bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2025–04–20
34 papers selected by
Kıvanç Görgülü, Technical University of Munich



  1. bioRxiv. 2025 Apr 06. pii: 2025.04.04.645324. [Epub ahead of print]
      High-fat diet (HFD) intake has been linked to an increased risk of pancreatic ductal adenocarcinoma (PDAC), a lethal and therapy-resistant cancer. However, whether and how specific dietary fats drive cancer development remains unresolved. Leveraging an oncogenic Kras -driven mouse model that closely mimics human PDAC progression, we screened a dozen isocaloric HFDs differing solely in fat source and representing the diversity of human fat consumption. Unexpectedly, diets rich in oleic acid - a monounsaturated fatty acid (MUFA) typically associated with good health - markedly enhanced tumorigenesis. Conversely, diets high in polyunsaturated fatty acids (PUFAs) suppressed tumor progression. Relative dietary fatty acid saturation levels (PUFA/MUFA) governed pancreatic membrane phospholipid composition, lipid peroxidation, and ferroptosis sensitivity in mice, concordant with circulating PUFA/MUFA levels being linked to altered PDAC risk in humans. These findings directly implicate dietary unsaturated fatty acids in controlling ferroptosis susceptibility and tumorigenesis, supporting potential "precision nutrition" strategies for PDAC prevention.
    DOI:  https://doi.org/10.1101/2025.04.04.645324
  2. Cell Metab. 2025 Apr 08. pii: S1550-4131(25)00149-4. [Epub ahead of print]
      The release of cytochrome c, somatic (CYCS) from mitochondria to the cytosol is an established trigger of caspase-dependent apoptosis. Here, we unveil an unexpected role for cytosolic CYCS in inhibiting ferroptosis-a form of oxidative cell death driven by uncontrolled lipid peroxidation. Mass spectrometry and site-directed mutagenesis revealed the existence of a cytosolic complex composed of inositol polyphosphate-4-phosphatase type I A (INPP4A) and CYCS. This CYCS-INPP4A complex is distinct from the CYCS-apoptotic peptidase activating factor 1 (APAF1)-caspase-9 apoptosome formed during mitochondrial apoptosis. CYCS boosts INPP4A activity, leading to increased formation of phosphatidylinositol-3-phosphate, which prevents phospholipid peroxidation and plasma membrane rupture, thus averting ferroptotic cell death. Unbiased screening led to the identification of the small-molecule compound 10A3, which disrupts the CYCS-INPP4A interaction. 10A3 sensitized cultured cells and tumors implanted in immunocompetent mice to ferroptosis. Collectively, these findings redefine our understanding of cytosolic CYCS complexes that govern diverse cell death pathways.
    Keywords:  apoptosis; cytochrome c; ferroptosis; protein complex
    DOI:  https://doi.org/10.1016/j.cmet.2025.03.014
  3. Biochem Biophys Res Commun. 2025 Apr 05. pii: S0006-291X(25)00480-2. [Epub ahead of print]763 151766
      Cancer cachexia is a multifactorial metabolic syndrome characterized by progressive weight loss, muscle wasting, and systemic inflammation. Despite its clinical significance, the underlying mechanisms linking central and peripheral metabolic changes remain incompletely understood. In this study, we employed a murine model of cancer cachexia induced by intraperitoneal injection of Lewis lung carcinoma (LLC1) cells to investigate tissue-specific metabolic adaptations. Cachectic mice exhibited reduced food intake, body weight loss, impaired thermoregulation, and decreased energy expenditure. Metabolomic profiling of serum, skeletal muscle, and hypothalamus revealed distinct metabolic shifts, with increased fatty acid and ketone body utilization and altered amino acid metabolism. Notably, hypothalamic metabolite changes diverged from peripheral tissues, showing decreased neurotransmitter-related metabolites and enhanced lipid-based energy signatures. Gene expression analysis further confirmed upregulation of glycolysis- and lipid oxidation-related genes in both hypothalamus and muscle. These findings highlight coordinated yet compartmentalized metabolic remodeling in cancer cachexia and suggest that hypothalamic adaptations may play a central role in the systemic energy imbalance associated with cachexia progression.
    Keywords:  Cancer cachexia; Energy metabolism; Hypothalamus; Metabolites; Muscle
    DOI:  https://doi.org/10.1016/j.bbrc.2025.151766
  4. Cancers (Basel). 2025 Apr 04. pii: 1226. [Epub ahead of print]17(7):
      Pancreatic Ductal Adenocarcinoma (PDAC) belongs to the types of cancer with the highest lethality. It is also remarkably chemoresistant to the few available cytotoxic therapeutic options. PDAC is characterized by limited mutational heterogeneity of the known driver genes, KRAS, CDKN2A, TP53, and SMAD4, observed in both early-stage and advanced tumors. In this review, we summarize the two proposed models of genetic evolution of pancreatic cancer. The gradual or stepwise accumulated mutations model has been widely studied. On the contrary, less evidence exists on the more recent simultaneous model, according to which rapid tumor evolution is driven by the concurrent accumulation of genetic alterations. In both models, oncogenic KRAS mutations are the main initiating event. Here, we analyze the emerging topic of KRAS allelic imbalances and how it arises during tumor evolution, as it is often detected in advanced and metastatic PDAC. We also summarize recent evidence on how it affects tumor biology, metastasis, and response to therapy. To this extent, we highlight the necessity to include studies of KRAS allelic frequencies in the design of future therapeutic strategies against pancreatic cancer.
