Colorectal Cancer Cells Promote de novo Glycine Synthesis for Collagen Production in Cancer-Associated Fibroblasts by Secreting TGF-β1

Abstract

Metabolic reprogramming of cancer-associated fibroblasts (CAFs) plays an important role in colorectal cancer (CRC) progression. However, the mechanisms by which dysfunctional amino acid metabolism in CAFs contributes to cancer progression remain unclear. Here, we investigated amino acid metabolism in fibroblasts derived from human CRC tissues and the molecular interactions of this regulation with CRC progression. We revealed that amino acid metabolism, especially de novo glycine synthesis, was significantly activated in CAFs compared with normal fibroblasts in CRC tissues. Mechanistically, transforming growth factor β1 (TGF-β1) secreted by CRC cells was identified as a key factor that induced the activation of glycine synthesis and collagen production in CAFs. The inhibition of phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in de novo glycine synthesis, attenuated TGF-β1-induced collagen production in CAFs. Additionally, we found that collagen levels were significantly elevated in human CRC tissues. Collectively, these findings reveal a novel mechanism by which CRC cells enhance collagen production in CAFs through TGF-β1-induced de novo glycine synthesis. Our data not only highlight the pivotal role of de novo glycine synthesis in CRC progression but also provide a potential strategy for CRC treatment by targeting PHGDH.

Keywords

cancer-associated fibroblasts / collagen / colorectal cancer / glycine / transforming growth factor β1

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