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.

MYC as a Multifaceted Regulator of Tumor Microenvironment Leading to Metastasis

“…Cancer-associated fibroblasts are known to play a significant role in tumor progression and metastasis also through metabolic rewiring [ 156 , 157 ]. Higher levels of CAFs are associated with larger tumors and shorter survival time [ 158 ].…”

CCL5 derived from tumor-associated macrophages promotes prostate cancer stem cells and metastasis via activating β-catenin/STAT3 signaling

“…The PCSCs microenvironment is composed of different stromal cell populations while the most abundant cell types are cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), either resident or recruited from circulatory system 11 . It has been widely reported that CAFs exert a mandatory role in prostate cancer progression as they metabolically sustain prostate cancer cell survival and growth, recruit inflammatory and immune cells, and promote cancer cells stemness and EMT, thereby favoring metastatic dissemination 12,13 . As the most highly infiltrative immune cell population within the TME, TAMs account for 30-50% of the tumor mass 14 .…”

Mitochondria at Center of Exchanges between Cancer Cells and Cancer-Associated Fibroblasts during Tumor Progression

“…It fuels the tricarboxylic acid (TCA) cycle and subsequent mitochondrial respiration. CAFs can directly provide cancer cells with pyruvate (as shown in lymphoma [ 6 ]), and also indirectly by providing lactate (as shown in prostate cancer [ 7 , 8 ] and breast cancer [ 4 , 9 ]) or alanine (as shown in pancreatic cancer [ 10 ]), both latter metabolites being transformed into pyruvate via active lactate dehydrogenase and alanine aminotransferase, respectively. CAFs also fuel malignant cells with glutamine in glutamine-deprived conditions (as shown in ovarian cancer [ 11 ]), which is transformed into glutamate and then alpha-ketoglutarate to enter the TCA cycle and generate biosynthetic precursors.…”

“…More precisely, these metabolites fuel malignant cells’ TCA cycle, which feeds biosynthetic pathways to produce key precursors such as lipids, proteins and nucleic acids, thus promoting primary and metastatic cell growth [ 7 , 10 , 11 ]. In some of the studies, TCA cycle modulation induced by CAFs even leads to higher malignant cell oxygen consumption, reflecting mitochondrial respiration increase [ 8 , 10 ]. In addition, a CAFs-induced increase in TCA cycle activity is associated with primary patient malignant cell survival [ 6 ].…”