    Keywords:  KRAS; allelic imbalance; genomic rearrangements; loss of heterozygosity; metastasis; pancreatic ductal adenocarcinoma (PDAC); tumor evolution; wild-type allele
    DOI:  https://doi.org/10.3390/cancers17071226
  5. Cell. 2025 Apr 08. pii: S0092-8674(25)00292-2. [Epub ahead of print]
      Ferroptosis is a form of cell death due to iron-induced lipid peroxidation. Ferroptosis suppressor protein 1 (FSP1) protects against this death by generating antioxidants, which requires nicotinamide adenine dinucleotide, reduced form (NADH) as a cofactor. We initially uncover that NADH exists at significant levels on cellular membranes and then find that this form of NADH is generated by aldehyde dehydrogenase 7A1 (ALDH7A1) to support FSP1 activity. ALDH7A1 activity also acts directly to decrease lipid peroxidation by consuming reactive aldehydes. Furthermore, ALDH7A1 promotes the membrane recruitment of FSP1, which is instigated by ferroptotic stress activating AMP-activated protein kinase (AMPK) to promote the membrane localization of ALDH7A1 that stabilizes FSP1 on membranes. These findings advance a fundamental understanding of NADH by revealing a previously unappreciated pool on cellular membranes, with the elucidation of its function providing a major understanding of how FSP1 acts and how an aldehyde dehydrogenase protects against ferroptosis.
    Keywords:  aldehyde dehydrogenase 7A1; ferroptosis; ferroptosis suppressor protein 1; nicotinamide adenine dinucleotide reduced form
    DOI:  https://doi.org/10.1016/j.cell.2025.03.019
  6. Biophys J. 2025 Apr 14. pii: S0006-3495(25)00238-3. [Epub ahead of print]
      The assembly of integrin adhesion complexes at the inner leaflet of the plasma membrane regulates cell adhesion to the extracellular matrix. The multivalent protein interactions within the complexes and with the cell membrane display characteristics of membrane-associated biomolecular condensates driven by liquid-liquid phase separation. The composition of lipids and the distribution of the cell membrane are crucial for forming integrin adhesion complexes. Here, we report that PIP2 and PIP3in the model membrane synergistically regulate the formation of membrane-induced integrin adhesion condensates, which consist of β1 tails, kindlin, talin, paxillin, and FAK. We show that the preferential bindings of kindlin to PIP3 and talin to PIP2 enhance their recruitment to the membrane, which in turn increases the probability of membrane-associated phase separation. Our results indicate that modulating the intricate balance of membrane composition is a strategy to localize integrin adhesion complexes and optimize their density on lipid membranes.
    DOI:  https://doi.org/10.1016/j.bpj.2025.04.011
  7. Curr Opin Cell Biol. 2025 Apr 11. pii: S0955-0674(25)00051-1. [Epub ahead of print]94 102513
      Macropinocytosis is known as nonselective drinking of the cellular milieu for scavenging of nutrients and uptake of extracellular fluids. It has recently gained attention in cancer research, as targeting the uptake of nutrients or chemotherapeutic particles by tumor cells holds promise for new therapeutic interventions. Macropinocytic cups form from actin-based protrusions that coalesce into cups and collapse into large vesicles containing cargoes and transmembrane receptors, which can then be degraded in lysosomes or recycled back to the plasma membrane. How macropinocytosis is triggered and the various ways that cells utilize cargoes are topics of much interest. Here, we discuss emerging evidence that cargo or membrane receptor uptake in macropinocytosis may in some cases be selective and may substantially alter cell surface receptor trafficking and display.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102513
  8. J Cachexia Sarcopenia Muscle. 2025 Apr;16(2): e13781
       BACKGROUND: Cancer cachexia, affecting up to 80% of patients with cancer, is characterized by muscle and fat loss with functional decline. Preclinical research seeks to uncover the molecular mechanisms underlying cachexia to identify potential targets. Housing laboratory mice at ambient temperature induces cold stress, triggering thermogenic activity and metabolic adaptations. Yet, the impact of housing temperature on preclinical cachexia remains unknown.
    METHODS: Colon 26 carcinoma (C26)-bearing and PBS-inoculated (Ctrl) mice were housed at standard (ST; 20°C-22°C) or thermoneutral temperature (TN; 28°C-32°C). They were monitored for body weight, composition, food intake and systemic factors. Upon necropsy, tissues were weighed and used for evaluation of ex vivo force and respiration, or snap frozen for biochemical assays.
