bims-stacyt 2026-03-29 papers

Cancer Discov. 2026 Mar 27. OF1

Stress Responses Tied to Metastasis and Immune Evasion.

Two studies show that cancer cells co-opt the integrated stress response, via the transcription factor ATF4, to drive both metastasis and immune evasion. Targeting this pathway or its downstream effectors, such as glutamine metabolism and the secreted protein LCN2, may offer a way to limit tumor spread and restore antitumor immunity.

DOI: https://doi.org/10.1158/2159-8290.CD-NW2026-0029

Matrix Biol. 2026 Mar 25. pii: S0945-053X(26)00025-9. [Epub ahead of print]

Glutamine-dependent changes in fibroblast-derived extracellular matrix dictate cancer cell behavior.

Julien Guillard, Jessica Stradley, Kristof Turan, Marta R Storl-Desmond, Shan Lin, Yi-Chia Huang, Kevin Muñoz Forti, Christopher R Weber, Simon Schwӧrer.

The extracellular matrix (ECM) provides key biochemical and biomechanical cues that govern fundamental cellular processes, including growth and migration. ECM dysregulation and altered cell-matrix interactions are drivers of cancer progression, exemplified by pancreatic ductal adenocarcinoma (PDAC), where an abnormally dense, collagen-rich, and stiff ECM correlates with poor patient outcomes. The PDAC microenvironment is poorly perfused, resulting in altered nutrient availability, yet how this metabolic stress shapes the ECM and its biological activity remains largely unknown. Herein, using murine and patient-derived fibroblasts, we demonstrate that glutamine, a key amino acid depleted in poorly perfused PDAC regions, regulates the biochemical composition, mechanical properties, and biological activity of fibroblast-derived ECM. As glutamine availability decreases, fibroblasts shift from producing an interstitial, mature ECM enriched in fibrillar collagens toward a basement membrane-like ECM. Consistent with these observations, glutamine stress inversely correlates with fibrillar collagen expression in CAFs in patients with PDAC. ECM produced under low glutamine conditions is depleted in collagen I, more elastic, and promotes PDAC cell growth compared to ECM generated under glutamine-rich conditions. Reducing the stiffness of such matrices is sufficient to increase PDAC cell growth. Glutamine-dependent changes in ECM composition, stiffness, and biological activity are driven in part by glutamine-regulated alpha-ketoglutarate availability in fibroblasts. These findings establish nutrient availability as a key regulator of ECM biology and suggest the nutrient-dictated ECM as a novel mechanism by which glutamine stress in the tumor microenvironment shapes cancer cell behavior.

Keywords: ECM; Glutamine; PDAC; collagen; fibroblast; stiffness

DOI: https://doi.org/10.1016/j.matbio.2026.03.004

Cell Rep. 2026 Mar 26. pii: S2211-1247(26)00270-6. [Epub ahead of print]45(4): 117192

Gcn2 deficiency triggers anemia and hypoxic intolerance in zebrafish.

Chengdong Liu, Chenxi Wang, Jican Zhao, Weiyi Xia, Wanjuan Yu, Huihui Zhou, Xiya Wu, Mingjun Tang, Huan Zeng, Yanfei Tang, Ranran Zhao, Ling Lu, Xuan Wang, Kangsen Mai, Gen He.

The integrated stress response (ISR) is a conserved signaling hub that orchestrates cellular adaptation to diverse stressors to maintain intracellular homeostasis. However, the specific role of the ISR in regulating hypoxic adaptation and redox homeostasis remains poorly defined. Here, we identify general control nonderepressible 2 (GCN2) as an essential factor for maintaining redox balance and suppressing ferroptosis. Gcn2-deficient zebrafish exhibit hypersensitivity to hypoxia, characterized by excessive heme degradation and mitochondrial damage. Loss of Gcn2 leads to upregulation of hmox1a, reduced erythrocyte numbers, and elevated levels of free ionic iron, collectively contributing to the development of anemia. Mechanistically, loss of Gcn2 downregulates slc3a2b, resulting in disturbed cysteine metabolism. This defect impairs glutathione biosynthesis, triggering ferroptosis characterized by elevated oxidative stress and iron-dependent lipid peroxidation. GCN2 deficiency also induces ferroptosis in HeLa cells. Our findings elucidate a critical role for GCN2 in protecting against ferroptosis and promoting hypoxic tolerance.

Keywords: CP: cell biology; CP: metabolism; GCN2; SLC3A2; ferroptosis; hypoxia; integrated stress response; redox homeostasis; zebrafish

DOI: https://doi.org/10.1016/j.celrep.2026.117192

World J Exp Med. 2026 Mar 20. 16(1): 115478

Deciphering the interplay between hypoxia, angiogenesis, and endoplasmic reticulum stress in carcinogenesis: A narrative review.

Shikha Bhardwaj, Shweta Pandey, Debasish Kumar Ghosh, Tapan Sharma, Buddhi Prakash Jain.

