bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2025–07–27
28 papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Functional liver genomics identifies hepatokines promoting wasting in cancer cachexia.
  2. A STAT3/integrin axis accelerates pancreatic cancer initiation and progression.
  3. Combination of the MTA-Cooperative PRMT5 Inhibitor BMS-986504 and KRAS Inhibitors is an Effective Treatment Strategy for MTAP-Deleted KRAS-Mutant Pancreatic Cancer.
  4. High-resolution spatial mapping of cell state and lineage dynamics in vivo with PEtracer.
  5. Metabolic adaptations of brain metastasis.
  6. Primary and metastatic cellular landscapes in human pancreatic cancer.
  7. Ras-mediated dynamic and biphasic regulation of cell migration.
  8. Amino Acid Metabolism in Liver Mitochondria: From Homeostasis to Disease.
  9. Integrated single-cell and spatial transcriptomics uncover distinct cellular subtypes involved in neural invasion in pancreatic cancer.
  10. Assessment of the primary cancer cell secretome using amino acid-analog labeling.
  11. SenSet, a novel human lung senescence cell gene signature, identifies cell-specific senescence mechanisms.
  12. Statins and the Risk of Pancreatic Cancer.
  13. TMEM65 functions as the mitochondrial Na+/Ca2+ exchanger.
  14. Decoding subclonal anti-tumor immunity.
  15. Regulation of inflammatory responses by pH-dependent transcriptional condensates.
  16. A neomorphic protein interface catalyzes covalent inhibition of RASG12D aspartic acid in tumors.
  17. The colorectal liver metastasis growth pattern phenotype is not dependent on genotype.
  18. Prospective evaluation of surgical treatment of liver metastasizing pancreatic cancer - ScanPan study protocol.
  19. Npl3 is required for efficient autophagosome-vacuole fusion.
  20. Coping with stress: the essential role of brain autophagy in emotional homeostasis.
  21. Breaking point: mechanical stress helps NINJ1 protein to rupture membranes.
  22. The rapidly expanding role of LC3-interacting regions in autophagy.
  23. Lamins regulate cancer cell plasticity and chemosensitivity.
  24. Amino acid transfer free energies reveal thermodynamic driving forces in biomolecular condensate formation.
  25. NNMT inhibition in cancer-associated fibroblasts restores antitumour immunity.
  26. mTORC1 senses glutamine and other amino acids through GCN2.
  27. SenExo-cCCT2 Reprograms Senescence Response and Anti-Tumor Immunity Following FOLFIRINOX Chemotherapy in Pancreatic Ductal Adenocarcinoma.
  28. Closing in on pacemaker cells.
  1. Cell. 2025 Jul 18. pii: S0092-8674(25)00741-X. [Epub ahead of print]
    Functional liver genomics identifies hepatokines promoting wasting in cancer cachexia.
    Doris Kaltenecker, Søren Fisker Schmidt, Peter Weber, Anne Loft, Pauline Morigny, Juliano Machado, Julia Geppert, Kerstin Beate Saul, Pia Benedikt, Claudia-Eveline Molocea, Rachel Scott, Kerstin Haase, Marc E Martignoni, Ana Jimena Alfaro, Kan Kau Chow, Estefania Simoes, José Pinhata Otoch, Joanna D C C Lima, Charles Swanton, Nadine Spielmann, Martin Hrabé de Angelis, Markus Elsner, Ali Ertürk, Kenneth A Dyar, Maria Rohm, Olga Prokopchuk, Mariam Jamal-Hanjani, Marilia Seelaender, Johannes Backs, Stephan Herzig, Mauricio Berriel Diaz.
      In cancer cachexia, the presence of a tumor triggers systemic metabolic disruption that leads to involuntary body weight loss and accelerated mortality in affected patients. Here, we conducted transcriptomic and epigenomic profiling of the liver in various weight-stable cancer and cancer cachexia models. An integrative multilevel analysis approach identified a distinct gene expression signature that included hepatocyte-secreted factors and the circadian clock component REV-ERBα as key modulator of hepatic transcriptional reprogramming in cancer cachexia. Notably, hepatocyte-specific genetic reconstitution of REV-ERBα in cachexia ameliorated peripheral tissue wasting. This improvement was associated with decreased levels of specific cachexia-controlled hepatocyte-secreted factors. These hepatokines promoted catabolism in multiple cell types and were elevated in cachectic cancer patients. Our findings reveal a mechanism by which the liver contributes to peripheral tissue wasting in cancer cachexia, offering perspectives for future therapeutic interventions.
    Keywords:  INTACT; REV-ERB; adipose tissue wasting; cachexia; circadian clock; hepatic reprogramming; liver-secreted factors; muscle atrophy
    DOI:  https://doi.org/10.1016/j.cell.2025.06.039
  2. Cell Rep. 2025 Jul 18. pii: S2211-1247(25)00781-8. [Epub ahead of print] 116010
    A STAT3/integrin axis accelerates pancreatic cancer initiation and progression.
    Alejandro D Campos, Ryan M Shepard, Zachary Ortega, Ingrid Heumann, Anna E Wilke, Arin Nam, Carson Cable, Kourosh Kouhmareh, Richard Klemke, Nicole M Mattson, Trey Ideker, Camila De Arruda Saldanha, Sven Heinz, Valerie Weaver, Tami Von Schalscha, Hiromi I Wettersten, Sara M Weis, David A Cheresh.
