bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2026–02–22
eight papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. The integrated stress response promotes immune evasion through lipocalin 2.
  2. Tumor-Derived Polyamines Initiate Fat Wasting in Cancer Cachexia.
  3. Decoding the Integrated Stress Response of Pancreatic Cancer: Identifying a Serine-dependent Tumor Subset Under Metabolic Relationships With CAFs.
  4. Oxygen-dependent regulation of ADAMTS1 by VEGFA defines a novel VEGFA-HIF-ADAMTS1 axis in hepatocellular cancer.
  5. Nutrient Deprivation Promotes Bladder Cancer Metastasis through Beclin-1 Deacetylation-Mediated Autophagy Activation.
  6. The ISR downstream effector ATF4 promotes mGluR-dependent long-term depression and associated behavior.
  7. Glycolysis enzymes and cellular lactylation in tumour.
  8. The AMPK activator A769662 promotes ferroptosis and suppresses disulfidptosis by inhibiting SLC7A11.
  1. Nature. 2026 Feb 18.
    The integrated stress response promotes immune evasion through lipocalin 2.
    Jozef P Bossowski, Ray Pillai, John Kilian, Angela Wong Lau, Mari Nakamura, Ali Rashidfarrokhi, Yuan Hao, Ruxuan Li, Katherine Wu, Takamitsu Hattori, Eliezra Glasser, Akiko Koide, Lidong Wang, Andre L Moreira, Cristina Hajdu, Sahith Rajalingam, Sarah E LeBoeuf, Hortense Le, Seungeun Lee, Jin Woo Oh, Cheolyong Joe, Hyemin Kim, Chan-Young Ock, Se-Hoon Lee, Hao Wang, Angana A H Patel, Volkan I Sayin, Aristotelis Tsirigos, Kwok-Kin Wong, Sergei B Koralov, Mario Pende, Francisco J Sánchez-Rivera, Diane M Simeone, Ioannis K Zervantonakis, Shohei Koide, Thales Papagiannakopoulos.
      Cancer cells activate the integrated stress response (ISR) to adapt to stress and resist therapy1. ISR signals converge on activating transcription factor 4 (ATF4), which controls cell-intrinsic transcriptional programs that are involved in metabolic adaptation, survival and growth2,3. However, whether the ISR-ATF4 axis influences anti-tumour immune responses remains mostly unknown. Here we show that loss of ATF4 decreases tumour progression considerably in immunocompetent mice, but not in immunocompromised ones, by enhancing T cell-dependent anti-cancer immune responses. An unbiased genetic screen of ATF4-regulated genes identifies lipocalin 2 (LCN2) as the principal ATF4-dependent effector that impairs anti-tumour immunity by favouring infiltration with immunosuppressive interstitial macrophages. Furthermore, we find that LCN2 promotes T cell exclusion and immune evasion in preclinical mouse models, and correlates with decreased T cell infiltration in patients with lung and pancreatic adenocarcinomas. Anti-LCN2 antibodies promote robust anti-tumour T cell responses in mouse models of aggressive solid tumours. Our study shows that the ATF4-LCN2 axis has a cell-extrinsic role in suppressing anti-cancer immunity, and could pave the way for an immunotherapy approach that targets LCN2.
    DOI:  https://doi.org/10.1038/s41586-026-10143-0
  2. bioRxiv. 2025 Dec 03. pii: 2025.12.01.691597. [Epub ahead of print]
    Tumor-Derived Polyamines Initiate Fat Wasting in Cancer Cachexia.
    Matias Fabregat, Rachel J Fenske, Julia K Hansen, Cameron J Kaminsky, Jevin Lortie, Alexander Nassar, Kayla Kressin, Annie Jen, Lucia Cilloni, Katherine Overmeyer, Caroline M Alexander, John W Garrett, Perry J Pickhardt, Joshua J Coon, Costas A Lyssiotis, Marina Pasca di Magliano, Lingjun Li, Adam J Kuchnia, Andrea Galmozzi.