    RESULTS: C26 mice lost 7.5% body weight (p = 0.0001 vs. Ctrls), accounted by decreased fat mass (-35%, p < 0.0001 vs. Ctrls), showing mild cachexia irrespective of housing temperature. All C26 mice exhibited reduced force (-40%, p < 0.0001 vs. Ctrls) and increased atrogene expression (3-fold, p < 0.003 vs. Ctrls). Cancer altered white adipose tissue (WAT)'s functional gene signature (49%, p < 0.05 vs. Ctrls), whereas housing temperature reduced brown adipose tissue (BAT)'s (-78%, p < 0.05 vs. ST Ctrl). Thermogenic capacity measured by Ucp1 expression decreased upon cancer in both WAT and BAT (-93% and -63%, p < 0.0044 vs. Ctrls). Cancer-driven glucose intolerance was noted at ST (26%, p = 0.0192 vs. ST Ctrl), but restored at TN (-23%, p = 0.005 vs. ST C26). Circulating FGF21, GDF-15 and IL-6 increased in all C26 mice (4-fold, p < 0.009 vs. Ctrls), with a greater effect on IL-6 at TN (76%, p = 0.0018 vs. ST C26). Tumour and WAT Il6 mRNA levels remained unchanged, while cancer induced skeletal muscle (SkM) Il6 (2-fold, p = 0.0016 vs. Ctrls) at both temperatures. BAT Il6 was only induced in C26 mice at TN (116%, p = 0.0087 vs. ST C26). At the bioenergetics level, cancer increased SkM SERCA ATPase activity at ST (4-fold, p = 0.0108 vs. ST Ctrl) but not at TN. In BAT, O2 consumption enhanced in C26 mice at ST (119%, p < 0.03 vs. ST Ctrl) but was blunted at TN (-44%, p < 0.0001 vs. ST C26). Cancer increased BAT ATP levels regardless of temperature (2-fold, p = 0.0046 vs. Ctrls), while SERCA ATPase activity remained unchanged at ST and decreased at TN (-59%, p = 0.0213 vs. TN Ctrl).
    CONCLUSIONS: In mild cachexia, BAT and SkM bioenergetics are susceptible to different housing temperatures, which influences cancer-induced alterations in glucose metabolism and systemic responses.
    Keywords:  bioenergetics; cancer cachexia; cold‐induced stress; thermogenic tissues; thermoneutrality
    DOI:  https://doi.org/10.1002/jcsm.13781
  9. Nat Cancer. 2025 Apr 18.
      Comprehensively studying metabolism requires metabolite measurements. Such measurements, however, are often unavailable in large cohorts of tissue samples. To address this basic barrier, we propose a Bayesian framework ('UnitedMet') that leverages RNA-metabolite covariation to impute otherwise unmeasured metabolite levels from widely available transcriptomic data. UnitedMet is equally capable of imputing whole pool sizes and outcomes of isotope tracing experiments. We apply UnitedMet to investigate the metabolic impact of driver mutations in kidney cancer, identifying an association between BAP1 and a highly oxidative tumor phenotype. We similarly apply UnitedMet to determine that advanced kidney cancers upregulate oxidative phosphorylation relative to early-stage disease, that oxidative metabolism in kidney cancer is associated with inferior outcomes to anti-angiogenic therapy and that kidney cancer metastases demonstrate elevated oxidative phosphorylation. UnitedMet provides a scalable tool for assessing metabolic phenotypes when direct measurements are infeasible, facilitating unexplored avenues for metabolite-focused hypothesis generation.
    DOI:  https://doi.org/10.1038/s43018-025-00943-0
  10. Autophagy. 2025 Apr 16.
      Canonical autophagy is an intracellular pathway that degrades and recycles cellular components. A key step of this pathway is the formation of double-membraned organelles, known as autophagosomes, an emblematic feature of macroautophagy. For convenience, the formation of autophagosomes can be categorized into sequential steps, initiation (X), expansion (Y) and closure (Z). ATG9A is an integral membrane protein known for its role in the X and Y steps. whereby it organizes phagophore membrane assembly and its growth. Here, we report a previously unappreciated function of mammalian ATG9A in directing the last step Z. In particular, ATG9A partners with the key ESCRT-III component CHMP2A through IQGAP1 to facilitate autophagosome closure. Thus, ATG9A orchestrates all stages of autophagosome membrane biogenesis, from phagophore initiation to its closure. This makes ATG9A a unique ATG factor that works as a central hub in autophagosome biogenesis.
    Keywords:  Autophagy; ESCRT; IQGAP; closure; mitophagy; phagophore; tuberculosis
    DOI:  https://doi.org/10.1080/15548627.2025.2494802
  11. Cell Rep Methods. 2025 Apr 08. pii: S2667-2375(25)00063-3. [Epub ahead of print] 101027
      Mitochondrial stress arises from a variety of sources, including mutations to mitochondrial DNA, the generation of reactive oxygen species, and an insufficient supply of oxygen or fuel. Mitochondrial stress induces a range of dedicated responses that repair damage and restore mitochondrial health. However, a systematic characterization of transcriptional and metabolic signatures induced by distinct types of mitochondrial stress is lacking. Here, we defined how primary human fibroblasts respond to a panel of mitochondrial inhibitors to trigger adaptive stress responses. Using metabolomic and transcriptomic analyses, we established integrated signatures of mitochondrial stress. We developed a tool, stress quantification using integrated datasets (SQUID), to deconvolute mitochondrial stress signatures from existing datasets. Using SQUID, we profiled mitochondrial stress in The Cancer Genome Atlas (TCGA) PanCancer Atlas, identifying a signature of pyruvate import deficiency in IDH1-mutant glioma. Thus, this study defines a tool to identify specific mitochondrial stress signatures, which may be applied to a range of systems.