      The signal transducer and activator of transcription 3 (STAT3) pathway drives pancreatic ductal adenocarcinoma (PDAC) progression by coordinating cellular responses to stress and inflammation. We perform ChIP-seq on hypoxia- or oncostatin-M-treated PDAC cells to identify sites at which phospho-STAT3 binds to regulate the expression of genes linked to poor survival. A top hit among these is ITGB3, which we show promotes PDAC initiation and progression. Single-cell transcriptomics reveal that ITGB3 expression is enriched in PDAC cells experiencing oxidative stress due to chemotherapy. Moreover, high ITGB3 expression positively correlates with STAT3 signaling, hypoxia, and the basal subtype. Mechanistically, chromatin accessibility at ITGB3 enhancers controls STAT3's ability to induce ITGB3 expression, illuminating a plastic regulatory mechanism modulating STAT3 activity. Leveraging this insight, we identify additional STAT3 target genes regulated similarly to ITGB3 to establish an 18-gene signature involved in adaptive responses and able to stratify survival outcomes. Collectively, these findings highlight a novel opportunity to stratify PDAC subpopulations for STAT3-targeted therapies.
    Keywords:  CP: Cancer; STAT3; cellular stress; cytokine; enhancer; gene signature; hypoxia; inflammation; integrin; pancreatic cancer; tumor initiation
    DOI:  https://doi.org/10.1016/j.celrep.2025.116010
  3. Cancer Res. 2025 Jul 22.
    Combination of the MTA-Cooperative PRMT5 Inhibitor BMS-986504 and KRAS Inhibitors is an Effective Treatment Strategy for MTAP-Deleted KRAS-Mutant Pancreatic Cancer.
    Kristina Drizyte-Miller, Lars D Engstrom, Jeffrey A Klomp, Clint A Stalnecker, Addison G Stamey, Khalilah E Taylor, Mallory K Roach, Ryan Robb, Laura M Waters, Andrew Calinisan, Seamus Degan, Wen-Hsuan Chang, Xousaen M Helu, David Nguyen, Elisa Baldelli, Mariaelena Pierobon, Emanuel F Petricoin, David M Briere, Jill Hallin, James G Christensen, Kirsten L Bryant, Adrienne D Cox, Peter Olson, Channing J Der.
      Protein arginine methyltransferase 5 (PRMT5) is a synthetic lethal target in MTAP-deleted (MTAP-del) cancers. The MTA-cooperative PRMT5 inhibitor BMS-986504 exhibited potent and selective anti-tumor activity in MTAP-del preclinical models and demonstrated activity in MTAP-del patients without the toxicity associated with previous PRMT5 inhibitors. Here, we focused on pancreatic ductal adenocarcinoma (PDAC), ~22% of which are MTAP-del, and demonstrated that BMS-986504 suppressed PRMT5 function and cell growth in MTAP-del cells and xenograft models. CRISPR/Cas9 loss-of-function screens implicated co-targeting KRAS as a combination strategy. Concurrent inhibition of PRMT5 and KRASG12C/D enhanced and prolonged suppression of PDAC growth. RNA-sequencing analysis revealed that PRMT5 inhibition disrupted RNA splicing of genes essential for PDAC growth. While PRMT5 and KRAS regulated distinct transcriptomes, they converged on pathways governing cancer cell growth and expression of PDAC-essential genes. These findings provide rationale for combined inhibition of PRMT5 and KRAS in MTAP-deleted/KRAS-mutant PDAC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-1507
  4. Science. 2025 Jul 24. eadx3800
    High-resolution spatial mapping of cell state and lineage dynamics in vivo with PEtracer.
    Luke W Koblan, Kathryn E Yost, Pu Zheng, William N Colgan, Matthew G Jones, Dian Yang, Arhan Kumar, Jaspreet Sandhu, Alexandra Schnell, Dawei Sun, Can Ergen, Reuben A Saunders, Xiaowei Zhuang, William E Allen, Nir Yosef, Jonathan S Weissman.
      Charting the spatiotemporal dynamics of cell fate determination in development and disease is a long-standing objective in biology. Here we present the design, development, and extensive validation of PEtracer, a prime editing-based, evolving lineage tracing technology compatible with both single-cell sequencing and multimodal imaging methodologies to jointly profile cell state and lineage in dissociated cells or while preserving cellular context in tissues with high spatial resolution. Using PEtracer coupled with MERFISH spatial transcriptomic profiling in a syngeneic mouse model of tumor metastasis, we reconstruct the growth of individually-seeded tumors in vivo and uncover distinct modules of cell-intrinsic and cell-extrinsic factors that coordinate tumor growth. More generally, PEtracer enables systematic characterization of cell state and lineage relationships in intact tissues over biologically-relevant temporal and spatial scales.
    DOI:  https://doi.org/10.1126/science.adx3800
  5. Nat Rev Cancer. 2025 Jul 24.
    Metabolic adaptations of brain metastasis.
    Pravat Kumar Parida, Srinivas Malladi.
      Brain metastases remain a major clinical challenge, characterized by high mortality rates and often limited therapeutic options. The cellular and molecular processes that drive brain metastases are highly intricate, underscored by dynamic metabolic adaptations that enable tumour cells to thrive in the unique microenvironment of the brain. Emerging clinical and preclinical evidence reveals that these metabolic adaptations are not uniform but vary based on the tumour's tissue of origin, oncogenomic landscape and capacity to endure nutrient stress. Notably, proliferative and dormant metastatic cells within the brain exhibit distinct metabolic profiles, highlighting the complexity of targeting these cells. Key metabolic pathways, including glucose, fatty acid and amino acid metabolism, are co-opted not only to sustain cancer cell survival and growth but also to modulate interactions with resident brain cells, reshaping their function to support metastasis. Importantly, this metabolic heterogeneity underscores the inadequacy of a one-size-fits-all therapeutic approach. Here, we review the adaptive metabolic reprogramming that facilitates brain metastases and discuss emerging strategies to tailor interventions aimed at preventing and treating overt brain metastases.
