We have previously shown that a loss of stromal Cav-1 is a
biomarker of poor prognosis in breast
cancers. Mechanistically, a loss of Cav-1 induces the metabolic reprogramming of stromal cells, with increased autophagy/mitophagy,
mitochondrial dysfunction and aerobic glycolysis. As a consequence, Cav-1-low CAFs generate nutrients (such as L-
lactate) and chemical building blocks that fuel mitochondrial metabolism and the anabolic growth of adjacent
breast cancer cells. It is also known that a loss of Cav-1 is associated with hyperactive TGF-β signaling. However, it remains unknown whether hyperactivation of the TGF-β signaling pathway contributes to the metabolic reprogramming of Cav-1-low CAFs. To address these issues, we overexpressed TGF-β
ligands and the TGF-β receptor I (TGFβ-RI) in stromal fibroblasts and
breast cancer cells. Here, we show that the role of TGF-β in
tumorigenesis is compartment-specific, and that TGF-β promotes
tumorigenesis by shifting cancer-associated fibroblasts toward catabolic metabolism. Importantly, the
tumor-promoting effects of TGF-β are independent of the cell type generating TGF-β. Thus, stromal-derived TGF-β activates signaling in stromal cells in an autocrine fashion, leading to fibroblast activation, as judged by increased expression of myofibroblast markers, and metabolic reprogramming, with a shift toward catabolic metabolism and oxidative stress. We also show that TGF-β-activated fibroblasts promote the mitochondrial activity of adjacent
cancer cells, and in a xenograft model, enhancing the growth of
breast cancer cells, independently of angiogenesis. Conversely, activation of the TGF-β pathway in
cancer cells does not influence
tumor growth, but
cancer cell-derived-TGF-β
ligands affect stromal cells in a paracrine fashion, leading to fibroblast activation and enhanced
tumor growth. In conclusion,
ligand-dependent or cell-autonomous activation of the TGF-β pathway in stromal cells induces their metabolic reprogramming, with increased oxidative stress, autophagy/mitophagy and glycolysis, and downregulation of Cav-1. These metabolic alterations can spread among neighboring fibroblasts and greatly sustain the growth of
breast cancer cells. Our data provide novel insights into the role of the TGF-β pathway in breast
tumorigenesis, and establish a clear causative link between the
tumor-promoting effects of TGF-β signaling and the metabolic reprogramming of the tumor microenvironment.