    Keywords:  CP: Metabolism; CP: Systems biology; cancer metabolism; integrated multi-omics; integrated stress response; metabolomics; mitochondria; mitochondrial stress response; mitochondrial unfolded protein response; stress signatures
    DOI:  https://doi.org/10.1016/j.crmeth.2025.101027
  12. Nutr Cancer. 2025 Apr 16. 1-10
      Cancer cachexia is a multifactorial syndrome characterized by progressive weight loss, predominantly due to the depletion of skeletal muscle mass and adipose tissue. This meta-analysis aimed to evaluate the prognostic impact of cancer cachexia on overall survival in patients with gastrointestinal cancers. Two independent investigators conducted a systematic literature search across PubMed, Embase, and Web of Science. Eligible studies included cohort studies and post hoc analyses of clinical trials that examined the association between cancer cachexia and overall survival in gastrointestinal cancer patients. A total of 22 studies involving 10,480 patients were included in the analysis. The pooled prevalence of cachexia among gastrointestinal cancer patients was 50% (95% confidence interval [CI] 41-59). Meta-analysis demonstrated that cancer cachexia was significantly associated with reduced overall survival (hazard ratio [HR] 1.50; 95% CI 1.35-1.68). Subgroup analyses further confirmed that cancer cachexia remained a robust predictor of poorer survival, irrespective of study design, gastrointestinal cancer subtype, patients' age, country of origin, tumor stage, cachexia definition, or follow-up duration. These findings indicate that cancer cachexia is highly prevalent among gastrointestinal cancer patients and serves as a significant independent predictor of shortened overall survival.
    DOI:  https://doi.org/10.1080/01635581.2025.2492126
  13. Cancer Cell. 2025 Apr 14. pii: S1535-6108(25)00125-4. [Epub ahead of print]43(4): 575-576
      
    DOI:  https://doi.org/10.1016/j.ccell.2025.03.024
  14. Mol Cancer. 2025 Apr 16. 24(1): 118
      The vast majority of cancer-related deaths are attributed to metastasis. The lung, being a common site for cancer metastasis, is highly prone to being a target for multiple cancer types and causes a heavy disease burden. Accumulating evidence has demonstrated that tumor metastasis necessitates continuous interactions between tumor cells and distant metastatic niches. Nevertheless, a comprehensive elucidation of the underlying mechanisms governing lung-specific metastasis still poses a formidable challenge. In this review, we depict the lung susceptibility and the molecular profiles of tumors with the potential for lung metastasis. Under the conceptual framework of "Reciprocal Tumor-Lung Metastatic Symbiosis" (RTLMS), we mechanistically delineate the bidirectional regulatory dynamics and coevolutionary adaptation between tumor cells and distal pulmonary niches during lung-specific metastasis, including the induction of pre-metastatic-niches, positive responses of the lung, tumor colonization, dormancy, and reawakening. An enhanced understanding of the latest mechanisms is essential for developing targeted strategies to counteract lung-specific metastasis.
    Keywords:  Coevolution; Dormancy; Lung-specific metastasis; Pre-metastatic niche; Reawakening; Reciprocal Tumor-Lung Metastatic Symbiosis (RTLMS); Tumor colonization
    DOI:  https://doi.org/10.1186/s12943-025-02318-6
  15. Nature. 2025 Apr;640(8059): 623-633
      The rapid advent of high-throughput omics technologies has created an exponential growth in biological data, often outpacing our ability to derive molecular insights. Large-language models have shown a way out of this data deluge in natural language processing by integrating massive datasets into a joint model with manifold downstream use cases. Here we envision developing multimodal foundation models, pretrained on diverse omics datasets, including genomics, transcriptomics, epigenomics, proteomics, metabolomics and spatial profiling. These models are expected to exhibit unprecedented potential for characterizing the molecular states of cells across a broad continuum, thereby facilitating the creation of holistic maps of cells, genes and tissues. Context-specific transfer learning of the foundation models can empower diverse applications from novel cell-type recognition, biomarker discovery and gene regulation inference, to in silico perturbations. This new paradigm could launch an era of artificial intelligence-empowered analyses, one that promises to unravel the intricate complexities of molecular cell biology, to support experimental design and, more broadly, to profoundly extend our understanding of life sciences.
    DOI:  https://doi.org/10.1038/s41586-025-08710-y
  16. STAR Protoc. 2025 Apr 15. pii: S2666-1667(25)00167-4. [Epub ahead of print]6(2): 103761
      Transit time is a key in vivo metric of gastrointestinal (GI) motility, which is a physiologic readout of cellular communication within the enteric system. Here, we present a protocol to characterize longitudinal gut motility in mice. We describe steps for transit testing, whole-mount immunostaining, and tissue harvest. We then detail procedures for image processing and manual cell counting. This protocol seeks to minimize inter-trial variability while assessing cellular and molecular features that may underpin motility differences between experimental conditions. For complete details on the use and execution of this protocol, please refer to Frith et al.1.
    Keywords:  Metabolism; Model Organisms; Systems biology
    DOI:  https://doi.org/10.1016/j.xpro.2025.103761
  17. Cell. 2025 Apr 17. pii: S0092-8674(25)00284-3. [Epub ahead of print]188(8): 2043-2062
      Major progress has been made in elucidating the molecular, cellular, and supracellular mechanisms underlying aging. This has spurred the birth of geroscience, which aims to identify actionable hallmarks of aging. Aging can be viewed as a process that is promoted by overactivation of gerogenes, i.e., genes and molecular pathways that favor biological aging, and alternatively slowed down by gerosuppressors, much as cancers are caused by the activation of oncogenes and prevented by tumor suppressors. Such gerogenes and gerosuppressors are often associated with age-related diseases in human population studies but also offer targets for modeling age-related diseases in animal models and treating or preventing such diseases in humans. Gerogenes and gerosuppressors interact with environmental, behavioral, and psychological risk factors to determine the heterogeneous trajectory of biological aging and disease manifestation. New molecular profiling technologies enable the characterization of gerogenic and gerosuppressive pathways, which serve as biomarkers of aging, hence inaugurating the era of precision geromedicine. It is anticipated that, pending results from randomized clinical trials and regulatory approval, gerotherapeutics will be tailored to each person based on their genetic profile, high-dimensional omics-based biomarkers of aging, clinical and digital biomarkers of aging, psychosocial profile, and past or present exposures.