    DOI:  https://doi.org/10.1038/s41568-025-00848-1
  6. iScience. 2025 Aug 15. 28(8): 113012
    Primary and metastatic cellular landscapes in human pancreatic cancer.
    Nina G Steele, Veerin R Sirihorachai, Ahmed M Elhossiny, Ian M Loveless, Padma Kadiyala, Monica Bonilla, Emily L Lasse-Opsahl, Carinna Solano Vargas, Katelyn L Donahue, Samantha B Kemp, Valerie Gunchick, Yatrik M Shah, Timothy L Frankel, Filip Bednar, Arvind Rao, Benjamin L Allen, Jiaqi Shi, Vaibhav Sahai, Howard C Crawford, Eileen S Carpenter, Marina Pasca di Magliano.
      Pancreatic ductal adenocarcinoma (PDAC) is characterized by a complex tumor microenvironment (TME). We utilized single cell RNA sequencing to compare the TMEs of metastatic sites and primary tumors. We detected increased prevalence of exhausted CD8+ T cells in metastases, as well as the enrichment of complement pathway encoding genes in immunosuppressive tumor-associated macrophages, consistent with profound immunosuppression in metastatic disease. In cancer-associated fibroblasts, we identified a unique upregulation of metabolic genes, including UPP1, in metastasis. In cancer cells, we uncovered a specific gene signature upregulated in liver metastases; this signature was present in a proportion of primary tumors in the TCGA dataset, where it correlated with worse survival. Overall, our analysis of primary and metastatic PDAC defines a "high-risk" gene signature, metabolic reprogramming, and increased immune suppression in metastasis.
    Keywords:  Cancer; Integrative aspects of cell biology; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2025.113012
  7. Proc Natl Acad Sci U S A. 2025 Jul 29. 122(30): e2503847122
    Ras-mediated dynamic and biphasic regulation of cell migration.
    Yiyan Lin, Eleana Parajón, Qinling Yuan, Siyu Ye, Guanghui Qin, Yu Deng, Jane Borleis, Ariel Koyfman, Pablo A Iglesias, Konstantinos Konstantopoulos, Douglas N Robinson, Peter N Devreotes.
      Ras has traditionally been regarded as a positive regulator and therapeutic target due to its role in cell proliferation, but recent findings indicate a more nuanced role in cell migration, where suppressed Ras activity can unexpectedly promote migration. To clarify this complexity, we systematically modulate Ras activity using various RasGEF and RasGAP proteins and assess their effects on migration dynamics. Leveraging optogenetics, we assess the immediate, nontranscriptional effects of Ras signaling on migration. Local RasGEF recruitment to the plasma membrane induces protrusions and new fronts to effectively guide migration, even in the absence of GPCR/G-protein signaling, whereas global recruitment causes immediate cell spreading halting cell migration. Local RasGAP recruitment suppresses protrusions, generates new backs, and repels cells, whereas global relocation either eliminates all protrusions to inhibit migration or preserves a single protrusion to maintain polarity. Consistent local and global increases or decreases in signal transduction and cytoskeletal activities accompany these morphological changes. Additionally, we performed cortical tension measurements and found that Ras activity is regulated by guanine nucleotide exchange factors generally increase cortical tension while Ras activity is regulated by GTPase-activating proteins decrease it. Our results reveal a biphasic relationship between Ras activity and cellular dynamics, reinforcing our previous findings that optimal Ras activity and cortical tension are critical for efficient migration.
    Keywords:  Ras GTPase; cell migration; cortical tension
    DOI:  https://doi.org/10.1073/pnas.2503847122
  8. Metabolites. 2025 Jul 02. pii: 446. [Epub ahead of print]15(7):
    Amino Acid Metabolism in Liver Mitochondria: From Homeostasis to Disease.
    Ranya Erdal, Kıvanç Birsoy, Gokhan Unlu.
      Hepatic mitochondria play critical roles in sustaining systemic nutrient balance, nitrogen detoxification, and cellular bioenergetics. These functions depend on tightly regulated mitochondrial processes, including amino acid catabolism, ammonia clearance via the urea cycle, and transport through specialized solute carriers. Genetic disruptions in these pathways underlie a range of inborn errors of metabolism, often resulting in systemic toxicity and neurological dysfunction. Here, we review the physiological functions of hepatic mitochondrial amino acid metabolism, with a focus on subcellular compartmentalization, disease mechanisms, and therapeutic strategies. We discuss how emerging genetic and metabolic interventions-including dietary modulation, cofactor replacement, and gene therapy-are reshaping treatment of liver-based metabolic disorders. Understanding these pathways offers mechanistic insights into metabolic homeostasis and reveals actionable vulnerabilities in metabolic disease and cancer.
    Keywords:  amino acids; cancer; inborn errors of metabolism; liver; metabolism; mitochondria
    DOI:  https://doi.org/10.3390/metabo15070446
  9. Cancer Cell. 2025 Jul 17. pii: S1535-6108(25)00270-3. [Epub ahead of print]
    Integrated single-cell and spatial transcriptomics uncover distinct cellular subtypes involved in neural invasion in pancreatic cancer.
    Min-Min Chen, Qinhang Gao, Huiheng Ning, Kang Chen, Yang Gao, Min Yu, Chao-Qun Liu, Wei Zhou, Jieying Pan, Lusheng Wei, Wenxian Dou, Dingwen Zhang, Linnan Zhu, Qingling Zhang, Rufu Chen, Zemin Zhang.
