muscle atrophy. We aim here to clarify the terminology describing these conditions, so as to avoid the misleading use of related expressions: cardiac atrophy and cardiac cachexia may sound alike but are very different. In particular, it is the expression "cardiac cachexia" that raises a problem of ambiguity and should be handled with care.
    DOI:  https://doi.org/10.4081/ejtm.2025.14147
  12. Neuron. 2025 Sep 03. pii: S0896-6273(25)00524-0. [Epub ahead of print]113(17): 2760-2790
    Entangled cellular and molecular relationships at the sensory neuron-cancer interface.
    Debpali Sur, Yi Zeng, Hiroki Kobayashi, Xiaofei Zhi, Mara R Goetz, Clara M Müller, Anastasia-Maria Zavitsanou, Caroline C Picoli, Andre A Martel Matos, Javier Pareja, Brajesh K Savita, Taeho Lee, Jair P Cunha-Junior, Jaime Henrique Amorim, Amin Reza Nikpoor, Alissa Dory, Ajitha Thanabalasuriar, Pedro A F Galante, Vincent T Ma, Aaron W James, Andrew J Shepherd, Madeleine J Oudin, Yuri L Bunimovich, Nicole N Scheff, Nisha J D'Silva, Karen O Dixon, Ishmail Abdus-Saboor, Timothy C Wang, Sebastien Talbot, Alexander Birbrair.
      Peripheral sensory neurons, once regarded merely as a passive route for nociceptive signals, are now acknowledged as active participants in solid tumor progression. This review explores how sensory neurons influence and are influenced by the tumor microenvironment (TME) through both chemical and electrical signaling, underscoring their pivotal role in the emerging field of cancer neuroscience. We summarize recent findings indicating that cancer-neuron interactions vary among different organs and experimental models, highlighting the ways in which various tumors recruit and reprogram sensory neurons to establish mutual communication loops that foster malignancy. Clinically, the degree of sensory innervation and the level of neuropeptide signaling show promise as diagnostic and prognostic biomarkers, while targeting these pathways may enhance the efficacy of standard cancer treatments. This review also highlights current knowledge gaps and proposes future research directions aimed at disrupting sensory neuron-tumor interactions, with the ultimate goal of improving clinical outcomes across multiple cancer types.
    Keywords:  cancer neuroscience; cancer progression; context-dependent roles; sensory neurons; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.neuron.2025.07.017
  13. Nat Biomed Eng. 2025 Sep 02.
    Fluid shear stress activates a targetable mechano-metastatic cascade to promote medulloblastoma metastasis.
    Hyun-Kee Min, Hongyu Zhao, Alexander Bahcheli, Peng Pan, Jade Chan, Junsheng Chen, Esther Low, Yuxiao Zhou, Xian Wang, Savo Bajic, Ran Peng, Siyi Wanggou, Qi Yang, Robert Du Yang Zhang, Leiming Wang, Xiufang Ren, Haoyue Qi, Yu Shi, Madeline N Hayes, Brian Ciruna, Jüri Reimand, Xinyu Liu, Xi Huang.
      Biofluid flow generates fluid shear stress (FSS), a mechanical force widely present in the tissue microenvironment. How brain tumour growth alters the conduit of biofluid and impacts FSS-regulated cancer progression is unknown. Dissemination of medulloblastoma (MB) cells into the cerebrospinal fluid initiates metastasis within the central nervous system. Here, by simulating cerebrospinal fluid dynamics based on magnetic resonance imaging of patients with MB, we discover that FSS is elevated at the cervicomedullary junction. MB-relevant FSS promotes metastasis along the mouse spinal cord. Mechanistically, FSS induces metastatic cell behaviours, including weakened cell-substrate adhesion, increased motility, cell clustering and plasma membrane localization of glucose transporter 1 (GLUT1) to enhance glucose uptake. FSS is perceived by the mechanosensitive ion channel PIEZO2, which drives actomyosin contractility-dependent GLUT1 recruitment at the plasma membrane. Genetic targeting of PIEZO2 or pharmacologic inhibition of GLUT1 mitigates metastasis. Collectively, these findings define a targetable FSS-activated mechano-metastatic cascade for the treatment of MB metastasis.
    DOI:  https://doi.org/10.1038/s41551-025-01487-5
  14. Nat Cancer. 2025 Aug 28.
    MIRO2-mediated mitochondrial transfer from cancer cells induces cancer-associated fibroblast differentiation.
    Michael Cangkrama, Huan Liu, Xiaoyu Wu, Josephine Yates, James Whipman, Christoph G Gäbelein, Mai Matsushita, Luca Ferrarese, Sibilla Sander, Francesc Castro-Giner, Simran Asawa, Magdalena K Sznurkowska, Manfred Kopf, Jörn Dengjel, Valentina Boeva, Nicola Aceto, Julia A Vorholt, Sabine Werner.
      Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment that commonly support cancer development and progression. Here we show that different cancer cells transfer mitochondria to fibroblasts in cocultures and xenograft tumors, thereby inducing protumorigenic CAF features. Transplantation of functional mitochondria from cancer cells induces metabolic alterations in fibroblasts, expression of CAF markers and release of a protumorigenic secretome and matrisome. These features promote tumor formation in preclinical mouse models. Mechanistically, the mitochondrial transfer requires the mitochondrial trafficking protein MIRO2. Its depletion in cancer cells suppresses mitochondrial transfer and inhibits CAF differentiation and tumor growth. The clinical relevance of these findings is reflected by the overexpression of MIRO2 in tumor cells at the leading edge of epithelial skin cancers. These results identify mitochondrial transfer from cancer cells to fibroblasts as a driver of tumorigenesis and provide a rationale for targeting MIRO2 and mitochondrial transfer in different malignancies.
    DOI:  https://doi.org/10.1038/s43018-025-01038-6
  15. bioRxiv. 2025 Aug 28. pii: 2025.08.22.671882. [Epub ahead of print]
    MYC-Driven Activation of USP39 Enhances SRSF1 Stability and Promotes PDAC Progression.
    Benteng Ma, Alexander J Kral, Xin Zhang, Neelu Singh, Astrid Deschenes, Paolo Cifani, Youngkyu Park, David A Tuveson, Adrian R Krainer, Ledong Wan.
      Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy primarily driven by oncogenic KRAS signaling. The splicing factor SRSF1 plays a key oncogenic role in PDAC, where its tightly regulated expression constrains KRAS-driven signaling under normal conditions, while its upregulation promotes tumorigenesis. SRSF1 expression is regulated in part by proteostasis. However, the precise mechanisms remain unclear. Here, we identify USP39 as a deubiquitinase that interacts with SRSF1 in an RNA-independent manner and stabilizes it by reducing ubiquitination. USP39 expression is elevated in PDAC tumors and precancerous lesions, and correlates with poor patient survival. USP39 knockdown suppresses PDAC cell proliferation and migration, effects that are partially rescued by SRSF1 overexpression. Mechanistically, we show that MYC directly activates USP39 transcription via E-box motifs within its exon 1b promoter, linking MYC-driven transcriptional regulation to post- translational stabilization of SRSF1. Together, these findings define a MYC-USP39-SRSF1 regulatory axis that integrates transcriptional and post-translational mechanisms in PDAC and highlight USP39 as a potential therapeutic target.
    DOI:  https://doi.org/10.1101/2025.08.22.671882
  16. Cell. 2025 Aug 25. pii: S0092-8674(25)00916-X. [Epub ahead of print]
    Proximity-specific ribosome profiling reveals the logic of localized mitochondrial translation.
    Jingchuan Luo, Stuti Khandwala, Jingjie Hu, Song-Yi Lee, Kelsey L Hickey, Zebulon G Levine, J Wade Harper, Alice Y Ting, Jonathan S Weissman.
      Localized translation broadly enables spatiotemporal control of gene expression. Here, we present LOV-domain-controlled ligase for translation localization (LOCL-TL), an optogenetic approach for monitoring translation with codon resolution at any defined subcellular location under physiological conditions. Application of LOCL-TL to mitochondrially localized translation revealed that ∼20% of human nuclear-encoded mitochondrial genes are translated on the outer mitochondrial membrane (OMM). Mitochondrially translated messages form two classes distinguished by encoded protein length, recruitment mechanism, and cellular function. An evolutionarily ancient mechanism allows nascent chains to drive cotranslational recruitment of long proteins via an unanticipated bipartite targeting signal. Conversely, mRNAs of short proteins, especially eukaryotic-origin electron transport chain (ETC) components, are specifically recruited by the OMM protein A-kinase anchoring protein 1 (AKAP1) in a translation-independent manner that depends on mRNA splicing. AKAP1 loss lowers ETC levels. LOCL-TL thus reveals a hierarchical strategy that enables preferential translation of a subset of proteins on the OMM.