      Cancer-associated cachexia (CC) is a fatal metabolic condition characterized by progressive loss of fat and muscle mass, yet its early molecular drivers remain poorly defined. Here, we identify a polyamine-dependent tumor-adipose crosstalk that triggers adipocyte lipolysis and fat wasting during the pre-cachexia stage, preceding systemic inflammation and muscle atrophy. Cancer-derived polyamines are enriched in extracellular vesicles and promote lipid mobilization via eIF5A hypusination, independent of adrenergic signaling. In preclinical models, polyamine accumulation associates with early fat loss and elevated circulating fatty acids. Clinically, automated CT imaging of newly diagnosed pancreatic cancer patients reveals increased adipose density, reflecting lipolysis, that correlates with circulating polyamine levels and predicts poor survival. These findings support polyamine metabolism as a mechanistic driver and candidate biomarker of early cachexia, providing a framework for early detection and targeted intervention.
    DOI:  https://doi.org/10.64898/2025.12.01.691597
  3. Adv Sci (Weinh). 2026 Feb 17. e15740
    Decoding the Integrated Stress Response of Pancreatic Cancer: Identifying a Serine-dependent Tumor Subset Under Metabolic Relationships With CAFs.
    Sauyeun Shin, Mehdi Liauzun, Jacobo Solorzano, Morgane Le Bras, Christine Jean, Benjamin Fourneaux, Margaux Dore, Lea Fevrier, Ismahane Belhabib, Alexia Brunel, Cindy Neuzillet, Marion Larroque, Carine Joffre, Stephane Rocchi, Nicolas Fraunhoffer, Aurelie Perraud, Muriel Mathonnet, Vera Pancaldi, Laetitia Linares, Juan Iovanna, Nelson Dusetti, Ola Larsson, Remy Nicolle, Stephane Pyronnet, Corinne Bousquet, Yvan Martineau.
      Pancreatic ductal adenocarcinoma (PDA) transcriptomic profiling has identified prognostic subtypes, yet patient-specific first-line therapies remain elusive. Here, we stratified PDA tumors by mRNA translation rates, a frequently dysregulated step in gene expression, using translatome profiling of 27 patient-derived xenografts (PDXs). Unsupervised analysis revealed a distinct tumor subset with low global protein synthesis but sustained translation of Integrated Stress Response (ISR) mRNAs, including ATF4. These ISR-activated cancer cells exhibited broad chemoresistance and apoptosis resistance, yet were auxotrophic for serine due to loss of PHGDH and CBS expression, impairing serine and cysteine biosynthesis. This vulnerability correlated with improved overall survival in patients with low expression of both enzymes. Notably, cancer-associated fibroblasts (CAFs) reprogrammed by ISR-activated cells, shifting from myCAF to iCAF phenotype with reduced collagen synthesis and glycine-to-serine conversion, produced serine and sustained tumor growth in amino acid-depleted environments. Our findings demonstrate the power of translatome profiling to reveal stable, drug-resistant PDA cell states and identify a targetable CAF-tumor metabolic symbiosis, opening new avenues for therapeutic intervention in this highly lethal malignancy.
    Keywords:  cancer‐associated fibroblast; integrated stress response; mRNA translation; pancreatic cancer; serine metabolism
    DOI:  https://doi.org/10.1002/advs.202515740
  4. Tissue Cell. 2026 Feb 16. pii: S0040-8166(26)00087-X. [Epub ahead of print]100 103395
    Oxygen-dependent regulation of ADAMTS1 by VEGFA defines a novel VEGFA-HIF-ADAMTS1 axis in hepatocellular cancer.
    Feray Kockar, Esra Tokay, Nelin Hacioglu, Kubilay Gunerhan, Yasemin Kalfa, Feyza Nur Sav, Merve Karaman, Meltem Balaban, Kubra Zehra Kalay.