      Nerves are integral to tumor biology, yet the peri- and intra-neural microenvironment and their roles in cancer-neural invasion (NI) remain underexplored. Here, we perform single-cell/single-nucleus RNA sequencing (sc/snRNA-seq) and spatial transcriptomics on 62 samples from 25 pancreatic ductal adenocarcinoma (PDAC) patients, mapping cellular composition, lineage dynamics, and spatial organization across varying NI statuses. Tertiary lymphoid structures are abundant in low-NI tumor tissues and co-localize with non-invaded nerves, while NLRP3+ macrophages and cancer-associated myofibroblasts surround invaded nerves in high-NI tissues. We identify a unique endoneurial NRP2+ fibroblast population and characterize three distinct Schwann cell subsets. TGFBI+ Schwann cells locate at the leading edge of NI, can be induced by transforming growth factor β (TGF-β) signaling, promote tumor cell migration, and correlate with poor survival. We also identify basal-like and neural-reactive malignant subpopulations with distinct morphologies and heightened NI potential. This landscape depicting tumor-associated nerves highlights critical cancer-immune-neural interactions in situ and enlightens treatment development targeting NI.
    Keywords:  NI; PDAC; Schwann cells; TLSs; TME; endoneurial fibroblast; neural invasion; neuro-immuno-oncology; pancreatic ductal adenocarcinoma; single-cell RNA sequenceing; spatial transcriptomics; tertiary lymphoid structures; tumor microenvironment; tumor-associated nerves
    DOI:  https://doi.org/10.1016/j.ccell.2025.06.020
  10. Methods Cell Biol. 2025 ;pii: S0091-679X(24)00239-5. [Epub ahead of print]196 43-65
    Assessment of the primary cancer cell secretome using amino acid-analog labeling.
    Annemieke C Bouwman, Antoinette van Weverwijk, Onno B Bleijerveld, Liesbeth Hoekman, Bob J Ignacio, Kimberly M Bonger, Karin E de Visser.
      It is well established that reciprocal communication between cancer cells and other cells in the tumor microenvironment plays a crucial role in cancer progression and therapy response. There are multiple ways by which cells communicate, including direct cell-cell contact and the secretion of soluble mediators. The secretome of cancer cells contains valuable information to disentangle the complex conversation that is happening between cancer cells and neighboring or distant cells such as immune cells, fibroblasts and endothelial cells. Here, we provide a workflow of mapping the cancer cell secretome in an unbiased way using amino acid-analog labeling in combination with mass spectrometry. The generation of single cells from fresh tumors, isolation of primary cancer cells from a complex multi-cellular pool, and the detection of newly synthesized proteins that are secreted into the medium is described in detailed protocols. Using this experimental pipeline the secretome of cancer cells across different tumors can be determined, paving the way to unravel cell-cell communication networks in the tumor microenvironment, which may uncover novel therapeutic targets.
    Keywords:  Amino acid-labeling; Cancer cell secretome; Cancer-immunity crosstalk; Cell-cell interaction; Mass spectometry; Tumor microenvironment
    DOI:  https://doi.org/10.1016/bs.mcb.2024.11.002
  11. bioRxiv. 2024 Dec 22. pii: 2024.12.21.629928. [Epub ahead of print]
    SenSet, a novel human lung senescence cell gene signature, identifies cell-specific senescence mechanisms.
    Euxhen Hasanaj, Delphine Beaulieu, Cankun Wang, Qianjiang Hu, Marta Bueno, John C Sembrat, Ricardo H Pineda, Maria Camila Melo-Narvaez, Nayra Cardenes, Zhao Yanwu, Zhang Yingze, Robert Lafyatis, Alison Morris, Ana Mora, Mauricio Rojas, Dongmei Li, Irfan Rahman, Gloria S Pryhuber, Mareike Lehmann, Jonathan Alder, Aditi Gurkar, Toren Finkel, Qin Ma, Barnabás Póczos, Ziv Bar-Joseph, Oliver Eickelberg, Melanie Königshoff.
      Cellular senescence is a major hallmark of aging. Senescence is defined as an irreversible growth arrest observed when cells are exposed to a variety of stressors including DNA damage, oxidative stress, or nutrient deprivation. While senescence is a well-established driver of aging and age-related diseases, it is a highly heterogeneous process with significant variations across organisms, tissues, and cell types. The relatively low abundance of senescence in healthy aged tissues represents a major challenge to studying senescence in a given organ, including the human lung. To overcome this limitation, we developed a Positive-Unlabeled (PU) learning framework to generate a comprehensive senescence marker gene list in human lungs (termed SenSet) using the largest publicly available single-cell lung dataset, the Human Lung Cell Atlas (HLCA). We validated SenSet in a highly complex ex vivo human 3D lung tissue culture model subjected to the senescence inducers bleomycin, doxorubicin, or irradiation, and established its sensitivity and accuracy in characterizing senescence. Using SenSet, we identified and validated cell-type specific senescence signatures in distinct lung cell populations upon aging and environmental exposures. Our study presents the first comprehensive analysis of senescent cells in the healthy aging lung and uncovers cell-specific gene signatures of senescence, presenting fundamental implications for our understanding of major lung diseases, including cancer, fibrosis, chronic obstructive pulmonary disease, or asthma.
    DOI:  https://doi.org/10.1101/2024.12.21.629928
  12. J Gastrointest Cancer. 2025 Jul 19. 56(1): 158
    Statins and the Risk of Pancreatic Cancer.
    Kuan-Fu Liao, Shih-Wei Lai.
      
    DOI:  https://doi.org/10.1007/s12029-025-01285-x
  13. Nat Cell Biol. 2025 Jul 21.
    TMEM65 functions as the mitochondrial Na+/Ca2+ exchanger.
    Jim Lu Zhang, Yu-Chen Chang, Po-Hsuan Lai, Han-I Yeh, Chen-Wei Tsai, Yu-Lun Huang, Tsung-Yun Liu, I-Chi Lee, North Foulon, Yan Xu, Bing Rao, Hsiu-Man Shih, Yung-Chi Tu, Andres V Reyes, Shou-Ling Xu, Liang Feng, Ming-Feng Tsai.
