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

Cell Rep. 2020 Jun 2;31(9):107701. doi: 10.1016/j.celrep.2020.107701.

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.

Keywords: breast cancer; cancer-associated fibroblasts; epigenetic alterations; hypoxia; metabolism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Actins / genetics
  • Actins / metabolism
  • Animals
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cancer-Associated Fibroblasts / cytology
  • Cancer-Associated Fibroblasts / metabolism*
  • Cell Line, Tumor
  • Epigenomics*
  • Female
  • Glucose / metabolism*
  • Glycolysis
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Lactic Acid / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Monocarboxylic Acid Transporters / antagonists & inhibitors
  • Monocarboxylic Acid Transporters / genetics
  • Monocarboxylic Acid Transporters / metabolism
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase / antagonists & inhibitors
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase / genetics
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase / metabolism
  • Pyruvic Acid / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Symporters / antagonists & inhibitors
  • Symporters / genetics
  • Symporters / metabolism

Substances

  • Actins
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Monocarboxylic Acid Transporters
  • Pdk4 protein, mouse
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • RNA, Small Interfering
  • Symporters
  • alpha-smooth muscle actin, mouse
  • monocarboxylate transport protein 1
  • Lactic Acid
  • Pyruvic Acid
  • Glucose