Lactate-induced COL1A1/DDR1 axis promotes prostate cancer aggressiveness and enhances metastatic colonization

Tumor progression is supported by relationships between tumor and stromal cells often impacting on the reciprocal metabolic behavior. Cancer-Associated Fibroblasts (CAFs) are key players in the reprogramming of cancer cell metabolism by supplying nutrients. Lactate from CAFs drives mitochondrial metabolic changes in prostate cancer (PCa) cells, culminating in the enhancement of their invasive potential, which is functional for the metastatic process. In this scenario, evidence shows that cancer cells can shape the extracellular matrix (ECM) of the metastatic niche by hydroxylating collagen to promote their own metastatic growth. Particular nutrients might support the ability of cancer cells to hydroxylate collagen, by inducing certain metabolic perturbations that dictate the activity of specific collagen-related enzymes. Our findings reveal a lactate-dependent rewiring of tumor lipid metabolism and TCA cycle intermediates whose the α-ketoglutarate production/exploitation is able to activate collagen hydroxylation by increasing the activity of the enzyme collagen prolyl-4-hydroxylase 1 (P4HA1). However, little is known about the mechanisms of collagen remodelling as a consequence of the intricate metabolic crosstalk among the stromal and cancer cells. Our aim was to investigate whether lactate could be able to drive collagen-based remodelling of the ECM to sustain the metastatic cascade of PCa cells. Human prostate cancer cell lines were used and exposed to healthy prostate fibroblasts (HPFs) or CAFs extracted from prostate cancer patients or to exogenous lactate 20mM, a concentration similar to that released by CAFs and generally resembling the amount found the TME. As CAFs lactate entry in PCa cells induces high succinate/α-ketoglutarate ratio, we identify a lactate-dependent expression of P4H isoform A1 (P4HA1) as putative molecule consuming α-ketoglutarate and this positively correlates with MCT1 expression and with a poor survival in PCa patient dataset. Interestingly, CAFs lactate-exposed PCa cells are able to deposit collagen and P4HA1 inhibition impacts on this behavior and on tumoral α-KG/succinate levels, suggesting that deregulated lactate metabolism drives ECM remodelling in PCa cells. Also, stromal lactate participates to higher formation of anchorage-independent tumor clusters and higher transendothelial migration in vitro and in vivo, suggesting a potential role of collagen in circulating tumor cells and metastatic dissemination of lactate-reprogrammed PCa cells. Interestingly, we find that such tumor collagen deposition is important for the activation of discoidin-domain collagen receptor 1 (DDR1) and its downstream signaling via STAT3 transcription factor. This results in higher enrichment of highly invasive and stem-like tumor populations via SOX2 and ALDH1A1 transcription factors activation, and genetically/pharmacologically interfering with DDR1 impairs this phenotype sustained by lactate-collagen axis. Overall, these findings uncover a new aspect of metabolic reprogramming of tumor cells driven by stromal lactate, which sustains ECM remodeling of tumor cells by potentiating their capacity to disseminate and metastasize through P4HA1-collagen-DDR1 axis.