Elevated production of collagen-rich extracellular matrix is a hallmark of cancer-associated fibroblasts (CAFs) and a central driver of cancer aggressiveness. Here we find that proline, a highly abundant amino acid in collagen proteins, is newly synthesized from glutamine in CAFs to make tumour collagen in breast cancer xenografts. PYCR1 is a key enzyme for proline synthesis and highly expressed in the stroma of breast cancer patients and in CAFs. Reducing PYCR1 levels in CAFs is sufficient to reduce tumour collagen production, tumour growth and metastatic spread in vivo and cancer cell proliferation in vitro. Both collagen and glutamine-derived proline synthesis in CAFs are epigenetically upregulated by increased pyruvate dehydrogenase-derived acetyl-CoA levels. PYCR1 is a cancer cell vulnerability and potential target for therapy; therefore, our work provides evidence that targeting PYCR1 may have the additional benefit of halting the production of a pro-tumorigenic extracellular matrix. Our work unveils new roles for CAF metabolism to support pro-tumorigenic collagen production.

富含胶原蛋白的细胞外基质的产生增加是癌症相关成纤维细胞（CAF）的标志，也是癌症侵袭性的核心驱动因素。在这里，我们发现脯氨酸是胶原蛋白中高度丰富的氨基酸，是由 CAF 中的谷氨酰胺新合成的，可在乳腺癌异种移植物中制造肿瘤胶原。 PYCR1 是脯氨酸合成的关键酶，在乳腺癌患者的基质和 CAF 中高度表达。降低 CAF 中的 PYCR1 水平足以减少体内肿瘤胶原蛋白的产生、肿瘤生长和转移扩散以及体外癌细胞增殖。 CAF 中胶原蛋白和谷氨酰胺衍生的脯氨酸合成均因丙酮酸脱氢酶衍生的乙酰辅酶 A 水平增加而在表观遗传上上调。 PYCR1 是癌细胞的脆弱性和潜在的治疗靶点；因此，我们的工作提供了证据，表明靶向 PYCR1 可能具有阻止促肿瘤细胞外基质产生的额外益处。我们的工作揭示了 CAF 代谢在支持促肿瘤胶原蛋白生成方面的新作用。