bims-stacyt 2023-03-19 papers

Cancer Res. 2023 Mar 13. pii: CAN-22-2316. [Epub ahead of print]

Hypoxia potentiates the inflammatory fibroblast phenotype promoted by pancreatic cancer cell-derived cytokines.

Simon Schwoerer, Francesco V Cimino, Manon Ros, Kaloyan M Tsanov, Charles Ng, Scott W Lowe, Carlos Carmona-Fontaine, Craig B Thompson.

Cancer-associated fibroblasts (CAFs) are a major cell type in the stroma of solid tumors and can exert both tumor-promoting and tumor-restraining functions. CAF heterogeneity is frequently observed in pancreatic ductal adenocarcinoma (PDAC), a tumor characterized by a dense and hypoxic stroma that features myofibroblastic CAFs (myCAFs) and inflammatory CAFs (iCAFs) that are thought to have opposing roles in tumor progression. While CAF heterogeneity can be driven in part by tumor cell-produced cytokines, other determinants shaping CAF identity and function are largely unknown. In vivo, we found that iCAFs displayed a hypoxic gene expression and biochemical profile and were enriched in hypoxic regions of PDAC tumors, while myCAFs were excluded from these regions. Hypoxia led fibroblasts to acquire an inflammatory gene expression signature and synergized with cancer cell-derived cytokines to promote an iCAF phenotype in a HIF-1α dependent fashion. Furthermore, HIF-1α stabilization was sufficient to induce an iCAF phenotype in stromal cells introduced into PDAC organoid co-cultures and to promote PDAC tumor growth. These findings indicate hypoxia-induced HIF-1α as a regulator of CAF heterogeneity and promoter of tumor progression in PDAC.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-2316

Mol Cells. 2023 Mar 17.

Nrf2 in TIME: The Emerging Role of Nuclear Factor Erythroid 2-Related Factor 2 in the Tumor Immune Microenvironment.

Jialin Feng, Oliver J Read, Albena T Dinkova-Kostova.

Nuclear factor erythroid 2-related factor 2 (Nrf2) mediates the cellular antioxidant response, allowing adaptation and survival under conditions of oxidative, electrophilic and inflammatory stress, and has a role in metabolism, inflammation and immunity. Activation of Nrf2 provides broad and long-lasting cytoprotection, and is often hijacked by cancer cells, allowing their survival under unfavorable conditions. Moreover, Nrf2 activation in established human tumors is associated with resistance to chemo-, radio-, and immunotherapies. In addition to cancer cells, Nrf2 activation can also occur in tumor-associated macrophages (TAMs) and facilitate an anti-inflammatory, immunosuppressive tumor immune microenvironment (TIME). Several cancer cell-derived metabolites, such as itaconate, L-kynurenine, lactic acid and hyaluronic acid, play an important role in modulating the TIME and tumor-TAMs crosstalk, and have been shown to activate Nrf2. The effects of Nrf2 in TIME are context-depended, and involve multiple mechanisms, including suppression of pro-inflammatory cytokines, increased expression of programmed cell death ligand 1 (PD-L1), macrophage colony-stimulating factor (M-CSF) and kynureninase, accelerated catabolism of cytotoxic labile heme, and facilitating the metabolic adaptation of TAMs. This understanding presents both challenges and opportunities for strategic targeting of Nrf2 in cancer.

Keywords: Keap1; Nrf2; anti-tumor immunity; immunosuppression; tumor microenvironment

DOI: https://doi.org/10.14348/molcells.2023.2183

J Cancer Res Clin Oncol. 2023 Mar 13.

Targeting adipocyte-immune cell crosstalk to control breast cancer progression.

Weihua Wang, Hongdan Chen, Supeng Yin, Zeyu Yang, Fan Zhang.

Adipocytes are crucial components of breast cancer and are involved in regulating the progression, therapeutic efficacy, and prognosis of breast cancer patients. Characterized by storing energy and producing a variety of secretory factors, adipocytes are responsible for inducing obesity and regulating the tumor immune activity. Adipocytes communicate with tumor infiltrating immune cells through the secreted adipokines, cytokines, and exosomes in the breast cancer TIME, which shapes the tumor supporting environment to facilitate the immune escape of tumor cells. In-depth studies of the crosstalk between adipocytes and TIME can not only provide a more comprehensive regulatory landscape of TIME, but also be conducive to screening novel targets for future precision targeted therapy. The aim of this review is to discuss recent studies for understanding the role of crosstalk between adipocytes and immune cells in shaping the breast cancer immune microenvironment.

Keywords: Adipocytes; Breast cancer; Immune cells; Tumor immune microenvironment

DOI: https://doi.org/10.1007/s00432-023-04685-3

J Biochem. 2023 Mar 15. pii: mvad023. [Epub ahead of print]

Response to acute hyperglycemia and high fructose in cultured tenocytes.

Rebecca Kuan, Shilpa Nath, Devendra K Agrawal, Finosh G Thankam.

High monosaccharide levels are intimately associated with diabetes and impact tendon cells through inflammation and impairment in metabolic homeostasis. Experiments were designed to understand the responses elicited by cultured tenocytes under monosaccharide stress induced by hyperglycemia and hyperfructosemia. We simulated hyperglycemia and hyperfructosemia in vitro by treating tenocytes with media containing sub-lethal concentrations of glucose and fructose, respectively. Exposure of tenocytes to high glucose and high fructose altered the levels of IL-1β, IL-2, IL-6, IL10, and IL-17A. AMPK expression was increased in high glucose and decreased in high fructose groups. High fructose increased the level of IRS-1 compared to the control. Increased mitochondrial superoxide levels and compromised mitochondrial membrane integrity were exhibited by both the groups. The findings from the network analysis revealed many altered genes that are related to pathways for enzyme-linked receptor protein signaling, positive regulation of metabolic processes, transmembrane receptor tyrosine kinase pathway, insulin receptor signaling, and regulation of cytokine production. Overall, the data suggest that the tenocytes under high monosaccharide levels exhibit survival responses by altering the expression status of cytokines and metabolic mediators that are involved in the underlying pathogenesis of tendinopathy.

Keywords: Diabetic tendinopathy; Hyperfructosemia; Hyperglycemia; Rotator cuff tendon injury; Tenocytes

DOI: https://doi.org/10.1093/jb/mvad023