      Mitochondria export Ca2+ via Na+/Ca2+ exchange machinery (mito-NCX) to regulate intracellular Ca2+ signalling and mitochondrial Ca2+ homeostasis. TMEM65 has recently been implicated as essential for mito-NCX, but its mechanisms and roles remain unclear. Here we show that TMEM65 depletion severely impairs mito-NCX. TMEM65 is highly expressed in the heart and brain but absent in the liver, correlating with mito-NCX activity in these tissues. Biochemical and functional analyses reveal that TMEM65 forms a homodimer, containing plausible ion-coordinating residues critical for function. Heterologous expression of TMEM65 induces Na+/Ca2+ exchange in cells lacking native mito-NCX activity. Moreover, purified, liposome-reconstituted TMEM65 exhibits key mito-NCX features. We further identify the binding site for CGP-37157, a potent, widely used mito-NCX inhibitor. Finally, TMEM65 deletion elevates mitochondrial Ca2+ and primes mitochondria to permeability transition. These findings firmly establish TMEM65 as the protein mediating mito-NCX, offering a new therapeutic target for diseases associated with mitochondrial Ca2+ dysregulation.
    DOI:  https://doi.org/10.1038/s41556-025-01721-x
  14. Cancer Cell. 2025 Jul 11. pii: S1535-6108(25)00268-5. [Epub ahead of print]
    Decoding subclonal anti-tumor immunity.
    Jason E Chan, Tuomas Tammela.
      Subclonal evolution allows tumors to evade the immune system. In this issue of Cancer Cell, Dijkstra et al. combine the TRACERx cohort with co-cultures of autologous tumors and immune cells to functionally profile subclonal immune escape at the single-clone resolution. This work highlights cancer-intrinsic immune-escape mechanisms that can be interrogated on a co-culture platform.
    DOI:  https://doi.org/10.1016/j.ccell.2025.06.018
  15. Cell. 2025 Jul 12. pii: S0092-8674(25)00735-4. [Epub ahead of print]
    Regulation of inflammatory responses by pH-dependent transcriptional condensates.
    Zhongyang Wu, Scott D Pope, Nasiha S Ahmed, Diana L Leung, Yu Hong, Stephanie Hajjar, Cathleen Krabak, Zhe Zhong, Krishnan Raghunathan, Qiuyu Yue, Diya M Anand, Elizabeth B Kopp, Daniel Okin, Weiyi Ma, Ivan Zanoni, Jonathan C Kagan, Jay R Thiagarajah, Diana C Hargreaves, Ruslan Medzhitov, Xu Zhou.
      Inflammation is an essential defense response but operates at the cost of normal tissue functions. Whether and how the negative impact of inflammation is monitored remains largely unknown. Acidification of the tissue microenvironment is associated with inflammation. Here, we investigated whether macrophages sense tissue acidification to adjust inflammatory responses. We found that acidic pH restructured the inflammatory response of macrophages in a gene-specific manner. We identified mammalian BRD4 as an intracellular pH sensor. Acidic pH disrupts transcription condensates containing BRD4 and MED1 via histidine-enriched intrinsically disordered regions. Crucially, a decrease in macrophage intracellular pH is necessary and sufficient to regulate transcriptional condensates in vitro and in vivo, acting as negative feedback to regulate the inflammatory response. Collectively, these findings uncovered a pH-dependent switch in transcriptional condensates that enables environment-dependent control of inflammation, with a broader implication for calibrating the magnitude and quality of inflammation by the inflammatory cost.
    Keywords:  BRD4; IDR; acidosis; gene expression; histidine; inflammatory response; innate immunity; macrophage; pH; transcriptional condensates
    DOI:  https://doi.org/10.1016/j.cell.2025.06.033
  16. Science. 2025 Jul 24. 389(6758): eads0239
    A neomorphic protein interface catalyzes covalent inhibition of RASG12D aspartic acid in tumors.
    Caroline Weller, G Leslie Burnett, Lingyan Jiang, Sujata Chakraborty, Dongyu Zhang, Nicole A Vita, Julien Dilly, Eejung Kim, Benjamin Maldonato, Kyle Seamon, Diane F Eilerts, Anthony Milin, Abby Marquez, Jessica Spradlin, Ciara Helland, Andrea Gould, Tamar Bar Ziv, Phuong Dinh, Shelby L Steele, Zhican Wang, Yunming Mu, Seema Chugh, Hanrong Feng, Conner Hennessey, Junning Wang, Jennifer Roth, Matthew Rees, Melissa Ronan, Brian M Wolpin, William C Hahn, Matthew Holderfield, Zhengping Wang, Elena S Koltun, Mallika Singh, Adrian L Gill, Jacqueline A M Smith, Andrew J Aguirre, Jingjing Jiang, John E Knox, David Wildes.
      Mutant RAS proteins are among the most prevalent drivers of human cancer, and the glycine to aspartic acid mutation at codon 12 (G12D) is the most common variant. Mutation-selective covalent inhibitors spare RAS in healthy tissue and enable extended pharmacodynamic effect, but covalent targeting of RASG12D is hindered by low nucleophilicity and high proteomic abundance of carboxylic acids. We overcame these challenges with compounds that bind cyclophilin A (CYPA) to create a neomorphic protein-protein interface between CYPA and active RAS that enables selective, enzyme-like rate enhancement of the covalent reaction between D12 and electrophilic warheads with exceptionally low intrinsic reactivity. This approach yielded orally bioavailable compounds with marked antitumor activity in multiple preclinical models of KRASG12D cancers, including the investigational agent zoldonrasib (RMC-9805) currently undergoing clinical evaluation (NCT06040541).
