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Cancer-associated fibroblasts promote prostate cancer malignancy via metabolic rewiring and mitochondrial transfer

Abstract

Cancer-associated fibroblasts (CAFs) are the major cellular stromal component of many solid tumors. In prostate cancer (PCa), CAFs establish a metabolic symbiosis with PCa cells, contributing to cancer aggressiveness through lactate shuttle. In this study, we report that lactate uptake alters the NAD+/NADH ratio in the cancer cells, which culminates with SIRT1-dependent PGC-1α activation and subsequent enhancement of mitochondrial mass and activity. The high exploitation of mitochondria results in tricarboxylic acid cycle deregulation, accumulation of oncometabolites and in the altered expression of mitochondrial complexes, responsible for superoxide generation. Additionally, cancer cells hijack CAF-derived functional mitochondria through the formation of cellular bridges, a phenomenon that we observed in both in vitro and in vivo PCa models. Our work reveals a crucial function of tumor mitochondria as the energy sensors and transducers of CAF-dependent metabolic reprogramming and underscores the reliance of PCa cells on CAF catabolic activity and mitochondria trading.

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Acknowledgements

The work was supported by Fondazione Umberto Veronesi to AM, Associazione Italiana Ricerca sul Cancro (AIRC) (grant 8797 to PC), AIRC and Fondazione Cassa di Risparmio di Firenze (grant 19515 to PC and AM), Istituto Toscano Tumori (grant 0203607 to PC), Programma operativo regionale Obiettivo “Competitività regionale e occupazione” della Regione Toscana cofinanziato dal Fondo europeo di sviluppo regionale 2007–2013 (POR CReO FESR 2007–2013, grant to PC), Interuniversity Attraction Pole from Belspo (grant #UP7–03 to PS), an Action de Recherche Concertée from the Communauté Française de Belgique (ARC 14/19-058 to PS), and the Belgian Fonds National de la Recherche Scientifique (F.R.S. FNRS, to PS). The authors thank: Dr Paolo E. Porporato (University of Turin, Italy) for providing mitochondria-targeted plasmids mt-HA-eGFP, AT-F001-D and mtDsRed, AT-F002-D (Aequotech srl); Dr Andrea Rasola (University of Padua, Italy) for providing pLJM1-EGFP plasmid for lentiviral infection; Dr Barbara Stecca (Istituto Toscano Tumori, Florence, Italy) for providing pCMV-dR8.91 packaging plasmid and pMD2G envelope plasmid; Dr. Nicla Lorito and Dr. Lavinia Ferrone for technical support. PS is a F.R.S.-FNRS Senior Research Associate. The MASSMET platform (https://www.uclouvain.be/en-massmet.html) is acknowledged for the access to the HLPC-MS.

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Ippolito, L., Morandi, A., Taddei, M.L. et al. Cancer-associated fibroblasts promote prostate cancer malignancy via metabolic rewiring and mitochondrial transfer. Oncogene 38, 5339–5355 (2019). https://doi.org/10.1038/s41388-019-0805-7

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