      ADAMTS1 is a matrix-associated protease involved in angiogenesis and tumor microenvironment remodeling, and its regulation under oxygen-limited conditions has not been fully elucidated. Vascular endothelial growth factor A (VEGFA) is one of the key regulators of angiogenesis and hypoxic signaling. This study aimed to reveal the effects of VEGFA on ADAMTS1 gene expression, promoter activity, and related signaling pathways under normoxic and hypoxic conditions. The findings show that VEGFA regulates ADAMTS1 expression in a time- and oxygen level-dependent manner. Under hypoxic conditions, ADAMTS1 mRNA and protein levels exhibited a biphasic increase, showing a stronger and more persistent response than that under normoxic conditions. Promoter analyses showed that under normoxic conditions, VEGFA suppressed transcriptional activity in both the long (P1) and short (P7) promoter regions, whereas under hypoxic conditions, it decreased P1 activity but induced activation in the P7 region. The partial reversal of this effect by the MEK/ERK inhibitor PD98059 confirmed the role of this pathway in the transcriptional control of VEGFA. Chromatin immunoprecipitation-qPCR further demonstrated oxygen-dependent recruitment of ELK1, c-JUN, and notably ATF-1 to multiple ADAMTS1 promoter regions, with hypoxia inducing a marked and widespread increase in ATF-1 occupancy. Furthermore, it has been determined that VEGFA creates an oxygen-sensitive positive feedback loop by increasing its own expression and HIF-1α stabilization, which in turn enhances ADAMTS1 induction. Integrative bioinformatic analyses of GEO and TCGA-LIHC datasets supported these experimental findings, revealing hypoxia-associated upregulation of VEGFA, positive correlations between hypoxia scores and VEGFA/HIF1A expression, and context-dependent associations between ADAMTS1 expression, hypoxia signaling, and angiogenesis-related gene networks. These results identify ADAMTS1 as a hypoxia-responsive gene regulated through VEGFA-driven convergence of MAPK and PI3K/AKT signaling on a transcriptionally complex promoter, providing mechanistic insight into hypoxia-associated extracellular matrix remodeling in cancer.
    Keywords:  ADAMTS1; Angiogenesis; HIF-1α; Hepatocellular cancer; VEGFA
    DOI:  https://doi.org/10.1016/j.tice.2026.103395
  5. Cancer Lett. 2026 Feb 16. pii: S0304-3835(26)00100-X. [Epub ahead of print] 218337
    Nutrient Deprivation Promotes Bladder Cancer Metastasis through Beclin-1 Deacetylation-Mediated Autophagy Activation.
    Yan Sun, Hang Tong, Guozhi Zhao, Linfeng Wu, Xiaoyu Zhang, Tinghao Li, Junlong Zhu, Kunyao Zhu, Hubin Yin, Xinyuan Li, Weiyang He.
      Deprivation of nutrients in the tumor microenvironment drives malignant progression, yet the molecular mechanisms linking metabolic stress to metastasis in bladder cancer remain incompletely understood. Here, we report that nutrient-deprivation stress promotes metastasis by orchestrating a post-translational modification cascade centered on Beclin-1. Clinical analysis revealed that acetylation of Beclin-1 at lysine residues K430 and K437 was significantly reduced in muscle-invasive bladder cancer (MIBC) compared with non-muscle-invasive bladder cancer (NMIBC), a molecular signature inversely correlated with elevated phospho-eIF2α, a marker of cellular starvation. Mechanistically, nutrient deprivation dynamically regulates the expression of the deacetylase SIRT1 and acetyltransferase p300, shifting the balance toward Beclin-1 deacetylation. This deacetylation event serves a dual function: it enhances Beclin-1 protein stability by shielding it from TRIM21-mediated K48-linked ubiquitination and proteasomal degradation, and it promotes autophagosome formation by strengthening its interaction with pro-autophagic partners VPS34, ATG14, and UVRAG while weakening its binding to the inhibitor Rubicon. Consequently, this leads to sustained autophagy activation and epithelial-mesenchymal transition. Genetic and pharmacological interventions further confirmed the central role of this axis, demonstrating that SIRT1 activation by resveratrol promoted metastasis, whereas p300 activation by CTB suppressed it. Crucially, these effects were abrogated in cells expressing acetylation-mimetic Beclin-1 mutants, suggesting a direct causal link. Our study unveils the SIRT1/p300-Beclin-1-TRIM21 axis as a key nutrient-sensing pathway that promotes bladder cancer metastasis through crosstalk between acetylation and ubiquitination. These findings identify new therapeutic vulnerabilities in advanced bladder cancer.
    Keywords:  Bladder cancer; acetylation; autophagy; nutrient deprivation; ubiquitination
    DOI:  https://doi.org/10.1016/j.canlet.2026.218337
  6. Proc Natl Acad Sci U S A. 2026 Feb 24. 123(8): e2532796123
    The ISR downstream effector ATF4 promotes mGluR-dependent long-term depression and associated behavior.
    Niaz Mahmood, Cong Loc Dang, Pei You Wu, Ziying Huang, Jung-Hyun Choi, Konstantina Psycharis, Reuben Portugese, Arkady Khoutorsky, Mauro Costa-Mattioli, R Anne McKinney, Nahum Sonenberg.
