bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2026–01–11
six papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Nutrient requirements of organ-specific metastasis in breast cancer.
  2. Hypoxia-Activated PERK Promotes Epithelial-Mesenchymal Transition in Gliomas: A Single-Cell and Spatial Transcriptomic Study With Therapeutic Implications.
  3. Inflammation-Insulin Resistance Crosstalk and the Central Role of Myokines.
  4. Inhibition of Tumor Microenvironment-Driven JAK-STAT Signaling Enhances Response to Arginine Deprivation Therapy in Triple-Negative Breast Cancer.
  5. Glutamine metabolism drives tumor aggressiveness but not chemoresistance in ovarian carcinoma cell lines.
  6. TNF/TNFR1 is a Key Regulator of Prolonged Fasting-Induced Decrease in Adipose Tissue.
  1. Nature. 2026 Jan 07.
    Nutrient requirements of organ-specific metastasis in breast cancer.
    Keene L Abbott, Sonu Subudhi, Raphael Ferreira, Yetiş Gültekin, Sophie C Steinbuch, Muhammad Bin Munim, Diya L Ramesh, Sophie E Honeder, Ashwin S Kumar, Michelle Wu, Jacob A Hansen, Anna Shevzov-Zebrun, Edrees H Rashan, Kian M Eghbalian, Sharanya Sivanand, Anna M Barbeau, Lisa M Riedmayr, Mark Duquette, Ahmed Ali, Nicole Henning, Sonia E Trojan, Millenia Waite, Tenzin Kunchok, Mayu A Nakano, Florian Gourgue, Gino B Ferraro, Brian T Do, Virginia Spanoudaki, Francisco J Sánchez-Rivera, Xin Jin, George M Church, Rakesh K Jain, Matthew G Vander Heiden.
      Cancer metastasis is a major contributor to patient morbidity and mortality1, yet the factors that determine the organs where cancers can metastasize are incompletely understood. Here we quantify the absolute levels of 124 metabolites in multiple tissues in mice and investigate how this relates to the ability of breast cancer cells to grow in different organs. We engineered breast cancer cells with broad metastatic potential to be auxotrophic for specific nutrients and assessed their ability to colonize different tissue sites. We then asked how tumour growth in different tissues relates to nutrient availability and tumour biosynthetic activity. We find that single nutrients alone do not define the sites where breast cancer cells can grow as metastases. In addition, we identify purine synthesis as a requirement for tumour growth and metastasis across many tissues and find that this phenotype is independent of tissue nucleotide availability or tumour de novo nucleotide synthesis activity. These data suggest that a complex interplay between multiple nutrients within the microenvironment dictates potential sites of metastatic cancer growth, and highlights the interdependence between extrinsic environmental factors and intrinsic cellular properties in influencing where breast cancer cells can grow as metastases.
    DOI:  https://doi.org/10.1038/s41586-025-09898-9
  2. Front Biosci (Landmark Ed). 2025 Dec 17. 30(12): 46692
    Hypoxia-Activated PERK Promotes Epithelial-Mesenchymal Transition in Gliomas: A Single-Cell and Spatial Transcriptomic Study With Therapeutic Implications.
    Jingyan Gu, Yue Kong, Yaohua Liu, Xu Wang, Hongyu Tang, Tingting Zang, Jian Yin, Lianping Gu.
       BACKGROUND: Glioma, the most common brain tumor in adults, exhibits marked hypoxia and invasiveness. Endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) have been implicated in tumor progression, while epithelial mesenchymal transition (EMT) drives invasion and metastasis.
    METHODS: This study explored the role of ERS, particularly the PKR-like endoplasmic reticulum kinase (PERK) pathway, in promoting EMT and malignancy in glioma. Based on publicly available bulk transcriptomic data, we analyzed PERK activity in high-grade and hypoxic gliomas. PERK activation across glioma subtypes was compared using publicly available single-cell sequencing, and its correlation with EMT upregulation was evaluated using pseudotime analysis. The effects of PERK on glioma migration and invasion in a hypoxic environment were investigated using PERK-silenced glioma cell lines. In vivo tumorigenicity was assessed in nude mice by measuring tumor size and EMT marker expression. Intercellular communication was examined using CellChat analysis. Hypoxic niche regions were identified using publicly available spatial transcriptomics with PERK-EMT co-localization.
    RESULTS: Hypoxia-induced PERK activation promoted EMT, enhancing glioma cell migration and tumor growth. High PERK signatures correlated with EMT activation in aggressive gliomas. Genetic silencing of PERK reduced the expression of EMT-related proteins, an effect partially reversed by hypoxia. Inhibition of PERK signaling decreased tumor size in mice. PERK-activated glioma subpopulations exhibited stronger cell-cell communication through secreted phosphoprotein 1 (SPP1)-CD44 interactions. Spatial transcriptomic analysis confirmed enrichment of the PERK/EMT pathway in hypoxic niches alongside SPP1-CD44 co-localization.
