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

The aberrant production of collagen by fibroblasts is a hallmark of many solid tumors and can influence cancer progression. How the mesenchymal cells in the tumor 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 tumor-associated fibroblasts contributes to tumor 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 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 tumor microenvironment. These results establish TCA cycle anaplerosis as a determinant of extracellular matrix collagen production, and identify PC as potential target to inhibit tumor desmoplasia.