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

• Autor: Ippolito, Luigi ; Morandi, Andrea ; Taddei, Maria Letizia ; Parri, Matteo ; Comito, Giuseppina ; Iscaro, Alessandra ; Raspollini, Maria Rosaria ; Magherini, Francesca ; Rapizzi, Elena ; Masquelier, Julien ; Muccioli, Giulio G ; Sonveaux, Pierre ; Chiarugi, Paola ; Giannoni, Elisa
• Assuntos: Care and treatment ; Cell Line, Tumor ; Citric Acid Cycle ; Fibroblasts ; Fibroblasts - pathology ; Genetic aspects ; Health aspects ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism ; Lactates ; Lactic acid ; Male ; Malignancy ; Metabolism ; Mitochondria ; Mitochondria - metabolism ; NAD ; NAD - metabolism ; NADH ; Neoplasm Invasiveness ; Oxidative Phosphorylation ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism ; Prostate cancer ; Prostatic Neoplasms - metabolism ; Prostatic Neoplasms - pathology ; Reactive Oxygen Species - metabolism ; SIRT1 protein ; Sirtuin 1 - metabolism ; Solid tumors ; Superoxide ; Symbiosis ; Tricarboxylic acid cycle
• É parte de: Oncogene, 2019-07, Vol.38 (27), p.5339-5355
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• Descrição: 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.
  
• Editor: England: Nature Publishing Group
  
• Idioma: Inglês