    DOI:  https://doi.org/10.1126/science.ads0239
  17. Br J Cancer. 2025 Jul 23.
    The colorectal liver metastasis growth pattern phenotype is not dependent on genotype.
    S:CORT consortium
       BACKGROUND: The histopathological growth patterns (HGPs) of colorectal cancer liver metastases broadly classify patients into two groups post-liver metastasectomy, with encapsulated HGP indicating a more favourable prognosis. The potential association between HGPs and specific mutations is poorly understood.
    METHODS: Using next-generation sequencing data of 461 resected patients (104 patients with encapsulated versus 357 patients with non-encapsulated HGP), 19 putative colorectal cancer driver genes, tumour mutational burden (TMB), and microsatellite instability (MSI) or POLE mediated hypermutation were compared.
    RESULTS: Most putative drivers, including KRAS (q = 0.89), NRAS (q = 0.98),) and BRAF (q = 0.97)), were not associated with HGP. However, mutations in B2M and PTEN were associated with a encapsulated phenotype (7% vs. 0%, q = 0.001, and 9% vs. 2%, q = 0.02, respectively). TMB was higher in encapsulated patients (median 5.8 vs. 5.1 mutations per megabase, p = 0.009). Multivariable overall survival analysis corrected for genetic and patient factors confirmed that the encapsulated phenotype was an independent prognostic factor (adjusted hazard ratio, 0.60; 95% confidence interval: 0.36-0.99). Upon stratified analysis, all identified genetic associations were equivocal between the cohorts.
    CONCLUSIONS: While an association between genetic drivers of adaptive immune responses seems probable and could explain a minority of encapsulated patients, these results primarily demonstrate that HGP phenotype is independent of the tumour genotype.
    DOI:  https://doi.org/10.1038/s41416-025-03103-4
  18. BMC Surg. 2025 Jul 19. 25(1): 299
    Prospective evaluation of surgical treatment of liver metastasizing pancreatic cancer - ScanPan study protocol.
    Kristina Hasselgren, Caroline Williamsson, Johanna Wennerblom, Poya Ghorbani, Maria Gustafsson Liljefors, Heikki Huhta, Margareta Heby, Christopher Månsson, Mia I Johansson, Nils O Elander, Minna Nortunen, Raija Kallio, Asif Halimi, Daniel Öhlund, Per Sandström, Ernesto Sparrelid, Bergthor Björnsson.
       INTRODUCTION: Patients with pancreatic ductal adenocarcinoma (PDAC) have a dismal prognosis. The majority of patients are diagnosed at an advanced stage, and for these patients, the only possible treatment is palliative chemotherapy. There are increasing data from retrospective studies indicating that a subgroup of patients with liver-limited metastases may benefit from surgical treatment of liver metastases. However, there is a need for prospective trials.
    OBJECTIVE: The aim of this study is to prospectively investigate the safety and feasibility of surgically treating patients who are resectable, including those with borderline venous resectable, histopathologically confirmed PDAC, and histopathologically or radiologically confirmed liver metastases.
    METHODS: Five Swedish and one Finnish hepatopancreaticobiliary (HPB) centre will participate. Eligible patients will be identified at regional multidisciplinary conferences (MDTs). Before inclusion, they will undergo computed tomography (CT), magnetic resonance imaging (MRI, ) and (positron emission tomography computed tomography)PET-CT to rule out extrahepatic metastases. To be included, patients will have to have four or fewer liver metastases, which must be no larger than 5 cm for patients planning for resection and no larger than 2 cm for patients planning for ablation. The metastases may be either synchronous or metachronous. Patients will undergo four months of chemotherapy before surgical treatment (either resection or ablation), and postoperatively, they will undergo two months of chemotherapy. For those with synchronous metastases, resection of the pancreatic tumour will be performed. Follow-up will be performed over two years postoperatively with regular CT scans and assessments of quality of life.
    CONCLUSIONS: In conclusion, this trial will provide increased knowledge concerning whether surgical treatment of liver metastases from pancreatic cancer can result in improved survival.
    CLINICAL TRIAL NUMBER: Clinical.
    TRIALS: gov (NCT05271110), registered February 26th 2022.
    Keywords:  Ablation; Liver metastases; Pancreatic cancer; Resection
    DOI:  https://doi.org/10.1186/s12893-025-02983-w
  19. Autophagy. 2025 Jul 23.
    Npl3 is required for efficient autophagosome-vacuole fusion.
    Zhangyuan Yin, Zhihai Zhang, Xu Liu, Daniel J Klionsky.
      Macroautophagy/autophagy is a highly conserved catabolic membrane trafficking process through which various intracellular constituents, from proteins to organelles, are targeted for vacuolar/lysosomal degradation. Autophagy is tightly regulated both temporally and in magnitude at multiple levels to prevent either excessive or insufficient activity. To date, only a few RNA-binding proteins have been characterized as regulating the expression of genes essential for autophagy, and the contribution of post-transcriptional regulation in autophagy activity remains poorly understood. Here, through a genetic screen for autophagy-defective mutants, we identified Npl3, a nucleus-cytoplasm shuttling mRNA-binding protein, as essential for both bulk and selective types of autophagy. Deletion of NPL3 does not affect autophagosome biogenesis, closure, or maturation; however, it severely impairs autophagosome-vacuole fusion and results in minimal autophagosome turnover. We further demonstrated that this regulation depends on the RNA-binding domain of Npl3 and its capability for nuclear re-import. Together, our results reveal a novel layer of post-transcriptional regulation of autophagy.
