bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2025–03–16
nine papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge



  1. bioRxiv. 2025 Feb 24. pii: 2025.02.20.638910. [Epub ahead of print]
      Macroautophagy (autophagy hereafter) captures intracellular components and delivers them to lysosomes for degradation and recycling 1 . In adult mice, autophagy sustains metabolism to prevent wasting by cachexia and to survive fasting, and also suppresses inflammation, liver steatosis, neurodegeneration, and lethality 2,3 . Defects in autophagy contribute to metabolic, inflammatory and degenerative diseases, however, the specific mechanisms involved were unclear 4 . Here we profiled metabolism and inflammation in adult mice with conditional, whole-body deficiency in an essential autophagy gene and found that autophagy deficiency altered fuel usage, and reduced ambulatory activity, energy expenditure, and food intake, and elevated circulating GDF15, CXCL10, and CCL2. While deletion of Gdf15 or Cxcl10 provided no or mild benefit, deletion of Ccl2 restored food intake, suppressed cachexia and rescued lethality of autophagy-deficient mice. To test if appetite suppression by CCL2 was responsible for lethal cachexia we performed single nucleus RNA sequencing of the hypothalamus, the center of appetite control in the brain. Notably, we found that autophagy deficiency was specifically toxic to PMCH and HCRT neurons that produce orexigenic neuropeptides that promote food intake, which was rescued by deficiency in CCL2. Finally, the restoration of food intake via leptin deficiency prevented lethal cachexia in autophagy-deficient mice. Our findings demonstrate a novel mechanism where autophagy prevents induction of a cachexia factor, CCL2, which damages neurons that maintain appetite, the destruction of which may be central to degenerative wasting conditions.
    Key points of paper: 1) Autophagy-deficient mice have reduced food intake, systemic inflammation, and cachexia2) CCL2, but not GDF15 or CXCL10, induces lethal cachexia caused by autophagy defect3) Autophagy-deficient mice have CCL2-dependent destruction of appetite-promoting neurons in the hypothalamus4) Leptin deficiency restores appetite and rescues lethal cachexia in autophagy-deficient mice5) Autophagy-deficient mice die from cachexia mediated by appetite loss6) Degenerative conditions due to impaired autophagy are caused by the inflammatory response to the damage7) Targeting CCL2 may be a viable approach to prevent degenerative wasting disorders.
    DOI:  https://doi.org/10.1101/2025.02.20.638910
  2. Cancer Lett. 2025 Mar 05. pii: S0304-3835(25)00177-6. [Epub ahead of print]617 217613
      Endoplasmic reticulum (ER) is the critical organelle that regulates essential cellular processes, including protein synthesis, folding, and post-translational modification, as well as lipid metabolism and calcium homeostasis. Disruption in ER homeostasis leads to a condition known as ER stress, characterized by the accumulation of misfolded or unfolded proteins. This triggers the unfolded protein response (UPR), an adaptive pathway mediated by three ER-resident sensors: inositol-requiring enzyme 1α (IRE1α), protein kinase R-like ER kinase (PERK), and activating transcription factor 6 (ATF6). Increasing evidence highlights sustained UPR activation in malignant and immune cells within the tumor microenvironment (TME), which promotes tumor progression and metastasis while simultaneously impairing antitumor immunity. This review explores how UPR-driven intercellular signaling influences immunotherapy resistance, focusing on the alterations occurring in tumor cells as well as in the surrounding immune environment. By providing insights into these mechanisms, we aim to highlight the therapeutic potential of targeting the UPR pathways in modulating cancer immunity.
    Keywords:  Immunotherapy resistance; Tumor microenvironment; UPR
    DOI:  https://doi.org/10.1016/j.canlet.2025.217613
  3. Int J Biol Macromol. 2025 Mar 08. pii: S0141-8130(25)02441-9. [Epub ahead of print]307(Pt 1): 141890
      Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by myofibroblasts accumulation and uncontrolled extracellular matrix (ECM) deposition. Here, we reported that activating transcription factor 4 (ATF4), a multifunctional transcription regulatory protein, is overexpressed in IPF lungs and mouse fibrotic lungs, mainly in myofibroblasts and macrophages. Haplodeletion of Atf4 in mice or blockage of Atf4 with Atf4 shRNA-loaded lentiviruses in mice reduced bleomycin (BLM)-induced pulmonary fibrosis (PF) in vivo. Mechanistically, we found that ATF4 directly binds to the promoter of Acta2 (encodes α-SMA), and promotes lung fibroblasts activation and myofibroblasts accumulation. Additionally, ATF4 regulates macrophage M2 program, and promotes TGFβ1 secretion by directly influencing Tgfb1 gene expression in macrophages, subsequently enhances crosstalk between macrophages and lung fibroblasts. These data suggest that strategies for inhibiting ATF4 may represent an effective treatment for PF.