    Keywords:  AKAP1; OXPHOS; cis-element analysis; cotranslational targeting; localized translation; mitochondrial bipartite targeting signal; outer mitochondrial membrane; oxidative phosphorylation; translation-independent mRNA targeting
    DOI:  https://doi.org/10.1016/j.cell.2025.08.002
  17. Cell. 2025 Aug 26. pii: S0092-8674(25)00927-4. [Epub ahead of print]
    Tumors hijack macrophages for iron supply to promote bone metastasis and anemia.
    Yujiao Han, Hirak Sarkar, Zhan Xu, Sereno Lopez-Darwin, Yong Wei, Xiang Hang, Fengshuo Liu, Kimberley Tran, Wei Wang, Jennifer M Miller, Christina J DeCoste, Dylan S Blohm, Robert L Satcher, Xiang H-F Zhang, Yibin Kang.
      Bone marrow is both a primary site for hematopoiesis and a fertile niche for metastasis. The mechanism of the common occurrence of anemia among patients with bone metastasis remains poorly understood. Here, we show that a specialized population of VCAM1+CD163+CCR3+ macrophages, normally essential for erythropoiesis by transporting iron to erythroblasts, are highly enriched in the bone metastatic niche in mouse models. Tumor cells hijack these macrophages for iron supply, reducing iron availability for erythroblasts, impairing erythropoiesis, and contributing to anemia. Increased iron supply enables tumor cells to produce hemoglobin in response to hypoxia, mimicking erythroblasts. We identify macrophages with similar iron-transporting features in human bone metastases and show that elevated HBB expression correlates with increased risk of bone metastasis. These findings establish iron-transporting macrophages as an essential component of the metastatic bone niche, revealing a critical interplay between immune cells, metal metabolism, and tumor cell plasticity in driving metastasis and anemia.
    Keywords:  anemia; bone metastasis; breast cancer; cellular plasticity; erythropoiesis; hypoxia; iron metabolism; macrophage; metastatic niche; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cell.2025.08.013
  18. Pancreas. 2025 Sep 03.
    Nuclear Symmetric Dimethylarginine Staining is Indicative of Pancreatic Ductal Adenocarcinoma.
    Kritisha Bhandari, Sheeja Aravindan, Chao Xu, Kar-Ming Fung, Wei-Qun Ding.
       OBJECTIVE: The protein arginine methyltransferase 5 (PRMT5) is a type II PRMT that is responsible for the majority of symmetric dimethylarginine (SDMA) in eukaryotic cells. While PRMT5 is overexpressed in pancreatic ductal adenocarcinoma (PDAC), the SDMA expression patterns in PDAC tissues have not been examined. This study is aimed to characterize the SDMA expression patterns in PDAC cells and patient tissues.
    METHODS: Tissue microarray (TMA), immunohistochemistry (IHC) of PDAC cell lines and archival PDAC tissue blocks, and western blotting were applied to this study.
    RESULTS: Expression of PRMT5 and SDMA is elevated in PANC-1 and MIA PaCa-2 cells compared with that in the pancreatic ductal HPNE cell line. Pharmacological inhibition of PRMT5 reduces the SDMA level, indicating that PRMT5 is primarily responsible for SDMA in PDAC cells. IHC staining of the TMA containing 158 patient samples demonstrates that nuclear SDMA staining is significantly enhanced in PDAC tissues compared to normal and tumor adjacent tissues. The elevated SDMA level is evident in tissues from patients with early-stage PDAC, which is further verified using the archival PDAC tissue blocks. In addition, the SDMA staining is highly clustered in the Islets of Langerhans of the pancreas, irrespective of the disease states.
    CONCLUSIONS: We demonstrate for the first time that nuclear SDMA staining is significantly enhanced in PDAC tissues and in the Islets of Langerhans of the pancreas, indicating novel tissue IHC markers for PDAC and the endocrine units of the pancreas.
    Keywords:  Islets of Langerhans; Pancreatic ductal adenocarcinoma (PDAC); immunohistochemistry (IHC); protein arginine methyltransferase 5 (PRMT5); symmetric dimethylarginine (SDMA)
    DOI:  https://doi.org/10.1097/MPA.0000000000002509
  19. Cancer Discov. 2025 Sep 04.
    Aryl hydrocarbon receptor ligands drive pancreatic cancer initiation and progression through pro-tumorigenic T cell polarization.
    Brian D Griffith, Padma Kadiyala, Jake McGue, Lei Sun, Aadith Kumar, Carlos E Espinoza, Katelyn L Donahue, Matthew K Iyer, Cameron Speyer, Sarah Nelson, Andrew Spiteri, Ahmed M Elhossiny, Kristee Brown, Holly Attebury, Filip Bednar, Eileen S Carpenter, Ilona Kryczek, Yaqing Zhang, Weiping Zou, Marina Pasca di Magliano, Timothy L Frankel.
      Although smoking is a risk factor for pancreatic adenocarcinoma (PDAC), the underlying mechanism promoting tumorigenesis and progression are unknown. Here, we show that aryl hydrocarbon receptor ligands found in cigarette smoke, like the carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), promote pancreatic dysplasia and PDAC progression in a mouse model of this disease. This effect is mediated by AhR activation in CD4+ T cells, leading to their polarization to interleukin-22 (IL22) producing TH22 cells and to regulatory T cells (Treg) accumulation, ultimately driving a blunted CD8+ T cell effector response. Analysis of human pancreata from organ donors revealed that smokers have increased AhR activation relative to non-smokers. Similarly, PDAC tumors from patients with a history of cigarette smoking presented with increased Treg accumulation compared to non-smokers. These findings support a model whereby AhRLs in cigarette smoke promote tumorigenesis and progression of PDAC through dysregulation of immune responses.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-0377
  20. Proc Natl Acad Sci U S A. 2025 Sep 09. 122(36): e2515009122
    Inflammation awakens dormant cancer cells by modulating the epithelial-mesenchymal phenotypic state.
    Jingwei Zhang, Jingwen Zhang, Longfei Han, Shiyi Wu, Jie Li, Elinor Ng Eaton, Bingbing Yuan, Ferenc Reinhardt, Hao Li, Patrick C Strasser, Sunny Das, Joana Liu Donaher, Md Imtiaz Khalil, Haiping Jiang, Alexander Deuschel, Danni Lin, Carolin Sebastiany, Mariana Maranga, Salomé Shubitidze, Xiaofei Liu, Arthur W Lambert, Yun Zhang, Yana Liu, Lufei Sui, Sarah Elmiligy, Umberto Pozza, Rauf Günsay, Ranjan Mishra, Jose Velarde, Sonia Iyer, Whitney S Henry, Kipp Weiskopf, Guihai Feng, Tobiloba E Oni, Randolph S Watnick, Xin Li, Robert A Weinberg.
      The awakening of dormant disseminated cancer cells appears to be responsible for the clinical relapses of patients whose primary tumors have been successfully cured months and even years earlier. In the present study, we demonstrate that dormant breast cancer cells lodged in the lungs reside in a highly mesenchymal, nonproliferative phenotypic state. The awakening of these cells is not triggered by a cancer cell-autonomous process. Instead, lung inflammation induced by the chemotherapeutic agent bleomycin effectively awakens dormant cancer cells, providing useful models for studying metastatic awakening. Mechanistically, the awakened cells shift from a highly mesenchymal to a quasi-mesenchymal phenotypic state in which they acquire tumorigenicity and proliferative ability. Once awakened, these cells can stably reside in this quasi-mesenchymal state and maintain their tumor-initiating ability, doing so without ongoing heterotypic signaling from the lung microenvironment. Epidermal growth factor receptor ligands released by the cells of the injured tissue microenvironment, including notably M2 type macrophages, promote dormant cancer cells to move toward this quasi-mesenchymal state, a transition that is critical for the awakening process. An understanding of the mechanisms of metastatic awakening may lead in the future to treatment strategies designed to prevent such awakening and resulting metastatic relapse.
    Keywords:  breast cancer; cancer dormancy and awakening; cancer metastasis; epithelial–mesenchymal transition; tumor microenvironment
    DOI:  https://doi.org/10.1073/pnas.2515009122
  21. Trends Biotechnol. 2025 Aug 29. pii: S0167-7799(25)00316-6. [Epub ahead of print]
    Targeting RAS-mutant cancer cells using a synthetic RAS-activated cancer killing system.
    Fei Teng, Qingqin Gao, Li Zhou, Tongtong Cui, Xiangtian Tan, Yali Ding, Rongqi Li, Bojin Li, Bei Zhong, Miao Miao, Qi Zhou, Wei Li.
