The extracellular matrix (ECM) is the central driver of the desmoplastic reaction that fosters cancer aggressiveness. Cancer associated fibroblasts (CAFs) are the major source of ECM in tumours, thus being the optimal target to limit deposition of pro-tumourigenic ECM to oppose cancer. CAFs are metabolically active cells, however, how they support the biosynthetic requirements of producing ECM, and whether this can be targeted to influence tumour progression has not been investigated.We found that the pyruvate dehydrogenase kinase 2 (PDK2), a major inhibitor of the pyruvate dehydrogenase complex (PDC), is highly downregulated in CAFs and in the tumour stroma, when compared to normal fibroblasts. As consequence, PDC is more activated and generates acetyl-CoA, which elicits an epigenetic reprogramming through the histone acetyl transferase P300/CBP. This epigenetic reprogramming drives increased ECM production through increasing transcription of collagen genes and proline synthesis. We found that increased proline availability is necessary to support the biosynthetic requirements that follow the epigenetic reprogramming, for the translation of collagen to make abundant ECM. Targeting the rate-limiting enzyme for proline synthesis, pyrroline-5-carboxylate reductase 1 (PYCR1), in CAFs was sufficient to limit collagen deposition and hamper tumour growth. In conclusion, ECM production in CAFs is under strict metabolic control, and our results warrant considering targeting proline synthesis to normalise ECM production in tumours and possibly other diseases involving collagen production, such as fibrosis.