    Keywords:  aging; aging clocks; anti-aging drugs; atherosclerosis; cancer; cardiovascular diseases; diabetes; epigenetic clocks; genomics; neurodegeneration; oncogene; oncosuppression; primary prevention
    DOI:  https://doi.org/10.1016/j.cell.2025.03.011
  18. STAR Protoc. 2025 Apr 11. pii: S2666-1667(25)00152-2. [Epub ahead of print]6(2): 103746
      Atomic force microscopy (AFM) is a powerful technique that enables the determination of cellular mechanics at the single-cell level. Here, we present a protocol for using AFM to measure membrane mechanical properties of mouse ventricular cardiomyocytes. The key steps include isolation of mouse cardiomyocytes, cantilever preparation, modification and calibration, and measurement of force-deformation profiles, from which membrane Young's moduli are quantified. The outcomes advance our knowledge of cardiomyocyte's unique mechanical and dynamic properties.
    Keywords:  Atomic Force Microscopy (AFM); Biophysics; Cell Biology; Cell isolation; Health Sciences; Single Cell
    DOI:  https://doi.org/10.1016/j.xpro.2025.103746
  19. Nat Commun. 2025 Apr 15. 16(1): 3554
      Ferroptosis, a form of cell death instigated by iron-dependent lipid peroxidation reactions (LPO), is emerging as a promising therapeutic target for cancer. While the mechanisms governing LPO induction and suppression have gradually been unveiled, questions persist regarding the specific cellular location of LPO and the utilization of iron in driving cell death. A comprehensive understanding of these aspects holds significant potential for advancing therapeutic applications in disease management. Here, we show lysosomal LPO in the initiation of ferroptosis, leveraging the hidden abilities of fluorescent detection probes. Intra-lysosomal LPO triggers iron leakage, fostering cell-wide LPO by augmenting lysosomal membrane permeabilization (LMP). Conversely, cell lines with low susceptibility to ferroptosis do not exhibit LMP. This deficiency is rectified by the concurrent administration of chloroquine, leading to LMP induction and subsequent cell death. These findings underscore enhancing LMP induction efficacy as a strategic approach to surmount resistance to therapies in cancer.
    DOI:  https://doi.org/10.1038/s41467-025-58909-w
  20. Cell Genom. 2025 Apr 15. pii: S2666-979X(25)00107-7. [Epub ahead of print] 100851
    Clinical Proteomic Tumor Analysis Consortium
      Cancer progression and therapeutic resistance are closely linked to a stemness phenotype. Here, we introduce a protein-expression-based stemness index (PROTsi) to evaluate oncogenic dedifferentiation in relation to histopathology, molecular features, and clinical outcomes. Utilizing datasets from the Clinical Proteomic Tumor Analysis Consortium across 11 tumor types, we validate PROTsi's effectiveness in accurately quantifying stem-like features. Through integration of PROTsi with multi-omics, including protein post-translational modifications, we identify molecular features associated with stemness and proteins that act as active nodes within transcriptional networks, driving tumor aggressiveness. Proteins highly correlated with stemness were identified as potential drug targets, both shared and tumor specific. These stemness-associated proteins demonstrate predictive value for clinical outcomes, as confirmed by immunohistochemistry in multiple samples. The findings emphasize PROTsi's efficacy as a valuable tool for selecting predictive protein targets, a crucial step in customizing anti-cancer therapy and advancing the clinical development of cures for cancer patients.
    Keywords:  biomarkers; cancer; drug targets; kinase activity; machine learning; mass spectrometry; multiomics; proteomics; stemness; tumor plasticity
    DOI:  https://doi.org/10.1016/j.xgen.2025.100851
  21. Bio Protoc. 2025 Apr 05. 15(7): e5257
      With the advancement of liquid chromatography-mass spectrometry (LC-MS/MS), the quantification of glycerophospholipid (PL) molecules has become more accessible, leading to the discovery of numerous enzymes responsible for determining the acyl groups attached to these molecules. Metabolic tracer experiments using radioisotopes and stable isotopes are powerful tools for defining the function of metabolic enzymes and metabolic flux. We have established an ex vivo muscle experimental system using stable isotope-labeled fatty acids to evaluate fatty acid incorporation into PL molecules. Here, we describe a method to incorporate fatty acids with stable isotope labels into excised skeletal muscle and detect the PL molecules containing labeled acyl chains by LC-MS/MS. Key features • Quantify the metabolism of fatty acids into phospholipid acyl chains. • Enable measurements in excised muscle samples. • Assess the effects of genetic recombination of acyltransferases.