      Despite being the most commonly mutated proteins in cancer, oncogenic RAS proteins remain largely untapped as pharmacological targets. Here, we report a synthetic cancer-killing platform, termed 'RAS-activated cancer killing (RACK)' system. Leveraging a transcriptional sensor designed to detect oncogenic RAS signals with high specificity, RACK achieves targeted identification and elimination of RAS-mutant cancer cells. RACK can potently target a range of RAS and non-RAS mutants, including, but not limited to KRAS, NRAS, BRAF, and RTKs. Notably, RACK can maintain its efficacy against cancer cells that have developed acquired resistance, outperforming conventional inhibitors. In vivo, RACK selectively inhibits RAS-mutant tumor growth in xenograft models, including those intractable by allele-specific inhibitors. Furthermore, the modular design of RACK allows rational optimization of promoter inputs and therapeutic outputs. Collectively, RACK introduces a pioneering drug approach for detecting and treating RAS-mutant cancers, paving the way for overcoming challenges associated with currently undruggable cancer targets.
    Keywords:  AAV; RACK; cancer gene therapy; synthetic promoter; transcriptional sensor
    DOI:  https://doi.org/10.1016/j.tibtech.2025.07.031
  22. STAR Protoc. 2025 Aug 28. pii: S2666-1667(25)00455-1. [Epub ahead of print]6(3): 104049
    Protocol for plasma membrane enrichment by ultracentrifugation for mass spectrometry of cell lines, xenografts, and patient tumors.
    Amber K Hamilton, Brian Mooney, Tina Glisovic-Aplenc, Alexander B Radaoui, Karina L Conkrite, Caitlyn De Jong, Simone Sidoli, Poul H Sorensen, Benjamin A Garcia, Richard Aplenc, John M Maris, Gregg B Morin, Sharon J Diskin.
      The success of immunotherapies hinges on identifying targetable cell surface proteins expressed in the cancer of interest. Here, we present a protocol for enriching plasma membrane proteins for mass spectrometry analysis using a density gradient ultracentrifugation approach. We describe steps for cell lysis, membrane isolation, and preparation for downstream analysis. This protocol is applicable to cell lines, cell-/patient-derived xenografts (CDX/PDX), and primary tissues. For complete details on the use and execution of this protocol, please refer to Glisovic-Aplenc et al.,1 Hamilton et al.,2 and Mooney et al.3.
    Keywords:  Cancer; Cell Biology; Cell Membrane; Clinical Protocol; Immunology; Mass Spectrometry; Protein Biochemistry; Proteomics; Structural Biology
    DOI:  https://doi.org/10.1016/j.xpro.2025.104049
  23. Nat Med. 2025 Sep 02.
    Targeting dormant tumor cells to prevent recurrent breast cancer: a randomized phase 2 trial.
    Angela DeMichele, Amy S Clark, Emily Shea, Lauren J Bayne, Christopher J Sterner, Killian Rohn, Samantha Dwyer, Tien-Chi Pan, Isoris Nivar, Yan Chen, Paul Wileyto, Lindsay R Berry, Shannon Deluca, Jessica Savage, Igor Makhlin, Dhruv K Pant, Heather Martin, Adetutu Egunsola, Nathan Mears, Brooke L Goodspeed, Elizabeth M Chislock, Jewell Graves, Jianping Wang, Natalie Shih, George K Belka, Don Berry, Anupma Nayak, Michael Feldman, Lewis A Chodosh.
      Breast cancer recurrence may arise from dormant disseminated tumor cells (DTCs) that persist in bone marrow and other sites. Clinically, DTCs are independently associated with breast cancer recurrence and death. Preclinical studies in mouse models identified autophagy and mammalian target of rapamycin (mTOR) signaling as critical mechanisms of tumor dormancy and escape. We subsequently tested the effects of transient versus chronic inhibition of autophagy with chloroquine or hydroxychloroquine (HCQ) and mTOR signaling with rapamycin (RAPA) or everolimus (EVE) on residual tumor cell (RTC) burden and recurrence-free survival (RFS). In mice harboring dormant RTCs, inhibition of mTOR alone or in combination with autophagy inhibition decreased RTC burden and improved RFS in a duration-dependent manner. RTC number was strongly and inversely correlated with RFS, suggesting that RTC reduction mediated an improvement in RFS. To translate findings clinically, we performed a randomized phase 2 trial (CLEVER) of HCQ, EVE or their combination in breast cancer survivors within 5 years of diagnosis who had detectable DTCs on bone marrow aspirate. Primary endpoints were feasibility and safety; secondary endpoints included DTC reduction/clearance and RFS. In total, 51 DTC+ patients initiated HCQ (n = 15), EVE (n = 15) or HCQ + EVE (n = 21). Treatment was feasible and tolerable; only one patient discontinued early for grade 3 toxicity. At 42 months median follow-up, landmark 3-year RFS for HCQ, EVE and HCQ + EVE was 91.7%, 92.9% and 100%, respectively, and was greater in those who cleared DTCs versus those who did not (hazard ratio (HR) = 0.21 (95% confidence interval 0.01-3.4)). Posterior probabilities were 98-99.9% that three cycles of HCQ, EVE or HCQ + EVE led to reduced or undetectable DTCs compared to observation alone, with estimated DTC reductions of 80%, 78% and 87%, respectively. These findings provide proof-of-concept that targeting dormant RTCs with HCQ, EVE or their combination in breast cancer survivors or mouse models depletes minimal residual disease, warranting a definitive human randomized controlled trial. ClinicalTrials.gov registration: NCT03032406 .
    DOI:  https://doi.org/10.1038/s41591-025-03877-3
  24. Nat Aging. 2025 Sep 02.
    Nerve-associated macrophages control adipose homeostasis across lifespan and restrain age-related inflammation.
    Elsie Gonzalez-Hurtado, Claire Leveau, Keyi Li, Manish Mishra, Rihao Qu, Emily L Goldberg, Sviatoslav Sidorov, Payal Damani-Yokota, Stephen T Yeung, Camille Khairallah, David Gonzalez, Taverlyn M Shepard, Christina Camell, Maxim N Artyomov, Yuval Kluger, Kamal M Khanna, Vishwa Deep Dixit.
      Age-related inflammation or 'inflammaging' increases disease burden and controls lifespan. Adipose tissue macrophages (ATMs) are critical regulators of inflammaging; however, the mechanisms involved are not well understood in part because the molecular identities of niche-specific ATMs are unknown. Using intravascular labeling to exclude circulating myeloid cells followed by single-cell sequencing with orthogonal validation via multiparametric flow cytometry, we define sex-specific changes and diverse populations of resident ATMs through lifespan in mice. Aging led to depletion of vessel-associated macrophages, expansion of lipid-associated macrophages and emergence of a unique subset of CD38+ age-associated macrophages in visceral adipose tissue with inflammatory phenotype. Notably, CD169+CD11c- ATMs are enriched in a subpopulation of nerve-associated macrophages (NAMs) that declines with age. Depletion of CD169+ NAMs in aged mice increases inflammaging and impairs lipolysis suggesting catecholamine resistance in visceral adipose tissue. Our findings reveal NAMs are a specialized ATM subset that control adipose homeostasis and link inflammation to tissue dysfunction during aging.
    DOI:  https://doi.org/10.1038/s43587-025-00952-9
  25. Cancer Res. 2025 Sep 03.
    MYC and p53 Alterations Cooperate through VEGF Signaling to Repress Cytotoxic T Cell and Immunotherapy Responses in Prostate Cancer.
    Katherine C Murphy, Kelly D DeMarco, Lin Zhou, Jessica Peura, Hadiya K Giwa, Yvette Lopez-Diaz, Yu-Jui Ho, Junhui Li, Shi Bai, Karl Simin, Lihua J Zhu, Jason R Pitarresi, Arthur M Mercurio, Marcus Ruscetti.
      Patients with castration-resistant prostate cancer (CRPC) are generally unresponsive to tumor targeted treatments and immunotherapies. Genetic alterations acquired during the evolution of CRPC may impact anti-tumor immunity and immunotherapy responses, which could inform personalized therapeutic strategies. Using our innovative electroporation-based mouse models, we generated distinct genetic subtypes of CRPC found in patients and uncovered unique immune microenvironments. Specifically, mouse and human prostate tumors with MYC amplification and p53 disruption had weak cytotoxic lymphocyte infiltration and an overall dismal prognosis. MYC and p53 cooperated to induce tumor intrinsic secretion of VEGF, which signaled through VEGFR2 expressed on CD8+ T cells to directly inhibit T cell migration and effector functions. Targeting VEGF-VEGFR2 signaling in vivo remodeled the immune suppressive prostate tumor microenvironment, leading to CD8+ T cell-mediated primary tumor and metastasis growth suppression and significantly increased overall survival in MYC and p53 altered CPRC. VEGFR2 blockade also led to induction of PD-L1 in tumors and produced anti-tumor efficacy in combination with PD-L1 immune checkpoint blockade in multiple preclinical CRPC mouse models. Thus, these results identify a genetic mechanism of immune suppression through VEGF signaling in prostate cancer that can be targeted to reactivate immune and immunotherapy responses in an aggressive subtype of CRPC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-2532
  26. bioRxiv. 2025 Aug 25. pii: 2025.08.21.671520. [Epub ahead of print]
    FSP1 and histone deacetylases suppress cancer persister cell ferroptosis.