    Keywords:  Autophagy; RNA-binding protein; membrane trafficking
    DOI:  https://doi.org/10.1080/15548627.2025.2537559
  20. Autophagy. 2025 Aug;21(8): 1621-1622
    Coping with stress: the essential role of brain autophagy in emotional homeostasis.
    Dimitra Dialynaki, Daniel J Klionsky.
      
    DOI:  https://doi.org/10.1080/15548627.2025.2520091
  21. Nature. 2025 Jul 22.
    Breaking point: mechanical stress helps NINJ1 protein to rupture membranes.
    Ishan Deshpande, Vishva M Dixit.
      
    Keywords:  Cell biology; Immunology
    DOI:  https://doi.org/10.1038/d41586-025-02130-8
  22. J Cell Biol. 2025 Aug 04. pii: e202504076. [Epub ahead of print]224(8):
    The rapidly expanding role of LC3-interacting regions in autophagy.
    Brian J North, Dorotea Fracchiolla, Michael J Ragusa, Sascha Martens, Christopher J Shoemaker.
      LC3-interacting regions (LIRs), or Atg8-interacting motifs (AIMs), are short linear motifs found in unstructured loops or intrinsically disordered regions of many autophagy-related proteins. LIRs were initially identified for their role in binding to Atg8 family proteins on autophagosomal membranes. However, emerging evidence suggests that LIRs and their surrounding residues mediate interactions with a wide array of proteins beyond Atg8s. This broadens the biological significance of LIRs in autophagy, rendering them an organizing principle of the autophagy machinery. In this perspective, we explore recent advances highlighting the multifunctional roles of LIRs, including their capacity to mediate binding with diverse factors. We discuss insights into the mechanisms underlying LIR-mediated interactions and propose an updated model to explain Atg8 diversification in higher eukaryotes. We conclude by addressing key challenges and outlining future directions for understanding LIR biology and its broader implications for cellular homeostasis.
    DOI:  https://doi.org/10.1083/jcb.202504076
  23. Front Oncol. 2025 ;15 1599175
    Lamins regulate cancer cell plasticity and chemosensitivity.
    Guofang Chen, Tingyi Wei, Ao Huang, Junwei Shen, Furong Ju, Shichao Huang, Haisen Li.
       Background: Stem cell plasticity plays key roles in mammalian organogenesis, tissue homeostasis, and carcinogenesis. Given its tolerance to anti-tumor therapy and its promotion on immunosuppressive microenvironment, cancer cell plasticity is a major contributor to cancer recurrence and metastasis. It is necessary to explore novel avenues to resolve the limitations of current treatments.
    Methods: We established stable cancer cell lines harboring all lamin knockdown and then explored the effects of all lamin deficiency on cancer plasticity and tumorigenesis in both cell and subcutaneous mouse models.
    Results: We found that all lamin knockdown disrupts cancer cell plasticity and impairs tumor progression. The deficiency of all lamin subtypes impaired the stemness and cell cycle transition of cancer cell. Lamin knockdown modulated genomic damage and repair pathways, inhibited mitochondrial function, and triggered cellular senescence. Moreover, lamin knockdown within cancer cell suppressed cancer growth in vivo by enhancing the infiltration and activation of functional T cells. Mechanistically, lamin knockdown reduced the expression of inhibitory immune checkpoints and inflammatory factors in cancer cell via the HIF-1 signaling pathway, which led to the increased sensitivity of cancer cells to chemotherapy.
    Conclusions: Overall, our findings characterize the significance of nuclear lamins in cancer cell plasticity and offer an attractive way to improve the effectiveness of anti-cancer therapy.
    Keywords:  HIF-1 signaling; PD-L1; cancer cell plasticity; chemosensitivity; lamin
    DOI:  https://doi.org/10.3389/fonc.2025.1599175
  24. Proc Natl Acad Sci U S A. 2025 Jul 29. 122(30): e2425422122
    Amino acid transfer free energies reveal thermodynamic driving forces in biomolecular condensate formation.
    Shiv Rekhi, Jeetain Mittal.
      The self-assembly of intrinsically disordered proteins into biomolecular condensates depends on their primary sequence, leading to sequence-dependent phase separation. Computational methods to study this behavior often rely on residue-level interaction potentials that estimate the propensity of amino acids to partition between the dilute and dense phases. While distribution coefficients would provide the most direct measure of these potentials, their unavailability has led to the use of proxies, most notably, hydropathy. However, recent studies have highlighted limitations in hydropathy-based models. Here, we address this fundamental gap by calculating the transfer free energies for amino acid side chain analogs moving from the dilute phase to the dense phase of biomolecular condensates. We find that, net transfer free energies arise from a balance between favorable protein-mediated and unfavorable water-mediated interactions, with a striking asymmetry between the contributions of positive and negatively charged residues. This asymmetry originates from the stronger solvation of negatively charged species, and extends to modified amino acids. We further demonstrate that the sequence features of the condensate-forming protein modulate these transfer free energies in a context-dependent, but qualitatively similar manner. These findings help explain nontrivial experimental trends and provide a foundation for interpreting the sequence-dependent driving forces underlying condensate formation.
    DOI:  https://doi.org/10.1073/pnas.2425422122
  25. Nature. 2025 Jul 23.
    NNMT inhibition in cancer-associated fibroblasts restores antitumour immunity.
    Janna Heide, Agnes J Bilecz, Samarjit Patnaik, Maria Francesca Allega, Leonhard Donle, Kaiting Yang, Ethan Teich, Yan Li, Qiaoshan Lin, Ke Kong, Li Liu, Tae Gyun Yang, Ken Chih-Chien Cheng, Jonathan H Shrimp, Quinlin M Hanson, Min Shen, Hongmao Sun, Hardik Shah, Lisa Schweizer, Katarzyna Zawieracz, Andrea Olland, Andre White, Robert K Suto, Razzaq Alhunayan, Medine Taşdemir, Noa Longman, Hua Liang, Matthias Mann, Gordon M Stott, Matthew D Hall, Simon Schwörer, Ralph R Weichselbaum, András Piffkó, Ernst Lengyel.