    CONCLUSION: These findings reveal PERK-driven EMT as a key mechanism linking ER stress to glioma progression, with hypoxia reinforcing this axis. Targeting the PERK signaling axis or SPP1-CD44 interactions may offer novel therapeutic strategies against aggressive gliomas.
    Keywords:  PERK kinase; endoplasmic reticulum stress; epithelial-mesenchymal transition; glioma; hypoxia
    DOI:  https://doi.org/10.31083/FBL46692
  3. Int J Mol Sci. 2025 Dec 20. pii: 60. [Epub ahead of print]27(1):
    Inflammation-Insulin Resistance Crosstalk and the Central Role of Myokines.
    Maria-Zinaida Dobre, Bogdana Virgolici, Daciana Costina Andrada Dunca-Stefan, Ioana-Cristina Doicin, Iulia-Ioana Stanescu-Spinu.
      Insulin resistance develops when skeletal muscle (SM), adipose tissue (AT), and the liver fail to respond adequately to insulin, a dysfunction closely intertwined with chronic low-grade inflammation. This combination leads to compensatory hyperinsulinemia, dysglycemia, and metabolic stress, driving major disorders such as type 2 diabetes, metabolic syndrome, metabolic dysfunction-associated steatotic liver disease (MASLD), and cardiovascular disease. Both adipokines and myokines are central modulators of this metabolic-inflammatory axis. In obesity, diabetes, MASLD, and thyroid dysfunction, alterations in myokines such as myostatin, irisin, fibroblast growth factor 21 (FGF-21), apelin, brain-derived neurotrophic factor (BDNF), interleukin-6 (IL-6), and interleukin-15 (IL-15) influence glucose uptake, lipid oxidation, mitochondrial function, and systemic inflammation. Exercise-induced myokines exert insulin-sensitizing and anti-inflammatory effects, whereas myostatin and tumor necrosis factor-alpha (TNF-α) promote metabolic impairment. These pathways reveal extensive crosstalk between SM and key metabolic organs-including the liver, pancreas, AT, intestine, heart, and thyroid gland. In metabolic disease, inflammation-driven changes in deiodinase activity and triiodothyronine (T3) availability further link muscle dysfunction with thyroid imbalance. The aim of this narrative review was to elucidate the complex interplay between myokines, adipokines, inflammation, and insulin resistance, and to clarify their clinical relevance in metabolic and thyroid disorders. Given this integrative role of SM, sarcopenia should be recognized as a clinical marker of metabolic or thyroid dysregulation, and preserving muscle mass through structured physical activity should be a core therapeutic target.
    Keywords:  chronic inflammation; insulin resistance; metabolic disorders; myokines; sarcopenia; thyroid dysfunction
    DOI:  https://doi.org/10.3390/ijms27010060
  4. Cells. 2025 Dec 23. pii: 25. [Epub ahead of print]15(1):
    Inhibition of Tumor Microenvironment-Driven JAK-STAT Signaling Enhances Response to Arginine Deprivation Therapy in Triple-Negative Breast Cancer.
    Hila Tishler, Shahar Ziman, Kuoyuan Cheng, Kun Wang, Neel Sanghvi, Lital Adler, Gil Stelzer, Hillary Maniriho, Bareket Dassa, Elizabeta Bab-Dinitz, Michal Levi, Sivan Galai, Omer Goldman, Yarden Ariav, Naama Darzi, Saar Ezagouri, Nitsan Nimni, Nataly Rosenfeld, Ron Rotkopf, Alexander Brandis, Tevie Mehlman, Roni Oren, Mirie Zerbib, Yuri Kuznetsov, Sara Donzelli, Giovanni Blandino, Rony Seger, Eytan Ruppin, Ayelet Erez.
      Argininosuccinate synthetase 1 (ASS1) expression and arginine availability are key metabolic determinants that influence tumor fitness and regulate immune interactions within the tumor microenvironment (TME). Using an orthotopic triple-negative breast cancer (TNBC) model, we demonstrate that arginine deprivation heightens tumor dependence on the TME for survival. Mechanistically, fibroblasts sustain tumor viability by supplying arginine, whereas macrophages cooperate with stromal cues to activate Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling, thereby enhancing tumor survival. Concordantly, a JAK-STAT gene-expression signature correlates with ASS1 levels in human TNBC datasets. Translationally, combined pharmacological inhibition of JAK signaling with arginine deprivation markedly suppresses tumor growth. Together, these findings reveal a TME-driven, targetable stromal-immune circuit that enables tumors to withstand arginine deficiency-induced metabolic stress. Broadly, our work highlights that mapping and strategically inducing metabolic dependencies can reveal actionable compensatory pathways, offering opportunities to improve cancer therapy.
    Keywords:  ASS1; JAK-STAT; arginine; tumor microenvironment
    DOI:  https://doi.org/10.3390/cells15010025
  5. Transl Cancer Res. 2025 Dec 31. 14(12): 8448-8461
    Glutamine metabolism drives tumor aggressiveness but not chemoresistance in ovarian carcinoma cell lines.