    Masayoshi Higuchi, August F Williams, Anna E Stuhlfire, Ariel H Nguyen, David A G Gervasio, Claire E Turkal, Suejean Chon, Matthew J Hangauer.
      Cancer persister cells populate minimal residual disease and contribute to acquired drug resistance. We previously discovered that persister cells are sensitized to ferroptosis. However, our understanding of this emergent persister cell vulnerability remains limited, impeding ferroptosis drug development efforts. Here, we sought to understand key factors which govern persister cell ferroptosis to inform combinatorial treatment strategies. We found that persister cells can downregulate oxidative phosphorylation, a key source of reactive oxygen species, to avoid death from GPX4 inhibition. However, this can be overcome by pretreatment with clinically available histone deacetylase inhibitors which induce reactive oxygen species in persister cells and synergize with GPX4 inhibition. Furthermore, we found that while levels of iron, glutathione, and antioxidant genes are not universally dysregulated in persister cells, persister cells consistently downregulate alternative ferroptosis suppressor FSP1 and rely upon residual FSP1 to survive GPX4 inhibition. These findings reveal new strategies to eliminate persister cells by combining GPX4 inhibitors with histone deacetylase or FSP1 inhibitors.
    DOI:  https://doi.org/10.1101/2025.08.21.671520
  27. Life Sci Alliance. 2025 Nov;pii: e202503324. [Epub ahead of print]8(11):
    Differential cell survival outcomes in response to diverse amino acid stress.
    Marion Russier, Alessandra Fiore, Ana Bici, Annette Groß, Maria Tanzer, Assa Yeroslaviz, Matthias Mann, Peter J Murray.
      Amino acid (AA) detection is fundamental for cellular function, balancing translation demands, biochemical pathways, and signaling networks. Although the GCN2 and mTORC1 pathways are known to regulate AA sensing, the global cellular response to AA deprivation remains poorly understood, particularly in non-transformed cells, which may exhibit distinct adaptive strategies compared with cancer cells. Here, we employed murine pluripotent embryonic stem (ES) cells as a model system to dissect responses to AA stress. Using multi-omics analyses over an extended time course, we examined the effects of arginine (Arg) and leucine (Leu) deprivation. We uncovered a broad array of proteomic, phosphoproteomic, transcriptomic, and metabolomic adaptations, including an increase in lysosome production, all occurring without lethality. We found that Arg or Leu starvation induces reversible cell cycle exit, promoting a quiescent state that enhances resistance to cytotoxic stressors. In contrast, cysteine (Cys) and threonine (Thr) deprivation led to cell death via distinct pathways: ferroptosis for Cys starvation, whereas Thr deprivation triggered a previously uncharacterized form of cell death, which could be entirely suppressed by methionine (Met) co-starvation, and mTOR or translational inhibition. These findings suggest that ES cells implement specialized survival strategies in response to different AA limitations, highlighting their ability to reprogram cellular biochemistry under nutrient stress.
    DOI:  https://doi.org/10.26508/lsa.202503324
  28. bioRxiv. 2025 Aug 30. pii: 2025.08.27.672666. [Epub ahead of print]
    Processing bodies promote lysosomal quality control and cell survival during recovery from lysosomal damage.
    Jingyue Jia, 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/10.1101/2025.08.27.672666
  29. Adv Sci (Weinh). 2025 Aug 30. e09861
    Hypoxia-Induced PRMT1 Lactylation Drives Vimentin Arginine Asymmetric Dimethylation in Tumor Metastasis.
    Jia Zhou, Shuying Qiu, Xia Yang, Yan Wu, Xinxia Yao, Hangqi Hu, Jingfeng Luo, Chandra Sugiarto Wijaya, Lingfeng Ma, Xiaojun Long, Lingna Xu, Jinquan Liu, Chaoqun Wang, Yibin Pan, Xiaona Chen, Hongchuan Jin, Xian Wang.
      Metastasis contributes to around 90% of cancer mortality, but effective strategies to disrupt metastatic cascades remain elusive. Hypoxia-driven epithelial-mesenchymal transition (EMT) promotes cancer cell spread, yet the post-translational mechanisms governing cytoskeletal reprogramming here remain incompletely defined. This study reports a hypoxia-inducible post-translational modification cascade: under hypoxia, protein arginine methyltransferase 1 (PRMT1) is lactylated at evolutionarily conserved residues K134/K145, enhancing its methyltransferase activity to catalyze the asymmetric dimethylation (aDMA) of vimentin at R64. This modification drives vimentin filament assembly, cytoskeletal remodeling, and metastasis in preclinical models. shPRMT1 or vimentin R64K mutation (methylation-deficient) abrogates hypoxia-enhanced migration in vitro and metastasis in vivo. Hypoxia reduces the protein levels of HDAC8 (PRMT1's delactylase), boosting PRMT1 lactylation. PRMT1 K134R/K145R mutants (lactylation - deficient) lose the ability to bind vimentin and fail to rescue filament formation. In triple-negative breast cancer (TNBC), vimentin R64 aDMA levels correlate with advanced tumor stage and poor patient survival. PRMT1 inhibitor MS023 reduces xenograft metastasis with low toxicity. These findings establish a hypoxia-PRMT1-vimentin axis, identifying vimentin R64 aDMA as a metastatic regulator. Inhibiting PRMT1 represents a promising anti-metastasis strategy.
    Keywords:  PRMT1; arginine methylation; cancer metastasis; hypoxia; lactylation; vimentin
    DOI:  https://doi.org/10.1002/advs.202509861
  30. JCO Precis Oncol. 2025 Sep;9 e2500332
    Open-Label, Phase II Trial of Extracellular Regulated Kinase Inhibition Alone and in Combination With Autophagy Inhibition in Patients With Metastatic Pancreatic Cancer.
    Rishi Surana, Micaela Morgado, Ashwin Somasundaram, Bruno Bockorny, Colin D Weekes, Emma C Coleman, Alexandra Bird, Junning Wang, Hannah L Williams, Hui Zheng, Lauren K Brais, Neetu Saxena, Christopher Graham, Lauren Ritterband, Mark Sawin, Mary Linton Peters, Peter Whooley, Andrea Bullock, Jessica Zerillo, Hanna K Sanoff, Jeffrey W Clark, Aparna R Parikh, Matthew B Yurgelun, Anuj K Patel, Robert J Mayer, James M Cleary, Peter Enzinger, Douglas A Rubinson, Nadine J McCleary, Andrea Enzinger, Sarah Slater, Kimmie Ng, Leah H Biller, Thomas A Abrams, Brandon M Huffman, Harshabad Singh, Srivatsan Raghavan, Joseph D Mancias, Kirsten L Bryant, Jonathan O Nowak, Andrew J Aguirre, Channing J Der, Brian M Wolpin, Kimberly Perez.
       PURPOSE: Oncogenic mutations in Kirsten rat sarcoma virus are present in over 90% of pancreatic ductal adenocarcinomas (PDACs). Preclinical data suggest that PDAC cells treated with inhibitors of the mitogen-activated protein kinase pathway demonstrate elevated autophagic flux. In this study, we evaluate the clinical efficacy of combining LY3214996 (extracellular regulated kinase inhibitor) with hydroxychloroquine (HCQ; autophagy inhibitor) in patients with metastatic PDAC.
    METHODS: Eligible patients had metastatic PDAC and at least one, but no more than two prior lines of systemic therapy. A safety lead-in evaluating the combination was conducted and the maximum tolerated dose level of LY3214996 was identified. Patients were then randomly assigned in a 1:1 fashion to receive either LY3214996 200 mg orally (PO) once daily + HCQ 600 mg PO twice a day (arm 1) or LY3214996 400 mg PO once daily (arm 2). The primary end point for this study was disease control rate (DCR). Secondary end points included overall survival (OS) and progression-free survival (PFS).
    RESULTS: Thirty-nine patients enrolled (20 in arm 1, 19 in arm 2). The DCR rates were 5% in arm 1 and 5.3% in arm 2. The median OS was 2.4 months in arm 1 (95% CI, 1.3 to 5.8) and 4.6 months in arm 2 (95% CI, 3.1 to 5.7). The median PFS was 1.3 months in arm 1 (95% CI, 0.8 to 1.8) and 1.9 months in arm 2 (95% CI, 1.644 to 2.4). The most frequently observed toxicities in both arms included nausea, diarrhea, elevated creatine phosphokinase, anorexia, and cytopenias. Exploratory analysis using patient-derived PDAC organoids did not show evidence of synergistic antiproliferative activity of LY3214996 in combination with chloroquine.
    CONCLUSION: LY3214996 alone or in combination with HCQ did not result in clinical activity in patients with metastatic PDAC.
