Cancer associated fibroblast FAK regulates malignant cell metabolism

Nat Commun. 2020 Mar 10;11(1):1290. doi: 10.1038/s41467-020-15104-3.

Abstract

Emerging evidence suggests that cancer cell metabolism can be regulated by cancer-associated fibroblasts (CAFs), but the mechanisms are poorly defined. Here we show that CAFs regulate malignant cell metabolism through pathways under the control of FAK. In breast and pancreatic cancer patients we find that low FAK expression, specifically in the stromal compartment, predicts reduced overall survival. In mice, depletion of FAK in a subpopulation of CAFs regulates paracrine signals that increase malignant cell glycolysis and tumour growth. Proteomic and phosphoproteomic analysis in our mouse model identifies metabolic alterations which are reflected at the transcriptomic level in patients with low stromal FAK. Mechanistically we demonstrate that FAK-depletion in CAFs increases chemokine production, which via CCR1/CCR2 on cancer cells, activate protein kinase A, leading to enhanced malignant cell glycolysis. Our data uncover mechanisms whereby stromal fibroblasts regulate cancer cell metabolism independent of genetic mutations in cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / blood supply
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cancer-Associated Fibroblasts / enzymology*
  • Cell Line, Tumor
  • Cell Proliferation
  • Chemokines / metabolism
  • Female
  • Focal Adhesion Protein-Tyrosine Kinases / metabolism*
  • Glycolysis
  • Humans
  • Male
  • Metabolic Networks and Pathways
  • Mice, Inbred C57BL
  • Neoplasms / blood supply
  • Neoplasms / metabolism*
  • Neoplasms / pathology*
  • Pancreatic Neoplasms / blood supply
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Phosphoproteins / metabolism
  • Stromal Cells / metabolism
  • Survival Analysis
  • Xenograft Model Antitumor Assays

Substances

  • Chemokines
  • Phosphoproteins
  • Focal Adhesion Protein-Tyrosine Kinases