bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2026–07–26
seven papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. GDF15: A Novel Insight Into Its Biology and Therapeutic Potential in Obesity.
  2. Context-dependent regulation of IL-6 in exercise and colorectal cancer cachexia.
  3. ER stress-dependent Ddit4/REDD1 induction contributes to translational suppression during cisplatin-induced skeletal muscle atrophy.
  4. mTORC1 activation induces B7-H3-dependent metabolic reprogramming in renal cell carcinoma (RCC).
  5. Lipid-driven epigenetic exhaustion: linking palmitate metabolism to CD8+ T-cell dysfunction in cancer.
  6. Hypoxia and endothelial interaction cooperatively amplify free fatty acid receptor 1 (FFAR1)-mediated malignancy in highly invasive lung cancer cells.
  7. IL-6/IL-6R-Mediated Mechanisms in Lung Cancer: From Pathogenesis to Potential Therapeutic Targets.
  1. J Diabetes Res. 2026 ;2026(1): e3024772
    GDF15: A Novel Insight Into Its Biology and Therapeutic Potential in Obesity.
    Kamil Ahmed, Asia Saturnino, Paolo Pozzilli.
      Growth differentiation factor 15 (GDF15) is a stress-responsive cytokine that has recently been identified as a key regulator of appetite homeostasis. Although GDF15 was previously regarded as only a biomarker of disease burden, the discovery of its exclusive receptor, GFRAL, repositioned it as a key mediator of sickness-associated anorexia. The clinical significance of GDF15 and its receptor, GFRAL, is supported by evidence that established weight-loss agents influence circulating GDF15 levels and that GDF15 agonists induce marked weight loss in both preclinical and early-phase clinical studies. This review integrates recent advances in GDF15 biology from evolutionary, mechanistic and translational perspectives, with particular emphasis on its emerging therapeutic potential in obesity.
    Keywords:  body weight; cellular stress signalling; growth differentiation factor 15 (GDF15); obesity; therapy
    DOI:  https://doi.org/10.1155/jdr/3024772
  2. Front Oncol. 2026 ;16 1792184
    Context-dependent regulation of IL-6 in exercise and colorectal cancer cachexia.
    Jingwen Xiong, Sihan Liu, Jie Xu, Jinghan Zhang, Yundong Peng, Yibei Xia, Jinghua Qian.
      Colorectal cancer (CRC) is a common malignancy of the digestive system and remains a major cause of cancer-related morbidity and mortality worldwide. Its development and progression are influenced by genetic susceptibility, lifestyle factors, metabolic dysregulation, and chronic inflammatory states. Cancer cachexia is a multifactorial wasting syndrome characterized by weight loss, skeletal muscle atrophy, metabolic disturbances, and functional decline, which substantially impairs quality of life and survival outcomes in patients with CRC. In this context, interleukin-6 (IL-6) has emerged as a context-dependent regulatory mediator linking inflammation, metabolism, tumor biology, and skeletal muscle wasting. The biological effects of IL-6 are shaped by signaling mode, cellular source, concentration, temporal dynamics, and the broader tumor-host environment. This review discusses the regulatory roles of IL-6 in CRC and CRC-related cachexia, with particular attention to exercise-associated IL-6 responses. Rather than viewing exercise-induced IL-6 as inherently beneficial or antitumor, we emphasize that IL-6 is one component of a broader exercise-responsive network involving metabolic adaptation, immune regulation, skeletal muscle function, and systemic inflammatory remodeling. We also summarize current evidence regarding how exercise modality and intensity may influence IL-6 dynamics, while distinguishing mechanistic and preclinical findings from limited and heterogeneous human data. Overall, IL-6 dynamics may provide a hypothesis-generating framework for understanding exercise responses in CRC-related cachexia, but current evidence is insufficient to support IL-6-guided individualized exercise prescription or therapeutic decision-making in clinical practice.
    Keywords:  IL-6; cachexia; colorectal cancer (CRC); exercise oncology; exercise therapy
    DOI:  https://doi.org/10.3389/fonc.2026.1792184
  3. Chem Biol Interact. 2026 Jul 18. pii: S0009-2797(26)00368-6. [Epub ahead of print]437 112260
    ER stress-dependent Ddit4/REDD1 induction contributes to translational suppression during cisplatin-induced skeletal muscle atrophy.
    Hayato Nanri, Hiroyasu Sakai, Kaisei Umeyama, Takayuki Ogiwara, Shinki Soga, Yuya Chigusa, Shiori Yonamine, Risako Kon, Nobutomo Ikarashi, Yoshihiko Chiba, Kumiko Ogawa.