    DOI:  https://doi.org/10.1200/PO-25-00332
  31. Cell Rep Methods. 2025 Aug 26. pii: S2667-2375(25)00184-5. [Epub ahead of print] 101148
    Feature-driven whole-tissue imaging with subcellular resolution.
    Jinlong Lin, Zach Marin, Xiaoding Wang, Hazel M Borges, Qionghua Shen, Pierre-Emmanuel Y N'Guetta, Xuemei Luo, Baylee A Porter, Yuanyuan Xue, Md Torikul Islam, Tai Ngo, Doreen Idonije, Seweryn Gałecki, Arin B Aurora, Hu Zhao, Suzanne D Conzen, Sean J Morrison, Shuang Liang, Zhenyu Zhong, Lori L O'Brien, Kevin M Dean.
      Existing microscopy approaches are often unable to identify and contextualize rare but biologically meaningful events due to limitations associated with simultaneously achieving both high-resolution imaging and a cm-scale field of view. Here, we present multiscale cleared tissue axially swept light-sheet microscopy (MCT-ASLM), a platform combining cm-scale imaging with targeted high-resolution interrogation of intact tissues in human-guided or autonomous modes. Capable of capturing fields of view up to 21 mm at micron-scale resolution, MCT-ASLM can seamlessly transition to a targeted imaging mode with an isotropic resolution that approaches ∼300 nm. This versatility enables detailed studies of hierarchical organization and spatially complex processes, including mapping neuronal circuits in rat brains, visualizing glomerular innervation in mouse kidneys, and examining metastatic tumor microenvironments. By bridging subcellular- to tissue-level scales, MCT-ASLM offers a powerful method for unraveling how local events contribute to global biological phenomena.
    Keywords:  CP: Imaging; LSFM; cancer; development; feature-driven cleared tissue imaging; multiscale ASLM; neuroscience
    DOI:  https://doi.org/10.1016/j.crmeth.2025.101148
  32. Adv Exp Med Biol. 2025 ;1478 113-153
    Muscle Proteome Dynamics.
    Connor A Stead, Aaron Thomas, Yusuke Nishimura, Marjan Abbasi, Jennifer Barrett, Jatin G Burniston.
      Skeletal muscle demonstrates remarkable malleability and can alter in metabolic and contractile properties in response to changes in environmental stimuli, in particular contractile work. The muscle proteome defines muscle by dictating its functional characteristics and coordinating its adaptive responses to external stimuli. The dynamic aspects of the proteome have not yet been widely studied and most current proteomic data chart changes to the abundance profile or post-translational state of proteins during the process of adaptation. Nevertheless, the proteome is a dynamic entity. Proteins exist in a constant cycle of renewal, known as protein turnover, which is essential to maintain the quality of the proteome and to facilitate adaptation. Adaptation is only possible because proteins exist in a flux of synthesis and degradation. Furthermore, synthesis and degradation are each highly regulated processes and, in themselves, change in response to stimuli. Isotope tracers are required to study proteome dynamics, and stable isotopes, such as deuterium that impart a mass tag to newly synthesised proteins, are ideally suited to mass spectrometry-based proteomic analyses. New proteomic methods are now emerging that simultaneously measure the abundance and synthesis rate of large numbers of individual proteins. This chapter provides an overview of developments in this field.
    Keywords:  Deuterium oxide; Mass spectrometry; Muscle protein synthesis; Proteomics; Proteostasis; Stable isotopes
    DOI:  https://doi.org/10.1007/978-3-031-88361-3_7
  33. Nat Commun. 2025 Sep 01. 16(1): 8160
    Capillary constrictions prime cancer cell tumorigenicity through PIEZO1.
    Giulia Silvani, Chantal Kopecky, Sara Romanazzo, Vanina Rodríguez, Ayan Das, Elvis Pandzic, John G Lock, Christine L Chaffer, Kate Poole, Kristopher A Kilian.
      Metastasis is responsible for most cancer-related deaths. However, only a fraction of circulating cancer cells succeed in forming secondary tumours, indicating that adaptive mechanisms during circulation play a part in dissemination. Here, we report that constriction during microcapillary transit triggers reprogramming of melanoma cells to a tumorigenic cancer stem cell-like state. Using a microfluidic device mimicking physiological flow rates and gradual capillary narrowing, we show that compression through narrow channels causes cell and nuclear deformation, rapid chromatin remodelling and increased calcium signalling via mechanosensor PIEZO1. Within minutes, cells upregulate transcripts associated with metabolic reprogramming and metastatic processes. Over time, this results in the stable adoption of a cancer stem cell-like state. Squeezed cells express elevated melanoma stem cell markers, exhibit increased trans-endothelium invasion and display enhanced tumorigenicity in vitro and in vivo. Pharmacological inhibition of PIEZO1 blocks this transition, while activation with Yoda1 induces the stem cell-like state irrespective of constriction. Deletion of PIEZO1 completely abolishes the constriction-induced phenotype. Together, these findings demonstrate that compressive forces during circulation reprogram circulating cancer cells into tumorigenic, stem cell-like states, primed for extravasation and metastatic colonization.
    DOI:  https://doi.org/10.1038/s41467-025-63374-6
  34. Cancer Res. 2025 Aug 29.
    MYADM Activates RhoA-Mediated Amoeboid Migration to Drive Metastasis.
    Yi-Ta Tsai, En-Ting Liu, Ming-Hsin Yang, Chien Chang Kao, Sheue-Fen Tzeng, Yu-Chi Chen, Pei-Wen Hsiao, An-Chieh Feng, Grace S Shieh, Mong-Hsun Tsai, Shau-Kwaun Chen, Yi-Lin Chiu, Chin Li Chen, Sheng-Tang Wu, En Meng, Wen-Chiuan Tsai, Tai-Kuang Chao, Guang-Huan Sun, Sun-Yran Chang, Mien-Chie Hung, Tai-Lung Cha.
      Metastasis, the leading cause of cancer-related mortality, remains the most critical challenge in cancer treatment. Cancer cells can adopt amoeboid migration to facilitate metastasis, highlighting the need elucidate the molecular pathways regulating the amoeboid migration phenotype. Here, we identified that MYADM, a transmembrane protein expressed during myeloid cell maturation, enabled cancer cells to acquire amoeboid migration plasticity, promoting metastasis and contributing to poor patient outcomes. Cancer cells exploited MYADM-mediated adhesion and migration to mimic leukocyte trafficking. By interacting with RhoGDI, MYADM activated RhoA-mediated leukocyte trafficking-associated genes (LTAG) enrichment, invasiveness, membrane blebbing, and anoikis resistance. MYADM modulated chromatin accessibility (CA)-regulatory genes, influencing intermediate filament cytoskeleton dynamics of cancer cells and tumor tissues. MYADM loss in cancer cells triggered CA-driven death signaling, blocking metastasis, which was not observed in monocytes. These findings position MYADM as a potential therapeutic target to disrupt metastasis, offering avenues for clinical intervention.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-0006
  35. Proc Natl Acad Sci U S A. 2025 Sep 09. 122(36): e2427125122
    Lysosomal reduced thiols are essential for mouse embryonic development.
    Charles H Adelmann, Avanthika Venkatachalam, Lingjuan Huang, Michelle Liu, Sharon Germana, Stefan A Harry, Paul C Rosen, Joshua Herron, Pei-Chieh Tien, Liron Bar-Peled, David M Sabatini, David E Fisher.
      While it has been appreciated for decades that lysosomes can import cysteine, its significance for whole-organism physiology has remained uncertain. Recent work identified MFSD12 as a transmembrane protein required for cysteine import into lysosomes (and melanosomes), enabling genetic interrogation of this pathway. Here, we show that Mfsd12 knockout mice die between embryonic days 10.5 and 12.5, indicating that MFSD12 is essential for organogenesis. Mfsd12 loss results in the expression of genes involved in cellular stress and thiol metabolism and likely disproportionately affects the erythroid, myeloid, and neuronal lineages. Within lysosomes, imported cysteine is largely oxidized to cystine, which is exported to the cytosol by the cystinosin (CTNS) transporter. However, unlike Mfsd12, loss of Ctns is compatible with viability, suggesting that the essential role of MFSD12 lies not in supplying cystine to the cytosol, but in providing reduced cysteine within the lysosomal lumen. Supporting this model, maternal treatment with cysteamine-a lysosome-penetrant thiol-rescued the development of Mfsd12 knockout embryos, yielding viable adult offspring. These findings establish lysosomal thiol import as a critical metabolic pathway and provide genetic tools to further clarify its physiological and biochemical roles.
    Keywords:  MFSD12; cysteine; lysosome; redox
    DOI:  https://doi.org/10.1073/pnas.2427125122
  36. Cancer Res. 2025 Sep 05.
    Molecular Magnetic Resonance Imaging of Dysregulated Zinc Secretion Detects Pancreatic Ductal Adenocarcinoma Lesions and Response to KRASG12D Inhibitor Treatment.