    Keywords:  Acyl chain; Free-fatty acid; Liquid chromatography–mass spectrometry; Phospholipid; Skeletal muscle; Stable isotope tracer
    DOI:  https://doi.org/10.21769/BioProtoc.5257
  22. Nat Metab. 2025 Apr 15.
      Psychological stress changes both behaviour and metabolism to protect organisms. Adrenaline is an important driver of this response. Anxiety correlates with circulating free fatty acid levels and can be alleviated by a peripherally restricted β-blocker, suggesting a peripheral signal linking metabolism with behaviour. Here we show that adrenaline, the β3 agonist CL316,243 and acute restraint stress induce growth differentiation factor 15 (GDF15) secretion in white adipose tissue of mice. Genetic inhibition of adipose triglyceride lipase or genetic deletion of β-adrenergic receptors blocks β-adrenergic-induced increases in GDF15. Increases in circulating GDF15 require lipolysis-induced free fatty acid stimulation of M2-like macrophages within white adipose tissue. Anxiety-like behaviour elicited by adrenaline or restraint stress is eliminated in mice lacking the GDF15 receptor GFRAL. These data provide molecular insights into the mechanisms linking metabolism and behaviour and suggest that inhibition of GDF15-GFRAL signalling might reduce acute anxiety.
    DOI:  https://doi.org/10.1038/s42255-025-01264-3
  23. J Cell Sci. 2025 Apr 14. pii: jcs.263665. [Epub ahead of print]
      The mechanistic links between mechanical forces and bioenergetics remain elusive. We report an increase in mitochondrial membrane potential (MMP) along the leading row of collectively migrating Xenopus laevis mesendoderm cells at sites where fibronectin- a5b1 integrin substrate traction stresses are greatest. Real-time metabolic analyses reveal a5b1 integrin-dependent increases in respiration efficiency in cells on fibronectin substrates. Elevation of metabolic activity is reduced following pharmacologic inhibition of focal adhesion kinase (FAK) signaling. Attachment of mesendoderm cells to fibronectin fragments that support differing a5b1 integrin conformational and ligand-binding affinity states, increases MMP when both the Arg-Gly-Asp (RGD) and Pro-Pro-Ser-Arg-Asn (PPSRN) synergy sites of fibronectin are engaged by the receptor. Cell stretch on deformable fibronectin substrates also results in a FAK-dependent increase in MMP. Inhibition of MMP or ATP-synthase activity slows collective cell migration velocity in vivo, further suggesting that integrin-dependent adhesion and signaling contribute to metabolic changes. These data highlight an underexplored link between ECM-integrin adhesion and metabolic activity in embryonic cell migration. We propose that fibronectin-integrin adhesion and signaling help shape the metabolic landscape of collectively migrating cells.
    Keywords:  Adhesion; Cell migration; Extracellular matrix; Integrin; Mitochondria; Morphogenesis
    DOI:  https://doi.org/10.1242/jcs.263665
  24. J Med Chem. 2025 Apr 15.
      Aberrant expression of the phosphatase SHP2 is implicated in numerous cancers, including KRAS G12D mutation driven PDAC. Although several SHP2 inhibitors have been reported, specific inhibitors with potent efficacy are not yet available. Given the elevated autophagy in PDAC, herein, we first designed novel SHP2 degraders through autophagosome-tethering compound strategy. Among them, the preferred 11n formed hydrogen bonds with Arg 111 and Glu 250 residues of SHP2 to enhance interactions between SHP2 and LC3. 11n also possessed great efficacy and selectivity against KRAS G12D mutant cancer cells versus the wild type. Moreover, the degradation caused by 11n manipulated the signaling pathways associated with cell apoptosis, metastasis, and invasion to inhibit the tumor growth both in vitro and in vivo. These findings not only generated a useful tool for exploring the potential of targeting SHP2 degradation but also offered promising candidates to develop novel drugs based on the autophagy mechanism.
    DOI:  https://doi.org/10.1021/acs.jmedchem.4c02682
  25. bioRxiv. 2025 Apr 02. pii: 2025.03.28.645975. [Epub ahead of print]
      Immune checkpoint blockade (ICB) has transformed cancer treatment, but success rates remain low in most cancers. Recent research suggest that dietary fiber enhances ICB response in melanoma patients and murine preclinical models through microbiome-dependent mechanisms. Yet, the robustness of this effect across cancer types and dietary contexts remains unclear. Specifically, prior literature compared grain-based chow (high fiber) to low-fiber purified diet, but these diets differ also on other dimensions including phytochemicals. Here we investigated, in mice fed grain-based chow or purified diets with differing quantities of isolated fibers (cellulose and inulin), metabolite levels and ICB activity in multiple tumor models. The blood and fecal metabolome were relatively similar between mice fed high- and low-fiber purified diets, but differed massively between mice fed purified diets or chow, identifying the factor as diet type, independent of fiber. Tumor growth studies in three implantable and two spontaneous genetically engineered tumor models revealed that fiber has a weaker impact on ICB (anti-PD-1) efficacy than previously reported. In some models, dietary modulation impacted ICB activity, but not in a consistent direction across models. In none of the models did we observe the pattern expected if fiber controlled ICB efficacy: strong efficacy in both chow and high-fiber purified diet but low efficacy in low-fiber purified diet. Thus, dietary fiber appears to have limited or inconsistent effect on ICB efficacy in mouse models, and other dietary factors that correlate with fiber intake may underlie the clinical correlations between fiber consumption and immunotherapy outcomes.