      Cisplatin is a widely used chemotherapeutic agent whose clinical utility is limited by various adverse effects. Although skeletal muscle loss during chemotherapy is often attributed to cachexia or generalized wasting, accumulating evidence indicates that cisplatin directly induces skeletal muscle atrophy. However, the underlying cellular stress responses and signaling pathways remain unclear. In this study, we investigated the involvement of endoplasmic reticulum (ER) stress and translational regulation in cisplatin-induced skeletal muscle atrophy, focusing on DNA damage-inducible transcript 4/Regulated in development and DNA damage response-1 (Ddit4/REDD1), a stress-responsive inhibitor of mammalian target of rapamycin complex 1 (mTORC1). Using a mouse model and differentiated C2C12 myotubes, we examined ER stress signaling, protein synthesis, and mTORC1 activity following cisplatin treatment, and evaluated the effects of tauroursodeoxycholic acid (TUDCA), an ER stress-suppressing chemical chaperone. Cisplatin induced skeletal muscle atrophy accompanied by ER stress activation and suppression of protein synthesis in mice. TUDCA significantly attenuated muscle mass and strength loss without affecting body weight reduction. Cisplatin upregulated ER stress-responsive genes and decreased phosphorylation of p70 S6 kinase, whereas these changes were suppressed by TUDCA. Pharmacological ER stress induction increased Ddit4/REDD1 expression, and PERK inhibition reduced cisplatin-induced Ddit4/REDD1 upregulation in C2C12 myotubes. Furthermore, Ddit4/REDD1 knockdown partially restored protein synthesis and mTORC1 signaling. These findings indicate that cisplatin induces skeletal muscle atrophy via ER stress-associated translational suppression, at least partly through Ddit4/REDD1-mediated inhibition of mTORC1.
    Keywords:  Cisplatin; Ddit4/REDD1; ER stress; Muscle atrophy; mTORC1
    DOI:  https://doi.org/10.1016/j.cbi.2026.112260
  4. Oncogene. 2026 Jul 20.
    mTORC1 activation induces B7-H3-dependent metabolic reprogramming in renal cell carcinoma (RCC).
    Keying Li, Heng Du, Yifan Wang, Damir Khabibullin, Michel Alchoueiry, Melissa Daou, John M Asara, David J Kwiatkowski, Elizabeth P Henske, Heng-Jia Liu.
      Renal cell carcinoma (RCC) affects over 435,000 people worldwide each year and remains a significant cause of cancer mortality. Aberrant activation of pathways such as mTORC1 is frequently observed in RCC, yet the mechanisms by which mTORC1 contributes to tumor development remain poorly understood. The lack of suitable animal models has limited progress in uncovering these mechanisms and advancing targeted treatments. Here, we performed single-cell transcriptomic, proteomic, and metabolomic profiling of kidneys from mice with embryonic Tsc2 deletion at E17.5, which revealed a distinct tumor cell population characterized by intercalated cell signatures, co-expression of Foxi1 and Rhcg, and hyperactivated mTORC1. These lesions closely resemble human chromophobe renal cell carcinoma (ChRCC), a subtype of RCC. The tumors show marked upregulation of the immune checkpoint molecule B7-H3. Mechanistically, the transcription factor NRF1 is elevated in Tsc2-deficient lesions and drives B7-H3 expression in tumor cells. In human specimens, B7-H3 is broadly expressed in both classical and sarcomatoid ChRCC and correlates with hallmark markers FOXI1, MUC2, and HEPACAM2. Strikingly, B7-H3 deletion in mice suppresses Tsc2 loss-driven cystic and tumor formation, restores amino acid metabolism, and attenuates aminoacyl-tRNA biosynthesis and proteasome activity. Collectively, these findings identify B7-H3 as a functional driver of Tsc2-mediated ChRCC and a promising therapeutic target in TSC-associated renal tumors.
    DOI:  https://doi.org/10.1038/s41388-026-03891-w
  5. Immunometabolism (Cobham). 2026 Jul;8(3): e00086
    Lipid-driven epigenetic exhaustion: linking palmitate metabolism to CD8+ T-cell dysfunction in cancer.
    Desh Raj, Mahesh Kathania, Tuoqi Wu, Arianne L Theiss, K Venuprasad.