    Veronica Clavijo Jordan, Mozhdeh Sojoodi, Farzad Moloudi, Patricia Gonzalez-Pagan, Manyu Jin, Pamela Pantazopoulos, Ethan French, Ibrahim Eissa, Jonah Weigand-Whittier, Nicholas Rotile, Mehrad Tavallai, Jill Hallin, Ian Ramsay, Eric M Gale, Stephen C Barrett, Nabeel El-Bardeesy, Stuti Shroff, Motaz Qadan, Kenneth K Tanabe, Peter Caravan.
      Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, primarily due to late-stage diagnosis and limited treatment options. Zinc homeostasis is markedly dysregulated in PDAC, and this dysregulation can be probed by administering a secretagogue to stimulate zinc secretion (SSZS) in the exocrine pancreas and imaging with a zinc sensitive magnetic resonance imaging (MRI) probe. This study demonstrated the potential of SSZS MRI for sensitive detection, monitoring treatment response, and assessing recurrence after treatment withdrawal in PDAC. The approach relied on interrogating the pancreas, circumventing the challenge of locating small, elusive tumors. SSZS MRI enabled PDAC detection by observing the unique zinc hypersecretory activity of the pancreas when malignancy was present. PDAC led to dysregulation of zinc transporters in both human and mouse pancreas. Combining secretagogues such as secretin and caerulein maximized zinc secretion and MRI signal in the pancreas. Notably, SSZS MRI detected treatment responses to KRASG12D inhibition within 3-5 days and identified cancer recurrence as early as one day post-treatment withdrawal. Additionally, secretagogue stimulation improved treatment responses and delayed recurrence in both treatment models. These findings suggest that SSZS MRI could significantly enhance PDAC diagnosis and management, providing an imaging modality that can help to optimize patient outcomes.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-3384
  37. Cell Rep. 2025 Sep 01. pii: S2211-1247(25)00922-2. [Epub ahead of print]44(9): 116151
    Cancer cell and microenvironmental rewiring by ADAR1 loss impairs glioblastoma tumor growth and extends survival.
    Ángel F Álvarez-Prado, Alberto Hernández-Barranco, Livia Rentsch, Catia F Costa, Johanna A Joyce.
      Glioblastomas are the most frequent and aggressive primary brain tumors. Current treatments invariably fail, a consequence of the pronounced heterogeneity and plasticity of glioblastoma cells, as well as the contribution of an immunosuppressive microenvironment that promotes tumor progression and resistance to therapy. Here, we exploited an innate immunity checkpoint, RNA sensing, to simultaneously target cancer cells and their supporting microenvironment. Using various immunocompetent mouse models of glioblastoma, we found that genetic deletion of adenosine deaminase acting on RNA 1 (Adar1), a key regulator of the RNA-sensing pathway, resulted in significantly reduced tumor growth and prolonged survival. Mechanistically, these effects were mediated by two processes: cancer-cell-intrinsic responses and reprogramming of the immune microenvironment that fostered a pro-inflammatory, anti-tumoral state via type I interferon signaling. These findings establish proof of concept for the therapeutic potential of targeting ADAR1 in glioblastoma, offering new strategies for the treatment of this aggressive disease.
    Keywords:  ADAR1; CP: Cancer; PKR; RNA sensing; T lymphocytes; glioblastoma; macrophages; tumor microenvironment; type I interferon
    DOI:  https://doi.org/10.1016/j.celrep.2025.116151
  38. bioRxiv. 2025 Aug 23. pii: 2025.08.12.670003. [Epub ahead of print]
    Genetically encoded tool for manipulation of ATP/ADP ratio in human cells.
    Alex E Ekvik, Megan M Kober, Denis V Titov.
      The ability of cells to power energy-demanding processes depends on maintaining the ATP hydrolysis reaction a billion-fold away from equilibrium. Cells respond to changes in energy state by sensing changes in ATP, ADP, AMP, and inorganic phosphate. A key barrier to a better understanding of the maintenance of energy homeostasis is a lack of tools for direct manipulation of energy state in living cells. Here, we report the development of ATPGobble-a genetically encoded tool for controlling cellular ATP hydrolysis rate. We validated ATPGobble by showing that it doubles the energy demand, decreases [ATP]/[ADP] and [ATP]/[AMP] ratios, and activates AMPK activity in human cells. We then used ATPGobble to systematically characterize the proteome and phosphoproteome changes caused by direct manipulation of the energy state. Our results establish ATPGobble as a powerful approach for dissecting the regulatory roles of energy state in human cells, opening new opportunities to study how cellular energy state governs physiology, stress responses, and disease processes.
    DOI:  https://doi.org/10.1101/2025.08.12.670003
  39. J Chem Theory Comput. 2025 Sep 02.
    TS2CG as a Membrane Builder.
    Fabian Schuhmann, Jan A Stevens, Neda Rahmani, Isabell Lindahl, Chelsea M Brown, Christopher Brasnett, Dimitrios Anastasiou, Adrià Bravo Vidal, Beatrice Geiger, Siewert J Marrink, Weria Pezeshkian.
      Molecular dynamics (MD) simulations excel at capturing biological processes at the molecular scale but rely on a well-defined initial structure. As MD simulations now extend to whole-cell-level modeling, new tools are needed to efficiently build initial structures. Here, we introduce TS2CG version 2, designed to construct coarse-grained membrane structures with any desired shape and lateral organization. This version enables precise placement of lipids and proteins based on curvature preference, facilitating the creation of large, near-equilibrium membranes. Additional features include controlled pore generation and the placement of specific lipids at membrane edges for stabilization. Moreover, a Python interface allows users to extend functionality while maintaining the high performance of the C++ core. To demonstrate its capabilities, we showcase challenging simulations, including a Möbius strip membrane, a vesicle with lipid domains as continental plates (Martini globe), and entire mitochondrial membranes exhibiting lipid heterogeneity due to curvature, along with a comprehensive set of tutorials.
    DOI:  https://doi.org/10.1021/acs.jctc.5c00833
  40. J Biol Chem. 2025 Aug 28. pii: S0021-9258(25)02488-3. [Epub ahead of print] 110636
    β-hydroxybutyrate dehydrogenase promotes pancreatic cancer cell proliferation through regulation of the NAD+/NADH balance and mitochondrial acetylation.
    Xiujuan Wei, Chengkai Zhang, Xiaoguang Zheng, Kexin Pan, Xiaojun Ren, Xiaoting Lou, Zhengquan Yang, Ting Fu, Hezhi Fang, Jianxin Lu.
      Ketone bodies are a key alternative energy source during carbohydrate deficiency. In addition to their metabolic function, they regulate essential cellular processes, including metabolism, signal transduction, and protein post-translational modifications (PTMs). However, the role of ketone body metabolism in tumorigenesis remains poorly understood. Here, we demonstrate that ketone body synthesis metabolism is activated in pancreatic cancer, while exogenous ketone supplementation does not affect PDAC cell proliferation. Moreover, we observe a significant upregulation of β-Hydroxybutyrate dehydrogenase (BDH1), a key enzyme in ketone body metabolism, in human pancreatic ductal adenocarcinoma (PDAC) tissues compared to adjacent normal pancreatic tissues. BDH1 promotes PDAC cell proliferation by maintaining mitochondrial acetylation levels through regulation of the intracellular NAD+/NADH ratio. These findings underscore the importance of ketone body metabolism in pancreatic cancer progression and highlight the regulatory role of BDH1 in maintaining cellular NAD+/NADH balance and mitochondrial acetylation.
    Keywords:  BDH1; Ketone body; NAD(+)/NADH; Pancreatic Cancer; mitochondrial acetylation
    DOI:  https://doi.org/10.1016/j.jbc.2025.110636
  41. Anal Chim Acta. 2025 Oct 22. pii: S0003-2670(25)00857-8. [Epub ahead of print]1372 344463
    A single fluorescent probe for simultaneous detection of polarity, viscosity, and esterase.
    Zehua Han, Taihe Han, Ziling Tang, Qin Huang, Junbao Ma, Shuai Mu, Huayu Wang, Xiaoyan Liu, Haixia Zhang.
       BACKGROUND: The dynamic interplay between esterase activity and physicochemical microenvironments-such as polarity and viscosity-is critical for decoding early cellular dysfunction in processes like apoptosis, ferroptosis, and drug-induced toxicity. However, conventional probes typically report only a single parameter, obscuring interdependent changes in enzyme activity and membrane properties. This technological gap limits our ability to capture real-time, spatially resolved fluctuations within subcellular compartments. Developing a multifunctional, dual-emission probe that concurrently monitors esterase activity, polarity, and viscosity would thus provide unprecedented insight into complex pathophysiological mechanisms and enhance diagnostic precision.