    DOI:  https://doi.org/10.1101/2025.03.28.645975
  26. Nat Chem Biol. 2025 Apr 17.
      The mechanism of ferroptosis propagation is still unclear. Here our results indicate that the cells undergoing ferroptosis secrete Galectin-13, which binds to CD44 and inhibits the plasma membrane localization of SLC7A11 in neighboring cells, thereby accelerating neighboring cell death and promoting ferroptosis propagation. FOXK1 was phosphorylated by PKCβII and then facilitated the expression and secretion of Galectin-13 during ferroptotic cell death. Correlation analysis and functional analysis revealed that ferroptosis propagation ability was a previously unrecognized determinant of ferroptosis sensitivity in human cancer cells. A synthetic Galectin-13 mimetic peptide was shown to strongly enhance the sensitivity of tumors to the imidazole ketone erastin, radiotherapy and immunotherapy by boosting ferroptosis. In particular, cancer stem cells were vulnerable to the combination of Galectin-13 mimetic peptide and ferroptosis inducers. Our study provides new insights into ferroptosis propagation and highlights novel strategies for targeting ferroptosis to treat tumors.
    DOI:  https://doi.org/10.1038/s41589-025-01888-2
  27. Nat Genet. 2025 Apr 16.
      Desmosomes are transmembrane protein complexes that contribute to cell-cell adhesion in epithelia and other tissues. Here, we report the discovery of frequent genetic alterations in the desmosome in human cancers, with the strongest signal seen in cutaneous melanoma, where desmosomes are mutated in more than 70% of cases. In primary but not metastatic melanoma biopsies, the burden of coding mutations in desmosome genes is associated with a strong reduction in desmosome gene expression. Analysis by spatial transcriptomics and protein immunofluorescence suggests that these decreases in expression occur in keratinocytes in the microenvironment rather than in primary melanoma cells. In further support of a microenvironmental origin, we find that desmosome gene knockdown in keratinocytes yields markedly increased proliferation of adjacent melanoma cells in keratinocyte and melanoma cocultures. Similar increases in melanoma proliferation are observed in media preconditioned with desmosome-deficient keratinocytes. Thus, gradual accumulation of desmosome mutations in neighboring cells may prime melanoma cells for neoplastic transformation.
    DOI:  https://doi.org/10.1038/s41588-025-02163-9
  28. Oncologist. 2025 Apr 04. pii: oyaf014. [Epub ahead of print]30(4):
       BACKGROUND: Weight loss and exocrine pancreatic insufficiency are common in advanced pancreatic ductal adenocarcinoma (PDAC) and are associated with adverse outcomes. However, there is limited evidence on the impact of pancreatic enzyme replacement therapy (PERT) in patients with advanced PDAC.
    PATIENTS AND METHODS: We retrospectively studied 501 patients with advanced PDAC and exocrine pancreatic insufficiency from the Virginia Mason Pancreas Cancer Program Data Resource treated between 2010 and 2019 with first-line chemotherapy. Clinical outcomes were compared between those who received PERT and those who did not at 8 weeks after chemotherapy start.
    RESULTS: In total 188 (38%) patients received PERT; 313 patients (62%) did not. PERT patients experienced less weight loss (-1.5 vs -2.5 kg, P = .04), less decline in the prognostic nutrition index -1.9 vs -3.0, P = .01), and a greater reduction in the additive score of the Patient-Generated Subjective Global Assessment (-8.4 vs --6.0, P = .02). Importantly, median (95% CI) overall survival (OS) was significantly longer in the PERT vs non-PERT group (17.1 months vs 12.5 months, respectively P = .001), and the adjusted hazards ratio indicated superior median OS in patients prescribed PERT (HR = 0.73, P < .001).
    CONCLUSIONS: Our findings suggest that treatment of exocrine pancreatic insufficiency (EPI) in advanced PDAC is associated with improvements in nutrition and overall survival.
    Keywords:  PERT; advanced pancreatic ductal adeno Ca; exocrine pancreatic insufficiency; pancreatic cancer associated weight loss
    DOI:  https://doi.org/10.1093/oncolo/oyaf014
  29. ACS Pharmacol Transl Sci. 2025 Apr 11. 8(4): 1096-1105
      With the challenge of limited early stage detection and a resulting five-year survival rate of only 13%, pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers. Replacing the high-cost and time-consuming grading of pancreatic samples by pathologists with automated diagnostic approaches can revolutionize PDAC detection and thus accelerate patient admission into the clinical setting for treatment. To address this unmet diagnostic need and facilitate the shift of tissue screening toward automated systems, we combined stain-free histology-specifically, Fourier-transform infrared (FT-IR) imaging-with machine learning. The obtained stain-free model was trained to distinguish between normal, benign, and malignant areas in analyzed specimens using hematoxylin and eosin stained pancreatic tissues isolated from KC (KrasG12D/+; Pdx1-Cre) or KPC mice (KrasG12D/+; Trp53R172H/+; Pdx1-Cre). Due to the pancreas-specific mosaic expression of the mutant Kras and Trp53 genes, changes in pancreatic tissues of this mouse model of PDAC closely mirror the gradual transformation of normal pancreatic epithelia into (pre)malignant structures. Thus, this mouse model provides a reliable representation of human disease progression, which we tracked in our study with a Random Forest classifier to achieve accurate detection at the cellular level. This approach yielded a comprehensive model that distinguishes normal pancreatic tissues from pathological features such as pancreatic intraepithelial neoplasia (PanIN), cancerous regions, hemorrhages, and collagen fibers, as well as a streamlined model designed to rapidly identify normal tissues versus pathologically altered regions, including PanINs. These models offer highly accurate diagnostic tools for the early detection of pancreatic malignancies, thus significantly improving the chance for timely therapeutic intervention against PDAC.