    Keywords:  Activating transcription factor 4; Fibroblast activation; M2 macrophages
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.141890
  4. Mol Ther. 2025 Mar 12. pii: S1525-0016(25)00186-8. [Epub ahead of print]
      Vascular endothelial growth factor B186 (VEGF-B186), a ligand for VEGF receptor 1 (VEGFR1) and neuropilin (NRP), promotes vascular growth in healthy and ischemic myocardium. However, the mechanisms and signaling of VEGF-B186 to support angiogenesis have remained unclear. We studied the effects of VEGF-B186 and its variant, VEGF-B186R127S, which cannot bind to NRPs, using VEGFR1 tyrosine kinase knockout (TK-/-) mice to explore the mechanism of VEGF-B186 in promoting vascular growth. Ultrasound-guided adenoviral VEGF-B186, VEGF-B186R127S, and control vector gene transfers were performed into VEGFR1 TK-/- mice hearts. In vitro studies in cardiac endothelial cells and further validation in normal and ischemic pig hearts, as well as in wild-type mice, were conducted. Both VEGF-B186 forms promoted vascular growth in VEGFR1 TK-/- mouse heart and increased the expression of proangiogenic and hematopoietic factors. Unlike VEGF-A, VEGF-B186 forms induced ER stress via the upregulation of Binding immunoglobulin Protein (BiP) as well as ER stress sensors (ATF6, PERK, IRE1α) through ITGAV and ITGA5 integrins, newly identified receptors for VEGF-B, activating the unfolded protein response (UPR) through XBP1. VEGFR1 and NRP are not essential for VEGF-B186-induced vascular growth. Instead, VEGF-B186 can stimulate cardiac regeneration through RGD-binding integrins and ER stress, suggesting a novel mechanism of action for VEGF-B186.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.03.012
  5. Sci Rep. 2025 Mar 12. 15(1): 8480
      Metabolic reprogramming and epigenetic alternations are implicated in tumor progression and metastasis, but the metabolic and epigenetic mechanisms underlying lymphatic and distant metastasis of bladder cancer (BCa) remain poorly understood. In this study, we provide the first evidence that glutamine-fructose-6-phosphate aminotransferase 1 (GFAT1), the crucial rate-limiting switch of the hexosamine biosynthesis pathway (HBP), is considerably upregulated in the nutrient-scarce microenvironment and causes a high O-GlcNAcylation of signal transducing adaptor molecule 2 (STAM2), further facilitating lymphatic and distant metastasis of BCa. Inhibition of GFAT1 and O-GlcNAcylation impairs STAM2-induced metastasis. Mechanistically, O-GlcNAcylation of STAM2 at serine 375 augments protein stability by inhibiting proteasome degradation and ubiquitination. In addition, STAM2 O-GlcNAcylation facilitates Janus kinase 2 (JAK2) and signal transducer and activator of transcription (STAT3) phosphorylation, thus activating the epithelial‒mesenchymal transition. In summary, these results reveal a novel metabolic and epigenetic link mediating tumor metastasis, and indicate that targeting GFAT1 and STAM2 O-GlcNAcylation may serve as a promising treatment strategy for BCa progression.
    Keywords:   O-GlcNAcylation; Bladder cancer; Metastasis; STAM2
    DOI:  https://doi.org/10.1038/s41598-025-92579-4
  6. Oncogenesis. 2025 Mar 11. 14(1): 6
      Cancer-associated fibroblast (CAF) recruitment and activation within the tumor microenvironment (TME) are increasingly acknowledged as drivers of oral squamous cell carcinoma (OSCC) tumor growth and metastasis. Therefore, the mechanisms underlying tumor cell and fibroblast crosstalk warrant further investigation. We discovered that ectopic interferon-stimulated gene 15 (ISG15) expression, which is a promising and novel oncoprotein biomarker elevated in a variety of cancers, enhanced OSCC growth and elevated collagen and α-smooth muscle actin (α-SMA) expression in ISG15-expressing tumors. Analysis of immunohistochemistry revealed high ISG15 expression in human oral tissues correlated with high expression of α-SMA and fibroblast activation protein (FAP). Fibroblast migration and recruitment by ISG15-expressing OSCC cells were confirmed by in vitro and in vivo experiments. Exogenous ISG15 induced fibroblast migration, morphological changes, and vimentin expression. Enrichment of glycolysis pathway genes, as well as increased glycolysis-related gene expression, glucose uptake, and lactate production were observed in ISG15-treated fibroblasts. Lactate release and fibroblast migration were blocked by a competitive inhibitor of glucose metabolism. Furthermore, the knockdown of integrin αL (ITGAL)/CD11a, a subunit of ISG15 receptor lymphocyte functional-associated antigen-1 (LFA-1), in immortalized fibroblasts diminished extracellular ISG15-mediated glycolysis and migration. Our findings suggest that ISG15 derived from OSCC cells interacts with fibroblasts through the LFA-1 receptor, leading to glycolytic reprogramming and promotion of fibroblast migration into the TME.