    RESULTS: We propose a dual-targeted fluorescent probe PQE, which achieves simultaneous monitoring of esterase activity, polarity and viscosity in living cells through mitochondria-localized red fluorescence (λex/em = 490/630 nm) and lipid droplet-anchored green fluorescence (λex/em = 405/525 nm). PQE integrates three functional modules: a quinoline-based polarity sensor exhibiting 48-fold fluorescence attenuation across solvent polarity Δƒ from 0.0205 to 0.3200, a pyrene-derived molecular rotor showing 50-fold fluorescence enhancement over a viscosity range of 0.89-965 cP, and an acetoxymethyl (AcOM) esterase-activatable group demonstrating 39-fold fluorescence increase after hydrolysis. Using PQE, we distinguished live cells, early apoptotic cells, and fixed cells, and observed that ferroptosis-induced esterase inactivation coincided with increased mitochondrial viscosity and decreased lipid droplet polarity. In addition, PQE also dynamically visualized esterase inhibition and viscosity-polarity imbalance in acetaminophen and LPS-induced hepatotoxicity models.
    SIGNIFICANCE: Compared to single-parameter detection, the simultaneous monitoring of multiple markers in a single probe enables comprehensive profiling of enzymatic activity, viscosity, and polarity within the same cellular context. This real-time, organelle-specific approach enhances sensitivity and accuracy in detecting ferroptotic, hepatotoxic events and may accelerate applications in diagnostics and drug screening.
    Keywords:  Esterase; Ferroptosis; Fluorescent probe; Liver injury; Polarity; Viscosity
    DOI:  https://doi.org/10.1016/j.aca.2025.344463
  42. Chem Asian J. 2025 Sep 01. e00328
    Organic Fluorophores for Studying Lipid Membrane Structures and Dynamics.
    Ritu Kumari, Prakriti Sharma, Vineeta Chaturvedi, Avik K Pati.
      Biomembranes act as boundaries between cells and their outside environment and between intracellular compartments, playing integral roles in cellular signaling and communications. A vast body of research has shown that biomembranes are dynamic and heterogeneous, and that they largely vary in lipid compositions and their organizations, governing a plethora of membrane-associated biological processes. Fluorescent tools, including fluorescent contrast agents (fluorophores) and fluorescence imaging modalities, have been demonstrated to be powerful in studying lipid membrane structures and dynamics. Here, we review recent progress in lipid membrane probes based on organic fluorophore designs and their uses in studying lipid membrane properties in plasma membranes and various organelle membranes. In this context, we also highlight applications of these fluorescent membrane probes in diverse fluorescence-based imaging settings that advance lipid membrane research.
    Keywords:  Biomembrane; Fluorophore; Lipid bilayer; Super‐resolution fluorescence imaging
    DOI:  https://doi.org/10.1002/asia.202500328
  43. bioRxiv. 2025 Aug 23. pii: 2025.08.22.671773. [Epub ahead of print]
    L1CAM signaling through planar cell polarity generates SOX2 + metastatic progenitors in lung adenocarcinoma.
    Jin Suk Park, Yasemin Kaygusuz, Carson Kenum, Lan He, Mohamed I Gatie, Xueqian Zhuang, Roshan Sharma, Ronan Chaligné, Umesh K Bhanot, Richard P Koche, Tuomas Tammela, Anna-Katerina Hadjantonakis, Charles M Rudin, Joan Massagué.
      Plasticity transitions during carcinoma progression generate fetal-like progenitor states with metastatic capacity. How these progenitors emerge and persist during tumor progression remains unknown. Here, we elucidate a process that drives the emergence of SOX2 + metastatic progenitors in lung adenocarcinomas (LUAD). LUAD cells in the tumor invasive front and distant metastases express the cell adhesion molecule L1CAM, a marker of regenerative epithelial progenitors and a mediator of cell-basement membrane and cell-cell interactions. L1CAM-mediated adhesion to perivascular basement membrane is known to stimulate the proliferation of extravasated micrometastatic cells. We now identify a distinct and broader role of L1CAM as promoter of the SOX2+ LUAD progenitor state. We show that L1CAM at cell-cell interfaces promotes the assembly of the planar cell polarity (PCP) complex in metastatic LUAD progenitors. L1CAM-dependent PCP acting through a non-canonical WNT signaling activates c-Jun, which cooperates with the chromatin remodeling factor CHD1 to drive SOX2 expression and metastatic activity. This axis sustains the tumor-initiating and regenerative capacity of LUAD progenitor cells. By illuminating the role of L1CAM and PCP signaling in the generation of SOX2 + LUAD progenitors, our findings identify potential new targets to treat metastatic cancer.
    DOI:  https://doi.org/10.1101/2025.08.22.671773
  44. Adv Exp Med Biol. 2025 ;1478 285-314
    Cancer Cachexia.
    Melissa J Puppa, James A Carson.
      Skeletal muscle's metabolic and mechanical functions make it critical for maintaining human health, physical function, and quality of life in adults. The impact of skeletal muscle mass and the metabolic quality of muscle tissue becomes even more critical with advancing age and in patients with chronic diseases. To this end, cachexia is the involuntary loss of body weight, including muscle and fat loss, accompanying an underlying disease or condition. Cancer-induced cachexia occurs across many types of cancer and contributes to increased patient mortality, morbidity, and treatment toxicities, negatively impacting survival. Furthermore, there are currently no approved pharmacological treatments and limited evidence-based therapeutic options to prevent muscle loss or promote muscle recovery in cancer patients. While the systemic effects of cancer and subsequent treatment continue to be examined as drivers of overall wasting, the impact of skeletal muscle mass and metabolic quality in the cancer patient remains a critical area of investigation. A vital knowledge gap exists in understanding how maintaining muscle function and metabolic properties improves cancer patients' survival. The chapter explores the current understanding of how cancer and subsequent treatment impact skeletal muscle mass, function, and metabolic quality. To this end, the current understanding of systemic mediators and metabolic crosstalk between tissues that promote cancer-induced wasting is explored. Additional factors related to sex, physical activity level, chemotherapy-specific effects, and cancer heterogeneity are discussed concerning their impact on cancer-induced muscle wasting.
    Keywords:  Cancer; Muscle atrophy; Wasting; Weight loss
    DOI:  https://doi.org/10.1007/978-3-031-88361-3_12
  45. Autophagy Rep. 2025 ;4(1): 2551028
    Liver-specific loss of Atg9a perturbs lipid metabolism and hepatocyte integrity.
    Elodie Mailler, Asmita Singh, Michal Jarnik, Yan Li, Lynne Holtzclaw, Victoria Hoffmann, Sohtaro Mine, Paulina Stallcup, Laleh Ordoubadinia, Carlos M Guardia.
      The autophagy-related protein ATG9A is integral to cellular autophagy and lipid mobilization, yet its importance in mammalian physiology remains underexplored. Using a liver-specific conditional Atg9a knockout (Atg9a-cKO) mouse model, we uncovered critical insights into the physiological function of ATG9A in this organ. Atg9a-cKO mice exhibited hepatomegaly, abnormal hepatocyte morphology, mitochondrial fragmentation, and lipid droplet accumulation. Blood chemistry and proteomics analyses revealed elevated serum cholesterol, reduced albumin, and dysregulation of pathways related to lipid metabolism and oxidative stress responses. These findings establish an essential role for ATG9A in maintaining hepatocyte integrity, lipid trafficking, and overall liver health, offering a model for studying autophagy-related hepatic pathologies.
    Keywords:  ATG9A; autophagy; lipid droplets; liver; mitochondria; mouse
    DOI:  https://doi.org/10.1080/27694127.2025.2551028
  46. EMBO J. 2025 Aug 29.
    Cytosolic DNA crosstalk in senescence: a new axis of inflammatory signaling?
    Zhixun Dou, Jill A Kreiling, Susanne Heynen-Genel, Diana Jurk, Nicola Neretti, Peter D Adams, John M Sedivy, João F Passos.
      
    DOI:  https://doi.org/10.1038/s44318-025-00531-z
  47. Adv Mater. 2025 Sep 06. e05445
    Chemoselective Characterization of New Extracellular Matrix Deposition in Bioengineered Tumor Tissues.
    Zihan Ling, Burke Niego, Qingyang Li, Dhruv Bhattaram, Vanessa Serna Villa, Michael Hu, Zhuowei Gong, Lloyd M Smith, Brian L Frey, Xi Ren.