      The integrated stress response (ISR) plays a crucial role in cognition via bidirectional modulation of the two major forms of synaptic plasticity, long-term potentiation, and long-term depression (LTD). Specifically, inhibition of the ISR blocks metabotropic glutamate receptor-dependent LTD (mGluR-LTD), whereas its activation facilitates this form of synaptic depression. However, the contribution of activating transcription factor 4 (ATF4), the best studied downstream effector of the ISR, to mGluR-LTD remains unknown. Here, we show that pharmacological activation of group I mGluRs in mouse hippocampal slices increases ATF4 protein levels without altering its transcription and concurrently downregulates the expression of oxidative phosphorylation (OXPHOS) proteins. Selective deletion of ATF4 in excitatory neurons impairs mGluR-LTD and prevents the downregulation of OXPHOS proteins. Notably, administration of a small molecule inhibitor of OXPHOS rescues the impaired mGluR-LTD in ATF4-depleted hippocampal slices, indicating that ATF4 regulates this type of synaptic plasticity by modulating mitochondrial function. Moreover, ATF4 deletion in excitatory neurons disrupts object-place learning, an mGluR-LTD-dependent behavior paradigm. Together, these findings reveal a role of ATF4 as a key mediator of protein synthesis-regulated synaptic depression and related behaviors.
    Keywords:  integrated stress response; mGluR-LTD; synaptic plasticity
    DOI:  https://doi.org/10.1073/pnas.2532796123
  7. Clin Transl Med. 2026 Feb;16(2): e70549
    Glycolysis enzymes and cellular lactylation in tumour.
    Chenyuan Dai, Lihua Wang.
      Cellular lactylation, a recently identified post-translational modification, has emerged as a crucial regulator in various biological processes, particularly in cancer. The discovery of lactylation provides a new perspective for understanding the functional significance of the Warburg effect in tumour cells. Enzymes involved in the glycolytic pathway modulate lactylation, influencing tumour genesis and progression. This review explores the intricate relationship between glycolysis, lactylation and tumour biology, with a focus on how enzymes participating in glycolysis impact lactylation in cancer cells. We discuss how glycolytic enzymes regulate lactylation and highlight their broader implications in tumour biology. The role of lactylation in shaping the tumour microenvironment underscores its increasing significance as a biomarker for cancer prognosis and a target for therapeutic intervention. Therefore, we also summarised the potential of targeting lactylation as a cancer therapy strategy. KEY POINTS: Glycolytic enzymes regulate lactylation in cancer cells. Lactylation drives tumour growth, metastasis, immune evasion and contributes to microenvironment remodelling Targeting lactylation holds promise for cancer therapy.
    Keywords:  glycolysis enzymes; lactylation; protein post‐translational modification; tumour genesis and progression
    DOI:  https://doi.org/10.1002/ctm2.70549
  8. Biochem Biophys Res Commun. 2026 Feb 14. pii: S0006-291X(26)00231-7. [Epub ahead of print]808 153467
    The AMPK activator A769662 promotes ferroptosis and suppresses disulfidptosis by inhibiting SLC7A11.
    Una Misono, Nanoka Ishida, Ayane Fumuro, Hironori Katoh.
      AMP-activated protein kinase (AMPK) plays a critical role in maintaining cellular energy homeostasis. Activation of AMPK negatively regulates ferroptosis, a form of cell death caused by iron-dependent accumulation of lipid peroxides. In the present study, we unexpectedly found that A769662, widely used as a selective AMPK activator, inhibited SLC7A11-mediated cystine uptake, thereby decreasing intracellular reduced glutathione (GSH) levels and promoting ferroptosis in glioblastoma cells. Deletion of the AMPKα1 gene or treatment with an AMPK inhibitor compound C did not inhibit A769662-induced promotion of ferroptosis. In addition, A769662 suppressed disulfidptosis, a recently identified form of cell death caused by SLC7A11-mediated cystine uptake under glucose deprivation. On the other hand, AICAR, another AMPK activator, had no effect on cystine uptake and intracellular GSH levels. These results suggest that A769662 inhibits SLC7A11-mediated cystine uptake to promote ferroptosis and suppress disulfidptosis in an AMPK-independent manner.
    Keywords:  AMPK; Cystine; Disulfidptosis; Ferroptosis; SLC7A11
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153467
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