Fibroblast pyruvate carboxylase is required for collagen production in the tumour microenvironment

Nat Metab. 2021 Nov;3(11):1484-1499. doi: 10.1038/s42255-021-00480-x. Epub 2021 Nov 11.


The aberrant production of collagen by fibroblasts is a hallmark of many solid tumours and can influence cancer progression. How the mesenchymal cells in the tumour microenvironment maintain their production of extracellular matrix proteins as the vascular delivery of glutamine and glucose becomes compromised remains unclear. Here we show that pyruvate carboxylase (PC)-mediated anaplerosis in tumour-associated fibroblasts contributes to tumour fibrosis and growth. Using cultured mesenchymal and cancer cells, as well as mouse allograft models, we provide evidence that extracellular lactate can be utilized by fibroblasts to maintain tricarboxylic acid (TCA) cycle anaplerosis and non-essential amino acid biosynthesis through PC activity. Furthermore, we show that fibroblast PC is required for collagen production in the tumour microenvironment. These results establish TCA cycle anaplerosis as a determinant of extracellular matrix collagen production, and identify PC as a potential target to inhibit tumour desmoplasia.

Publication types

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

MeSH terms

  • Animals
  • Cancer-Associated Fibroblasts / metabolism*
  • Cancer-Associated Fibroblasts / pathology
  • Cell Line
  • Citric Acid Cycle
  • Collagen / biosynthesis*
  • Disease Susceptibility
  • Enzyme Activation / drug effects
  • Fibrosis
  • Gene Expression Regulation, Enzymologic
  • Glutamine / metabolism
  • Humans
  • Lactic Acid / metabolism
  • Mice
  • Neoplasms / etiology*
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Protein Biosynthesis
  • Pyruvate Carboxylase / genetics
  • Pyruvate Carboxylase / metabolism*
  • Transforming Growth Factor beta / metabolism
  • Tumor Microenvironment* / genetics


  • Transforming Growth Factor beta
  • Glutamine
  • Lactic Acid
  • Collagen
  • Pyruvate Carboxylase