      In both native and engineered tissues, the extracellular matrix (ECM) supports and regulates nearly all aspects of cellular pathophysiology, and in response, cells extensively remodel their surrounding extracellular environments through new ECM protein deposition. Understanding this intricate bi-directional cell-ECM interaction is key to tissue engineering, but it remains challenging to investigate. This is partly due to the limited sensitivity of conventional proteomics to capture low-abundance newly synthesized ECM (newsECM). This study presents a glycosylation-enabled, chemoselective strategy to label, enrich, and characterize newsECM proteins with augmented specificity and sensitivity. Applying newsECM profiling to bioengineered tumor tissues, either built upon decellularized ECM materials (dECM-tumor) or as ECM-free tumoroids, revealed distinct ECM synthesis patterns. Tumor cells cultured within dECM scaffold present elevated ECM remodeling activities, mediated by augmented digestion of pre-existing ECM coupled with upregulated synthesis of tumor-associated ECM components. These findings highlight the sensitivity of newsECM profiling to capture remodeling events that are otherwise under-represented by bulk proteomics and underscore the significance of dECM support for enabling native-like tumor cell behaviors. The newsECM profiling described here is anticipated to be applicable to a wide range of engineered tissue models and pathophysiological processes to deliver fundamental insights regarding the mutual cell-ECM crosstalk.
    Keywords:  biomaterial; chemoselective chemistry; newly‐synthesized extracellular matrix; proteomics
    DOI:  https://doi.org/10.1002/adma.202505445
  48. Autophagy. 2025 Sep 03. 1-20
    Reconstitution of autophagic-like membrane tethering reveals that Atg11 can bind and cluster vesicles on cargo mimetics.
    Devika Andhare, Sarah Katzenell, Sarah I Najera, Sylvie C Mauras, Katherine M Bauer, Michael J Ragusa.
      Macroautophagy (hereafter, autophagy) is essential for the degradation of mitochondria from yeast to humans. Mitochondrial autophagy in yeast is initiated when the selective autophagy scaffolding protein Atg11 is recruited to mitochondria through its interaction with the selective autophagy receptor Atg32. This also results in the recruitment of small 30-nm vesicles that fuse to generate the initial phagophore membrane. We demonstrate that Atg11 can bind to autophagic-like membranes in vitro in a curvature-dependent manner in part via a predicted amphipathic helix. Deletion of the amphipathic helix from Atg11 results in a delay in the formation of mitophagy initiation sites in yeast. Furthermore, using a novel biochemical approach, we demonstrate that the interaction between Atg11 and Atg32 results in the tethering of autophagic-like vesicles in clusters to giant unilamellar vesicles containing a lipid composition designed to mimic the outer mitochondrial membrane. We also demonstrate that the N-terminal region of Atg11 is an important mediator of vesicle tethering to cargo mimetics and that clustering of autophagic-like vesicles requires the C-terminal region of Atg11. Taken together, our results reveal that Atg11 clusters into high-order oligomers, can tether autophagic-like membranes and due to its ability to oligomerize can cluster vesicles on the surface of cargo mimetics. This work provides new insight into the mechanisms of protein and membrane clustering by Atg11. Given the increasing importance of protein oligomerization and clustering in autophagy, these results have important implications in the initiation of mitochondrial autophagy.Abbreviations Atg11: autophagy related 11; Atg11-Cterm: C-terminal region of Atg11; Atg11-Nterm: N-terminal region of Atg11; Atg32: autophagy related 32; COV: coefficient of variance; DOPC: 1,2-dioleoyl-sn-glycero-3-phosphocholine; DOPE: 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine; DOPS: 1,2-dioleoyl-sn-glycero-3-phospho-L-serine; FRAP: fluorescence recovery after photobleaching; GLT: GUV and liposome tethering; GUV: giant unilamellar vesicle; MKO: multiple knockout; OMM: outer mitochondrial membrane; PC: phosphatidylcholine; PE: phosphatidylethanolamine; PtdIns: phosphatidylinositol; PtdIns3P: phosphatidylinositol-3-phosphate; RhPE: rhodamine phosphatidylethanolamine; SAR: selective autophagy receptor; SEC: size-exclusion chromatography; SLB: supported lipid bilayers; SMrT: supported membrane templates; YPL: yeast polar lipids.
    Keywords:  Biochemistry; membrane tethering; mitophagy; reconstitution; selective autophagy; yeast
    DOI:  https://doi.org/10.1080/15548627.2025.2551678
  49. Nat Cell Biol. 2025 Sep 05.
    Fusion oncoproteins acquire condensate propensity to initiate tumour formation.
      
    DOI:  https://doi.org/10.1038/s41556-025-01746-2
  50. Cancer Immunol Res. 2025 Sep 04.
    Liver metastases license neutrophils through IL-1 to potentiate cancer progression.
    Ashley N Pearson, Jessica Waninger, Amanda K Huber, Erin A Holcomb, Jadyn G James, Justine Kyi, Ameer L Elaimy, Zhuwen Wang, Emily L Lasse Opsahl, Shuvasree SenGupta, David A Elliott, Enid Choi, Qiang Zhang, Meredith A Morgan, Daniel T Chang, Theodore S Lawrence, Adam Courtney, Yatrik M Shah, Jason S Knight, Marina Pasca di Magliano, Shinjae Yoo, Silvia Crivelli, Carole A Parent, Nithya Ramnath, Alex K Bryant, Weiping Zou, Michael D Green.
      Liver metastases are associated with poor cancer outcomes in many solid malignancies, but the factors influencing the trajectory of patients with liver metastases are poorly defined. It is known that liver metastases suppress systemic antitumor immunity; however, the underlying mechanisms remain incompletely described. We report that liver metastases promote disease progression in patients and preclinical models. Patients with liver metastases progress rapidly, regardless of primary tumor type. In multiple murine models, we find that liver metastases potentiate neutrophil migration and activity. Neutrophils licensed by liver metastasis augment metastatic colonization in an IL-1 dependent manner. Thus, liver metastasis rewires systemic immunity to promote cancer progression. This work has implications for treatment strategies to address the poor clinical outcomes associated with liver metastasis.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-24-1074
  51. Aging Cell. 2025 Sep 04. e70203
    Asparaginase and Autophagy Inhibitors Effectively Remove Senescent Cells by Synergistically Limiting Asparagine Supply.
    Zhihua Huang, Xinxin Liu, Xiaojia Zhou, Keyu Chen, Honglin Diao, Mingyue Wang, Jianlei Wei, Zeping Li, Yang Yang, Zebin Mao, Wenhua Yu.
      The accumulation of senescent cells (SNCs) contributes to tissue dysfunction and age-related diseases, creating an urgent need for effective senolytic strategies. We identified a metabolic vulnerability in SNCs characterized by marked downregulation of asparagine synthetase (ASNS), rendering them uniquely dependent on exogenous asparagine (Asn). This vulnerability was exploited through combined treatment with L-asparaginase (ASNase) and autophagy inhibitors, which synergistically deplete Asn via complementary mechanisms: ASNase degrades extracellular Asn pools, while autophagy inhibition blocks intracellular protein recycling as an alternative Asn source. This dual approach induced selective synthetic lethality across multiple SNC types in vitro. In aged mice, the combination therapy significantly reduced SNC burden in diverse tissues, improved physiological function, and attenuated progression of age-related conditions including osteoporosis, atherosclerosis, and non-alcoholic fatty liver disease. Our findings establish concurrent targeting of extracellular and intracellular Asn supplies as a potent, selective senolytic strategy with broad therapeutic potential for age-related disorders.
    Keywords:  asparaginase; asparagine; asparagine synthetase; autophagy inhibitors; senescent cell
    DOI:  https://doi.org/10.1111/acel.70203
  52. Nat Mater. 2025 Sep 05.
    Local photocrosslinking of native tissue matrix regulates lung epithelial cell mechanosensing and function.
    Donia W Ahmed, Matthew L Tan, Yuchen Liu, Jackson Gabbard, Esther Gao, Avinava Roy, Michael M Hu, Firaol S Midekssa, Miriam Stevens, Fulei Wuchu, Minal Nenwani, Jingyi Xia, Adam Abraham, Deepak Nagrath, Lin Han, Rachel L Zemans, Brendon M Baker, Claudia Loebel.
      Within most tissues, the extracellular microenvironment provides mechanical cues that guide cell fate and function. Changes in the extracellular matrix such as aberrant deposition, densification and increased crosslinking are hallmarks of late-stage fibrotic diseases that often lead to organ dysfunction. Biomaterials have been widely used to mimic the mechanical properties of the fibrotic matrix and study pathophysiologic cell function. However, the initiation of fibrosis has largely been overlooked, due to challenges in recapitulating early stages of disease progression within the native extracellular microenvironment. Here, using visible-light-mediated photochemistry, we induced local crosslinking and stiffening of extracellular matrix proteins within ex vivo mouse and human lung tissue. In ex vivo lung tissue of epithelial cell lineage-traced mice, local matrix crosslinking mimicked early fibrotic lesions that increased alveolar epithelial cell mechanosensing, differentiation, and nascent protein deposition and remodelling. However, the inhibition of cytoskeletal tension, mechanosensitive signalling pathways or integrin engagement reduced epithelial cell spreading and differentiation. Our findings emphasize the role of local extracellular matrix crosslinking and nascent protein deposition in early stage tissue fibrosis and have implications for ex vivo disease modelling and applications to other tissues.
    DOI:  https://doi.org/10.1038/s41563-025-02329-0
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