| Title: |
Lactate supports cell-autonomous ECM production to sustain metastatic behavior in prostate cancer. |
| Authors: |
Ippolito, Luigi, Duatti, Assia, Iozzo, Marta, Comito, Giuseppina, Pardella, Elisa, Lorito, Nicla, Bacci, Marina, Pranzini, Erica, Santi, Alice, Sandrini, Giada, Catapano, Carlo V, Serni, Sergio, Spatafora, Pietro, Morandi, Andrea, Giannoni, Elisa, Chiarugi, Paola |
| Source: |
EMBO Reports; Aug2024, Vol. 25 Issue 8, p3506-3531, 26p |
| Abstract: |
Extracellular 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. Synopsis: Lactate, which is highly enriched in the prostate cancer environment, supports collagen remodeling and sensing in prostate cancer cells. Lactate-dependent metabolic rewiring sustains collagen hydroxylation via P4HA1 activation. De novo synthetized collagen activates discoidin domain receptor 1 (DDR1). P4HA1-DDR1-STAT3 axis is crucial for stemness and invasiveness of prostate cancer cells. Lactate, which is highly enriched in the prostate cancer environment, supports collagen remodeling and sensing in prostate cancer cells. [ABSTRACT FROM AUTHOR] |
|
Copyright of EMBO Reports is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) |
| Database: |
Complementary Index |