    DOI:  https://doi.org/10.1038/s41389-025-00549-2
  7. NPJ Precis Oncol. 2025 Mar 12. 9(1): 71
      Bladder cancer (BCa) is a prevalent malignancy with a poor prognosis. SLC7A7 has been linked to BCa progression and angiogenesis, but its specific role remains unclear. We established a SLC7A7-knockdown BCa cell line to investigate its effects on angiogenesis. In vivo experiments assessed tumor vascularization, while in vitro studies explored exosome involvement. MiRNA sequencing identified miR-152-3p as a key regulator. Further investigation using dual-luciferase reporter assays, qRT-PCR, and Western blot revealed that miR-152-3p inhibits the expression of FGFR3 by binding to its 3' UTR. Meanwhile, functional assays, including angiogenesis assays, Transwell assays, and wound healing assays, were performed to evaluate the effects of miR-152-3p on angiogenesis. We confirmed the significant role of SLC7A7 in BCa progression, specifically in promoting angiogenesis, through the involvement of exosomes and the regulatory axis of miR-152-3p/ FGFR3. Targeting FGFR3 might be a promising strategy to reverse control BCa progression for an improved prognosis.
    DOI:  https://doi.org/10.1038/s41698-025-00859-z
  8. Sci Rep. 2025 Mar 08. 15(1): 8101
      Growth differentiation factor-15 (GDF15) is a biomarker of multiple disease states and circulating GDF15 levels are increased during aging in both pre-clinical animal models and human studies. Accordingly, multiple stressors have been identified, including mitochondrial dysfunction, that lead to induction of Gdf15 expression downstream of the integrated stress response (ISR). For some disease states, the source of increased circulating GDF15 is evident based on the specific pathology. Aging, however, presents a less tractable system for understanding the source of increased plasma GDF15 levels in that cellular dysfunction with aging can be pleiotropic and heterogeneous. To better understand which organ or organs contribute to increased circulating GDF15 levels with age, and whether changes in metabolic and mitochondrial dysfunction were associated with these potential changes, we compared young 12-week-old and middle-aged 52-week-old C57BL/6 J mice using a series of metabolic phenotyping studies and by comparing circulating levels of GDF15 and tissue-specific patterns of Gdf15 expression. Overall, we found that Gdf15 expression was increased in skeletal muscle but not liver, white or brown adipose tissue, kidney or heart of middle-aged mice, and that insulin sensitivity and mitochondrial respiratory capacity were impaired in middle-aged mice. These data suggest that early changes in skeletal muscle mitochondrial function and metabolism contribute to increased circulating GDF15 levels observed during aging.
    Keywords:  Aging; Energy expenditure; Insulin resistance; Integrated stress response; Respirometry
    DOI:  https://doi.org/10.1038/s41598-025-92572-x
  9. Sci Immunol. 2025 Mar 14. 10(105): eadp7193
      Regulatory T cells (Tregs) have diverse functional specification in homeostasis and disease. However, how liver Tregs function and are transcriptionally regulated in obesity is not well understood. Here, we identified that effector Tregs expressing activating transcription factor 4 (ATF4) were enriched in the livers of obese mice. ATF4 was critical for driving an effector Treg transcriptional program, and ATF4-expressing Tregs promoted the development of obesity-induced liver fibrosis by enhancing transforming growth factor-β activation via integrin αvβ8. Treg-specific deletion of Atf4 resulted in reduced liver Tregs and attenuation of obesity-induced liver abnormalities. Furthermore, ATF4 was required to promote the differentiation of nonlymphoid tissue Treg precursors under steady state. These findings demonstrate that ATF4 is important for regulating Treg functional specification in homeostasis and obesity.
    DOI:  https://doi.org/10.1126/sciimmunol.adp7193