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Cancer-intrinsic Cxcl5 orchestrates global metabolic reprogramming of three dimensional cancers by upregulating Hif1α and Myc expression

ABSTRACT: The tumor microenvironment (TME) of pancreatic cancer is characterized by deposition of extracellular matrix (ECM). In 3D TME comprising cellular and non-cellular components, physical and chemical restriction induce oxygen and nutrients shortage in tumor site. Therefore, it is inevitable for cancer cells to manipulate the biological processes and metabolism for survival. However, it has not been fully explored the metablic phenotype coupling to the components existed in 3D and how the cancer cells exploit the metabolic reprogramming. In this study, we establisehd in vitro 3D tumor spheroid-in-Matrigel culture system recapitulating the 3D TME. We discovered the significant upregulation of Cxcl5 expression in murine pancreatic cancer cell line Panc02 by 3D culture with M1 macrophage conditioned media treatment. The loss of Cxcl5 in 3D Panc02 cells showed dramatical reduction of cancer growth. Importantly, the Cxcl5-deficient 3D cancer cells showed global alteration in metabolism. Additionally, Cxcl5 loss failed to control oxidative stress and in turn, increased ferroptotic cell death. Overexpression of Hif1α and Myc in Cxcl5-deficient cancer cells rescued the impaired metabolic processes, ferroptotic cell death, and cancer growth.

ORGANISM(S): Mus musculus

PROVIDER: GSE269318 | GEO | 2025/07/30

REPOSITORIES: GEO

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Project description:BACKGROUND: CXCR1/2 inhibitors are being implemented with immunotherapies in PDAC clinical trials. CXCL ligands are a family of cytokines responsible for stimulating these receptors; while typically secreted by activated immune cells, fibroblasts, and even adipocytes, they are also secreted by immune-evasive cancer cells. CXCL ligand release is known to occur in response to inflammatory stimuli, whether pathogenic (bacterial) or endogenous (obesity). Obesity has been linked to poor patient outcome and altered anti-tumor immunity in pancreatic cancer. Importantly, adipose-derived cytokines and chemokines have been implicated as potential drivers of tumor cell immune evasion; cumulatively these findings suggest that targeting CXC ligands may be beneficial in the context of obesity. METHODS: RNA-sequencing of human PDAC cell lines was used to assess differential influences of adipose conditioned media on the cancer cell transcriptome. In addition, the adipose-induced secretome of PDAC cells was validated with ELISA for induced CXCL5 secretion. Human tissue data from CPTAC was used to correlate IL-1β and TNF expression with both CXCL5 mRNA and protein levels. CRISPR-Cas9 was used to knock out CXCL5 from a murine PDAC cell line in order to assess orthotopic tumor studies in syngeneic, diet-induced obese mice. Flow cytometry was used to compare the immune profiles between tumors. Mice were monitored for differences in tumor size at endpoint in combination with Anti-PD-1 immune checkpoint blockade therapy. RESULTS: Human adipose conditioned media (hAT-CM) stimulates CXCL5 secretion from PDAC cells via either IL-1β or TNF; neutralization of both is required to significantly block release of CXCL5 from tumor cells. Ablation of CXCL5 from tumors promoted an enriched immune phenotype with an unanticipatedly increased number of exhausted CD8 T cells. Application of anti-PD-1 treatment to control tumors failed to alter tumor growth, yet treatment of CXCL5 deficient tumors showed response by significantly diminished tumor mass. CONCLUSIONS: In summary, our findings show that both TNF and IL-1β can stimulate CXCL5 release from PDAC cells in vitro, which correlates with expression in patient data. CXCL5 depletion in vivo alone is sufficient to promote T cell infiltration into tumors, increasing efficacy of checkpoint blockade inhibition and alleviating tumor burden.

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Cancer-intrinsic Cxcl5 orchestrates global metabolic reprogramming of three dimensional cancers by upregulating Hif1α and Myc expression

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