Epigenetic Reprogramming of Cancer-Associated Fibroblasts Deregulates Glucose Metabolism and Facilitates Progression of Breast Cancer

TLDR

Cancer‑associated fibroblasts (CAFs) play an unclear role in breast cancer progression, and the mechanisms by which their altered glucose metabolism fuels tumor growth remain poorly understood. Using patient‑derived fibroblasts and animal models, the authors show that CAFs shift toward lactate and pyruvate production to fuel cancer cell biosynthesis, and that this glycolytic phenotype is maintained by hypoxia‑induced epigenetic reprogramming of HIF‑1α and glycolytic enzymes. Reducing CAF lactate production changes tumor metabolism and slows growth, indicating that CAF glucose metabolism evolves during progression and is partly driven by oxygen‑dependent epigenetic changes.

Abstract

The mechanistic contributions of cancer-associated fibroblasts (CAFs) in breast cancer progression remain to be fully understood. While altered glucose metabolism in CAFs could fuel cancer cells, how such metabolic reprogramming emerges and is sustained needs further investigation. Studying fibroblasts isolated from patients with benign breast tissues and breast cancer, in conjunction with multiple animal models, we demonstrate that CAFs exhibit a metabolic shift toward lactate and pyruvate production and fuel biosynthetic pathways of cancer cells. The depletion or suppression of the lactate production of CAFs alter the tumor metabolic profile and impede tumor growth. The glycolytic phenotype of the CAFs is in part sustained through epigenetic reprogramming of HIF-1α and glycolytic enzymes. Hypoxia induces epigenetic reprogramming of normal fibroblasts, resulting in a pro-glycolytic, CAF-like transcriptome. Our findings suggest that the glucose metabolism of CAFs evolves during tumor progression, and their breast cancer-promoting phenotype is partly mediated by oxygen-dependent epigenetic modifications.