title: Metabolic reprogramming of cancer-associated fibroblasts by TGF-β drives tumor growth: connecting TGF-β signaling with "Warburg-like" cancer metabolism and L-lactate production.
abstract: 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.
authors.affiliation: The Jefferson Stem Cell Biology and Regenerative Medicine Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Carmela
authors.initials: C
authors.lastname: Guido
authors.forename: Diana
authors.initials: D
authors.lastname: Whitaker-Menezes
authors.forename: Claudia
authors.initials: C
authors.lastname: Capparelli
authors.forename: Renee
authors.initials: R
authors.lastname: Balliet
authors.forename: Zhao
authors.initials: Z
authors.lastname: Lin
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
authors.forename: Anthony
authors.initials: A
authors.lastname: Howell
authors.forename: Saveria
authors.initials: S
authors.lastname: Aquila
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Andò
authors.forename: Ubaldo
authors.initials: U
authors.lastname: Martinez-Outschoorn
authors.forename: Federica
authors.initials: F
authors.lastname: Sotgia
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D001343:Autophagy; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D065150:Cellular Reprogramming; D018920:Coculture Techniques; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis; D006801:Humans; D007150:Immunohistochemistry; D019344:Lactic Acid / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress; D019899:Paracrine Communication; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: C495540:CAV1 protein, human; D051242:Caveolin 1; D008024:Ligands; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D019344:Lactic Acid; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I