      Cancer-associated fibroblasts (CAFs) have a pivotal cancer-supportive role, yet CAF-targeted therapies are lacking1,2. Here, using spatial transcriptomics and single-cell RNA sequencing, we investigate the role of nicotinamide N-methyltransferase (NNMT) in high-grade serous ovarian cancer. Mechanistically, NNMT-induced H3K27me3 hypomethylation drives complement secretion from CAFs, attracting immunosuppressive myeloid-derived suppressor cells (MDSCs) to the tumour. Nnmt knockout in immunocompetent mice impairs tumour growth in syngeneic ovarian, breast and colon tumour models through enhanced CD8+ T cell activation. Using high-throughput screening, we develop a potent and specific NNMT inhibitor that reduces the tumour burden and metastasis in multiple mouse cancer models and restores immune checkpoint blockade efficacy by decreasing CAF-mediated recruitment of MDSCs and reinvigorating CD8+ T cell activation. Our findings establish NNMT as a central CAF regulator and a promising therapeutic target to mitigate immunosuppression in the tumour microenvironment.
    DOI:  https://doi.org/10.1038/s41586-025-09303-5
  26. EMBO J. 2025 Jul 21.
    mTORC1 senses glutamine and other amino acids through GCN2.
    Gianluca Figlia, Sandra Müller, Fabiola Garcia-Cortizo, Marilena Neff, Glynis Klinke, Gernot Poschet, Aurelio A Teleman.
      mTORC1 promotes cell growth when nutrients such as amino acids are available. While dedicated sensors relaying availability of leucine, arginine and methionine to mTORC1 have been identified, it is still unclear how mTORC1 senses glutamine, one of its most potent inducers. Here, we find that glutamine is entirely sensed through the protein kinase GCN2, whose initial activation is not triggered by depletion of glutamine itself, but by the concomitant depletion of asparagine. In turn, GCN2 leads to a succession of events that additively inhibit mTORC1: within 1 h, GCN2 inhibits mTORC1 through the Rag GTPases, independently of its function as an eIF2α kinase. Later, GCN2-mediated induction of ATF4 upregulates Ddit4 followed by Sestrin2, which together cause additional mTORC1 inhibition. Additionally, we find that depletion of virtually any other amino acid also inhibits mTORC1 through GCN2. GCN2 and the dedicated amino acid sensors thus represent two independent systems that enable mTORC1 to perceive a wide spectrum of amino acids.
    Keywords:  Amino Acid Sensors; Asparagine; GCN2; Glutamine; mTORC1
    DOI:  https://doi.org/10.1038/s44318-025-00505-1
  27. Adv Sci (Weinh). 2025 Jul 21. e08431
    SenExo-cCCT2 Reprograms Senescence Response and Anti-Tumor Immunity Following FOLFIRINOX Chemotherapy in Pancreatic Ductal Adenocarcinoma.
    Shuncang Zhu, Yinhao Chen, Hongyi Lin, Jinpeng Lu, Yu Pan, Ge Li, Yongding Wu, Haoxiang Zhang, Xiaoxiao Huang, Yiting Chen, Huangjing Chen, Long Jin, Min Huang, Chengyu Liao, Long Huang, Yifeng Tian, Zuwei Wang, Qiaowei Li, Shi Chen.
      Combination chemotherapy and immunotherapy have failed to achieve breakthroughs in pancreatic ductal adenocarcinoma (PDAC). Chemotherapy-induced senescence is a potential solution for this problem. This study integrates clinical samples with single-cell transcriptomic sequencing, proteomics, and RNA sequencing and reveals that FOLFIRINOX (a combination regimen of 5-fluorouracil, oxaliplatin, irinotecan, and leucovorin) treatment induces a higher proportion of senescent tumor cells (senTCs). This phenomenon is principally attributed to the presence of cCCT2, which inhibits SLX4 condensate-mediated DNA damage repair pathways by regulating small ubiquitin-like modifier conjugation, thereby promoting tumor cell senescence. In the tumor immune microenvironment, cCCT2-overexpressing senTCs exhibit a senescence-associated secretory phenotype (SASP) with preferential secretion of CXCL10, which induces chemotaxis of CD8+ T-cells. Based on the pro-senescence and immune-microenvironment-remodeling effects of cCCT2, an engineered exosome-loaded circRNA system, SenExo-cCCT2 is developed. When combined with SenExo-cCCT2, the FOLFIRINOX regimen enhances the capacity of pancreatic cancer cells to induce senescence. Subsequently, anti-PD-L1 therapy facilitates the immune-mediated clearance of senTCs, markedly improving the therapeutic efficacy of combined chemotherapy and immunotherapy for pancreatic cancer.
    Keywords:  CD8+ T‐cells; chemotherapy; circRNA; pancreatic ductal adenocarcinoma; senescence
    DOI:  https://doi.org/10.1002/advs.202508431
  28. Elife. 2025 Jul 22. pii: e108102. [Epub ahead of print]14
    Closing in on pacemaker cells.
    Pin-Ji Lei, Timothy P Padera.
      Lymphatic muscle cells orchestrate the contraction of collecting lymphatic vessels in mice.
    Keywords:  cell biology; cell contractions; lymphatic system; mouse; muscle cells; pacemaker cells
    DOI:  https://doi.org/10.7554/eLife.108102
This page is being maintained by Thomas Krichel. It was last updated on 2025‒07‒28 at 10:58.