    DOI:  https://doi.org/10.1021/acsptsci.4c00689
  30. Life Sci Alliance. 2025 Jul;pii: e202403163. [Epub ahead of print]8(7):
      Type IV P-type ATPases (P4-ATPases) serve as lipid flippases, translocating membrane lipids from the exoplasmic (or luminal) leaflet to the cytoplasmic leaflet of lipid bilayers. In mammals, these P4-ATPases are localized to distinct subcellular compartments. ATP8A1 and ATP9A, members of the P4-ATPase family, are involved in endosome-mediated membrane trafficking, although the roles of P4-ATPases in the exocytic pathway remain to be clarified. ATP9A and ATP9B are located in the TGN, with ATP9A also present in endosomal compartments. This study revealed the overlapping roles of ATP9A and ATP9B in transporting VSVG from the Golgi to the plasma membrane within the exocytic pathway. Furthermore, we demonstrated that the flippase activities of ATP9A and ATP9B were crucial for the transport process. Notably, we discovered the formation of homomeric and/or heteromeric complexes between ATP9A and ATP9B. Therefore, ATP9A and ATP9B play a role in the exocytic pathway from the Golgi to the plasma membrane, forming either homomeric or heteromeric complexes.
    DOI:  https://doi.org/10.26508/lsa.202403163
  31. Phys Rev Lett. 2025 Apr 04. 134(13): 138402
      The transition of an epithelial layer from a stationary, quiescent state to a highly migratory, dynamic state is required for wound healing, development, and regeneration. This transition, known as the unjamming transition (UJT), is responsible for epithelial fluidization and collective migration. Previous theoretical models have primarily focused on the UJT in flat epithelial layers, neglecting the effects of strong surface curvature characteristic of the epithelium in vivo. In this Letter, we investigate the role of surface curvature on tissue plasticity and cellular migration using a vertex model embedded on a spherical surface. Our findings reveal that increasing curvature promotes the UJT by reducing the energy barriers to cellular rearrangements. Higher curvature favors cell intercalation, mobility, and self-diffusivity, resulting in epithelial structures that are malleable and migratory when small, but become more rigid and stationary as they grow. Together, these results provide a conceptual framework to better understand how cell shape, cell propulsion, and tissue geometry contribute to tissue malleability, remodeling, and stabilization.
    DOI:  https://doi.org/10.1103/PhysRevLett.134.138402
  32. bioRxiv. 2025 Apr 05. pii: 2025.04.04.647255. [Epub ahead of print]
      Tumors require metabolic adaptations to support their rapid growth, but how they influence lipid metabolism in distant tissues remains poorly understood. Here, we uncover a novel mechanism by which gut tumors in adult flies reprogram lipid metabolism in distal hepatocyte-like cells, known as oenocytes, to promote tracheal development and tumor growth. We show that tumors secrete a PDGF/VEGF-like factor, Pvf1, that activates the TORC1-Hnf4 signaling pathway in oenocytes. This activation enhances the production of specific lipids, including very long-chain fatty acids and wax esters, that are required for tracheal growth surrounding the gut tumor. Importantly, reducing expression in oenocytes of either the transcription factor Hnf4 , or the elongase mElo that generates very long chain fatty acid suppresses tumor growth, tracheogenesis, and associated organ wasting/cachexia-like phenotypes, while extending lifespan. We further demonstrate that this regulatory pathway is conserved in mammals, as VEGF-A stimulates lipid metabolism gene expression in human hepatocytes, and lung tumor-bearing mice show increased hepatic expression of Hnf4 and the lipid elongation gene Elovl7 . Our findings reveal a previously unrecognized tumor-host interaction where tumors non-autonomously reprogram distal lipid metabolism to support their growth. This study not only identifies a novel non-autonomous role of the TORC1-Hnf4 axis in lipid-mediated tumor progression but also highlights potential targets for therapeutic intervention in cancer-associated metabolic disorders.
    DOI:  https://doi.org/10.1101/2025.04.04.647255
  33. Nature. 2025 Apr 16.
      Protein misfolding diseases, including α1-antitrypsin deficiency (AATD), pose substantial health challenges, with their cellular progression still poorly understood1-3. We use spatial proteomics by mass spectrometry and machine learning to map AATD in human liver tissue. Combining Deep Visual Proteomics (DVP) with single-cell analysis4,5, we probe intact patient biopsies to resolve molecular events during hepatocyte stress in pseudotime across fibrosis stages. We achieve proteome depth of up to 4,300 proteins from one-third of a single cell in formalin-fixed, paraffin-embedded tissue. This dataset reveals a potentially clinically actionable peroxisomal upregulation that precedes the canonical unfolded protein response. Our single-cell proteomics data show α1-antitrypsin accumulation is largely cell-intrinsic, with minimal stress propagation between hepatocytes. We integrated proteomic data with artificial intelligence-guided image-based phenotyping across several disease stages, revealing a late-stage hepatocyte phenotype characterized by globular protein aggregates and distinct proteomic signatures, notably including elevated TNFSF10 (also known as TRAIL) amounts. This phenotype may represent a critical disease progression stage. Our study offers new insights into AATD pathogenesis and introduces a powerful methodology for high-resolution, in situ proteomic analysis of complex tissues. This approach holds potential to unravel molecular mechanisms in various protein misfolding disorders, setting a new standard for understanding disease progression at the single-cell level in human tissue.
    DOI:  https://doi.org/10.1038/s41586-025-08885-4