Abstract
AbstractExtracellular matrix (ECM) is a major component of the tumor environment, promoting the establishment of a pro-invasive behavior. Such environment is supported by both tumor- and stromal-derived metabolites, particularly lactate. In prostate cancer (PCa), cancer-associated fibroblasts (CAFs) are major contributors of secreted lactate, able to impact on metabolic and transcriptional regulation in cancer cells. Here, we describe a mechanism by which CAF-secreted lactate promotes in PCa cells the expression of genes coding for the collagen family. Lactate-exploiting PCa cells rely on increased α-ketoglutarate (α-KG) which activates the α-KG-dependent collagen prolyl-4-hydroxylase (P4HA1) to support collagen hydroxylation. De novo synthetized collagen plays a signaling role by activating discoidin domain receptor 1 (DDR1), supporting stem-like and invasive features of PCa cells. Inhibition of lactate-induced collagen hydroxylation and DDR1 activation reduces the metastatic colonization of PCa cells. Overall, these results provide a new understanding of the link between collagen remodeling/signaling and the nutrient environment exploited by PCa.
Funder
Fondazione AIRC per la ricerca sul cancro ETS
Swiss Cancer League
Fondazione Ticinese Ricerca sul Cancro
European Union, National Recovery and Resilience Plan, Mission 4 Component 2 - Investment 1.4 - National Center for Gene Therapy and Drugs based on RNA Technology - NextGenerationEU
European Union, National Recovery and Resilience Plan, Mission 4 Component 2, Creation and strengthening of "innovation ecosystems", construction of "territorial R&D leaders"
Fondazione Pezcoller
Publisher
Springer Science and Business Media LLC