Cancer cells face oxygen and nutrient shortages, driving vascular endothelial growth factor (VEGF)-mediated angiogenesis and increasing protein-folding demand, which triggers endoplasmic reticulum (ER) stress and activates the unfolded protein response (UPR) pathways. The UPR is triggered through three major sensors: IRE1, PERK, and ATF6. Simultaneously, hypoxia stabilizes hypoxia-inducible factor (HIF) genes, enabling tumors to adapt, promote angiogenesis, and enhance survival. This review aims to decode the interconnected roles of hypoxia, angiogenesis, and ER stress in carcinogenesis, with a specific focus on how HIF-regulated signaling integrates these pathways to support tumor progression and impact clinical behavior. Researchers have found that both the UPR and hypoxia pathways influence VEGF expression by increasing the transcription factors ATF-4 and XBP-1, respectively, and by enhancing the expression of HIF genes. HIF genes are known as one of the master regulators of angiogenesis. The PERK/eIF2α pathway, IRE-1, and ATF6, all three branches of the UPR response, also help cancer cells survive under hypoxic conditions. On one hand, where PERK increases the heterodimerization between α levels at the translational level, the IRE-1 branch increases its stabilization via a process known as regulated IRE-1-dependent decay, an endoribonuclease activity. Understanding this triad will support the development of targeted therapies, including HIF inhibitors, anti-angiogenic agents, and UPR modulators, as well as biomarker-based patient selection and combination treatment strategies. Integrating hypoxia, angiogenesis, and ER stress biology reveals critical insights for designing more precise and effective anticancer interventions.

Keywords: Angiogenesis; Cancer; Endoplasmic reticulum stress; Hypoxia; Hypoxia-inducible factor; Vascular endothelial growth factor

DOI: https://doi.org/10.5493/wjem.v16.i1.115478

Trends Endocrinol Metab. 2026 Mar 26. pii: S1043-2760(26)00041-X. [Epub ahead of print]

Endocrine control of one-carbon metabolism in cachexia.

Yongrui Hai, Xuejing Duan, Gaofei Wei.

Cancer cachexia lacks effective therapies due to an incomplete understanding of its upstream drivers. A recent study by Morigny et al. identifies one-carbon metabolism as a conserved endocrine-metabolic program that links tumor signals to skeletal muscle hypermetabolism and systemic energy imbalance, highlighting methyl-donor pathways as actionable targets for treating cachexia.

Keywords: IL-6; cancer cachexia; glucose hypermetabolism; muscle atrophy; one-carbon metabolism

DOI: https://doi.org/10.1016/j.tem.2026.02.006

Metabolites. 2026 Mar 10. pii: 185. [Epub ahead of print]16(3):

Nexus of IDO1/Kynurenine Pathway to T-Cell Exhaustion: Hypoxia-Induced Tryptophan Metabolism in Glioblastoma.

Matthew Abikenari, George Nageeb, Joseph H Ha, Matthew Adam Sjoholm, Justin Liu, Brandon Bergsneider, Jocelyn Valenzuela, James Poe, Kwang Bog Cho, Rohit Verma, Caren Wu, Vivek Sanker, Ravi Medikonda, Lily H Kim, John Choi, Matei A Banu, Michael Lim.

Glioblastoma (GBM) is a universally fatal cancer for which the standard of care has remained largely unchanged for the last 20 years. Recent work has demonstrated that most therapeutic trials for GBM fail due to complex mechanisms of immunosuppression mediated by both the innate and adaptive immune systems. Various metabolic alterations in the tumor microenvironment help maintain this local and systemic immunosuppression, of which the axis of hypoxia-driven tryptophan degradation has garnered substantial attention over the last decade. This paper synthesizes a much-needed elucidation of the immunometabolic reshaping of glioma, myeloid, endothelial, and lymphoid cell lineages induced by hypoxia. The current paper critically evaluates the role of IDO1/TDO2-mediated breakdown of tryptophan and the consequent accumulation of kynurenine, a metabolite that triggers GCN2- and AHR-mediated CD8+ T-cell exhaustion and supports regulatory T-cell differentiation and expansion. Furthermore, we propose a synthesis of mechanistic evidence that establishes a role for the Trp-GCN2-ATF4-VEGFA axis in hypoxia-induced immunosuppression, supporting that pro-tumoral metabolic dysregulation is directly linked to angiogenesis. In GBM, hypoxia and tryptophan-kynurenine pathway dysregulation operate as an integrated metabolic circuit that drives widespread immunosuppression. These mechanisms can be captured by a metabolic signature shared across nearly every cell type in the GBM microenvironment. Drawing on recent spatial transcriptomic, metabolomic, and pharmacologic studies, we outline how this metabolic axis shapes disease biology and how it can be targeted to restore effective antitumor immunity.

Keywords: GCN2–AHR signaling; IDO1/TDO2; glioblastoma; hypoxia (HIF-1α/HIF-2α); immunometabolism; metabolic reprogramming; precision immunotherapy; spatial transcriptomics; tryptophan–kynurenine pathway; tumor microenvironment

DOI: https://doi.org/10.3390/metabo16030185