    Siegfried Hélage, Marie-Céline Blanc-Quintin, Nathalie Neveux, Antonin Ginguay, Jean-Pascal De Bandt, Luc Cynober, Jérôme Alexandre, François Goldwasser, Élisabeth Dion.
       Background: Glutamine, an essential nutrient for healthy cells, supports immunity and cytoprotection during anticancer treatments. However, intense glutaminolysis may promote proliferation and chemoresistance in ovarian carcinomas by activating the PI3K/AKT/mTORC1 pathway and overexpressing c-Myc. This study aimed to characterize glutamine metabolism in ovarian carcinomas and assess its impact on tumor aggressiveness and chemosensitivity, to inform nutritional supplementation or therapeutic targeting.
    Methods: Glutamine and glucose consumption, chemosensitivity to cisplatin and paclitaxel, and doubling time were analyzed in three ovarian carcinoma cell lines (ES-2, TOV-21G: clear cell; OVCAR-3: serous papillary) and primary ascites cells under varying glutamine concentrations (0.5, 1, 2, 4 mM). Expression of glutaminase, glutamate dehydrogenase 1 (GDH1), and c-Myc, as well as PI3K/AKT/mTORC1 activation, were assessed by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot.
    Results: TOV-21G exhibited significantly higher glutamine consumption (13.3±1.3 vs. 6.5±0.3 and 7±0.5 U/mg protein, P<0.001), increased expression of glutaminase, GDH1, and c-Myc, marked PI3K/AKT/mTORC1 activation (P=0.045), and a shorter doubling time (11.5±1.5 h, P=0.04) compared to ES-2 and OVCAR-3. OVCAR-3 showed significantly greater resistance to cisplatin and paclitaxel (P=0.03). Varying glutamine concentrations did not affect chemosensitivity.
    Conclusions: Intense glutaminolysis is associated with increased tumor aggressiveness, suggesting a prognostic role for 18F-(2S,4R)-4-fluoroglutamine (18F-fluoroglutamine) positron emission tomography (PET) imaging. Glutamine supplementation, without impacting chemoresistance, may mitigate iatrogenic effects, while targeting glutaminolysis offers a therapeutic perspective.
    Keywords:  Ovarian carcinoma; chemoresistance; glutamine; glutaminolysis; metabolic imaging
    DOI:  https://doi.org/10.21037/tcr-2025-1721
  6. FASEB J. 2026 Jan 15. 40(1): e71404
    TNF/TNFR1 is a Key Regulator of Prolonged Fasting-Induced Decrease in Adipose Tissue.
    Amanda Carla Clemente de Oliveira, Adma Maciel Babêtto, Mariele Lino Silva, Larisse de Souza Barbosa Lacerda, Thiago de Souza Rodrigues, Marina Chaves de Oliveira, Christine Rouault, Emmanuel L Gautier, André Gustavo Oliveira, Karine Clément, Mauro Martins Teixeira, Geneviève Marcelin, Adaliene Versiani Matos Ferreira.
      Nutrient availability influences white adipose tissue (WAT) inflammation, leading to decreased or increased adiposity. Tumor necrosis factor (TNF) is elevated in WAT under both conditions, being involved in lipolysis and regulation of interleukin 18 (IL-18) secretion, which may regulate lipolytic processes. However, the role of these cytokines in adiposity reduction due to low energy availability remains unclear. Wild-type (WT) mice fasted for 24 h showed decreased adiposity, whereas TNFR1 knockout mice (TNFR1-/-) were unresponsive to fat pad loss, even after 48-h fasting. TNFR1-/- mice were also resistant to β3-adrenergic receptor agonist CL316,243-induced fat mobilization, which was linked with reduced expression of lipases, β3-adrenergic receptors, and cytokines in WAT. Also, mice treated with the TNF-α inhibitor infliximab and fasted for 48 h showed resistance to adiposity loss, suggesting that prolonged fasting-induced TNF signaling may modulate adipose tissue reduction. Conversely, IL-18 does not seem to influence fat pad loss induced by 24-h fasting as IL-18 knockout mice (IL-18-/-) express TNF in WAT and respond to prolonged fasting similarly to WT animals. To assess the potential translational relevance of our findings to human obesity, we analyzed 53 samples from patients with obesity who underwent bariatric surgery. Interestingly, TNFR1 and IL-18 expressions in sWAT correlate with the expression of lipases and adipokines in the subcutaneous site despite no correlation with body weight or fat mass 1 year after surgery. In summary, this study suggests that the TNF/TNFR1 axis is crucial for metabolic adaptation and is a prerequisite for prolonged fasting-induced lipolysis in male mice.
    Keywords:  Interleukin‐18; adipose tissue; bariatric surgery; prolonged fasting; tumor necrosis factor
    DOI:  https://doi.org/10.1096/fj.202501928RR
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