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.
Lactate supports cell-autonomous ECM production to sustain metastatic behavior in prostate cancer / 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. - In: EMBO REPORTS. - ISSN 1469-3178. - ELETTRONICO. - (2024), pp. 0-0. [10.1038/s44319-024-00180-z]
Lactate supports cell-autonomous ECM production to sustain metastatic behavior in prostate cancer
Ippolito, Luigi;Duatti, Assia;Iozzo, Marta;Comito, Giuseppina;Pardella, Elisa;Lorito, Nicla;Bacci, Marina;Pranzini, Erica;Santi, Alice;Catapano, Carlo V;Serni, Sergio;Spatafora, Pietro;Morandi, Andrea;Giannoni, Elisa;Chiarugi, Paola
2024
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.File | Dimensione | Formato | |
---|---|---|---|
ippolito-et-al-2024-lactate-supports-cell-autonomous-ecm-production-to-sustain-metastatic-behavior-in-prostate-cancer.pdf
accesso aperto
Tipologia:
Pdf editoriale (Version of record)
Licenza:
Open Access
Dimensione
8.13 MB
Formato
Adobe PDF
|
8.13 MB | Adobe PDF |
I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.