      In a recent study published in Science Immunology, Tiberti and colleagues demonstrate that palmitate, a saturated fatty acid enriched in tumors, directly impairs CD8+ cytotoxic T lymphocyte function through mitochondrial and epigenetic reprogramming. Palmitate exposure reduced mitochondrial fitness, oxidative phosphorylation, and adenosine triphosphate production, resulting in defective proliferation, cytokine production, and antitumor activity. Mechanistically, mitochondrial dysfunction decreased intracellular acetyl-CoA availability, leading to reduced histone acetylation and loss of chromatin accessibility at loci that control effector programs. The study further identifies sphingosine kinase 2 as a critical mediator of lipid-induced dysfunction. Importantly, SPHK2 inhibition restored mitochondrial function, histone acetylation, and cytotoxic T lymphocyte antitumor activity, highlighting a potential therapeutic strategy for enhancing cancer immunotherapy.
    Keywords:  T-cell exhaustion; acetyl CoA; cytotoxic T cells; palmitate
    DOI:  https://doi.org/10.1097/IN9.0000000000000086
  6. Mol Cell Biochem. 2026 Jul 20.
    Hypoxia and endothelial interaction cooperatively amplify free fatty acid receptor 1 (FFAR1)-mediated malignancy in highly invasive lung cancer cells.
    Shion Nagano, Yuka Kusumoto, Moemi Tamura, Nanami Shimomura, Hinata Amano, Mahiro Yanome, Nozomi Kano, Mizuki Ishida, Miwa Kawamoto, Toshifumi Tsujiuchi.
      Free fatty acid receptor (FFAR)-mediated signaling plays a critical role in cancer pathogenesis. Within the tumor microenvironment (TME), stromal cells support cancer cell functions under hypoxic conditions, thereby promoting malignant progression. This study investigated whether FFAR1 contributes to stromal cell-induced malignancy in cancer cells under hypoxic conditions (1% O2), using highly invasive A549-M8 cells derived from lung cancer A549 cells. A549-M8 cells exhibit approximately eightfold higher invasiveness than A549 cells. Under 1% O2, FFAR1 expression was upregulated in A549-M8 cells but downregulated in A549 cells. A549-M8 cell invasion was markedly promoted by culturing at 1% O2, whereas A549 cell invasion decreased. TUG-770 (FFAR1 agonist) stimulated A549-M8 cell invasion, whereas GW1100 (FFAR1 antagonist) suppressed it. In contrast, A549-M8 cell invasion was inhibited by TUG-891 (FFAR4 agonist). Co-culture with mouse-derived endothelial F2 cells, which lack Ffar1 expression, further stimulated A549-M8 cell movement and motility relative to A549 cells. Under hypoxic co-culture conditions, A549-M8 cells exhibited significantly increased invasion, which was associated with elevated FFAR1 expression. These results suggest that FFAR1-mediated signaling is a key driver of tumor progression in highly invasive lung cancer cells under hypoxic conditions, with stromal cell interactions promoting FFAR1 induction and enhancing malignancy, whereas FFAR4 activation exerts a suppressive effect on invasive activity.
    Keywords:  Cell invasion; Endothelial cells; FFAR1; Hypoxia; Lung cancer cells
    DOI:  https://doi.org/10.1007/s11010-026-05663-2
  7. Immunology. 2026 Jul 22.
    IL-6/IL-6R-Mediated Mechanisms in Lung Cancer: From Pathogenesis to Potential Therapeutic Targets.
    Qamar Abuhassan, Hamzeh J Al-Ameer, S Renuka Jyothi, Priya Priyadarshini Nayak, P Prakash, Gunjan Mukherjee, Aashna Sinha, Ozoda Hazratkulova.
      Despite significant advancements in the oncology field, lung cancer remains the leading cause of cancer-related mortality worldwide. A key contributor to the increased mortality rate is the resistance exhibited by cancer cells to standard anticancer treatments, particularly in advanced stages of the disease. Evidence indicates that chronic inflammation within the tumour microenvironment (TME) promotes tumorigenesis and contributes to resistance to immunotherapy, radiotherapy and chemotherapy. Notably, the overexpression of the cytokine interleukin-6 (IL-6) has been documented in various tumours, including lung cancer. Both tumour-associated fibroblasts (TAFs) and tumour cells constitute the predominant sources of secreted IL-6 within the TME. Various research has elucidated the role of IL-6 and its signalling pathways in facilitating therapeutic resistance, metastasis and tumour progression in lung cancer. Consequently, targeting IL-6 and/or its receptor, in conjunction with other effective anticancer treatments, represents an ideal therapeutic technique for lung cancer management. This review aims to synthesize recent evidence on the function of the IL-6/IL-6R signalling pathway in lung cancer, with a focus on its role in therapy resistance, prognosis and tumour progression, on the basis of clinical and preclinical studies.
    Keywords:  immunotherapy; interleukin‐6; interleukin‐6 receptor; lung cancer
    DOI:  https://doi.org/10.1111/imm.70170
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