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

成纤维细胞异常产生胶原蛋白是许多实体瘤的一个标志，并且会影响癌症进展。当谷氨酰胺和葡萄糖的血管输送受阻时，肿瘤微环境中的间充质细胞如何维持其细胞外基质蛋白的产生仍不清楚。在此我们表明，肿瘤相关成纤维细胞中丙酮酸羧化酶（PC）介导的回补反应有助于肿瘤纤维化和生长。利用培养的间充质细胞和癌细胞以及小鼠同种异体移植模型，我们提供的证据表明，成纤维细胞可以利用细胞外乳酸通过PC活性维持三羧酸（TCA）循环回补和非必需氨基酸的生物合成。此外，我们表明肿瘤微环境中胶原蛋白的产生需要成纤维细胞PC。这些结果确定TCA循环回补是细胞外基质胶原蛋白产生的一个决定因素，并确定PC是抑制肿瘤间质增生的潜在靶点。