Metabolic remodeling of the tumor microenvironment: migration stimulating factor (MSF) reprograms myofibroblasts toward lactate production, fueling anabolic tumor growth.
Migration stimulating factor (MSF) is a genetically truncated N-terminal isoform of fibronectin that is highly expressed during mammalian development in fetal fibroblasts, and during tumor formation in human cancer-associated myofibroblasts. However, its potential functional role in regulating tumor metabolism remains unexplored. Here, we generated an immortalized fibroblast cell line that recombinantly overexpresses MSF and studied their properties relative to vector-alone control fibroblasts. Our results indicate that overexpression of MSF is sufficient to confer myofibroblastic differentiation, likely via increased TGF-b signaling. In addition, MSF activates the inflammation-associated transcription factor NFκB, resulting in the onset of autophagy/mitophagy, thereby driving glycolytic metabolism (L-lactate production) in the tumor microenvironment. Consistent with the idea that glycolytic fibroblasts fuel tumor growth (via L-lactate, a high-energy mitochondrial fuel), MSF fibroblasts significantly increased tumor growth, by up to 4-fold. Mechanistic dissection of the MSF signaling pathway indicated that Cdc42 lies downstream of MSF and fibroblast activation. In accordance with this notion, Cdc42 overexpression in immortalized fibroblasts was sufficient to drive myofibroblast differentiation, to provoke a shift towards glycolytic metabolism and to promote tumor growth by up to 2-fold. In conclusion, the MSF/Cdc42/NFκB signaling cascade may be a critical druggable target in preventing "Warburg-like" cancer metabolism in tumor-associated fibroblasts. Thus, MSF functions in the metabolic remodeling of the tumor microenvironment by metabolically reprogramming cancer-associated fibroblasts toward glycolytic metabolism.
The Jefferson Stem Cell Biology and Regenerative Medicine Center, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
Valentina
V
Carito
Gloria
G
Bonuccelli
Ubaldo E
UE
Martinez-Outschoorn
Diana
D
Whitaker-Menezes
Maria Cristina
MC
Caroleo
Erika
E
Cione
Anthony
A
Howell
Richard G
RG
Pestell
Michael P
MP
Lisanti
Federica
F
Sotgia
D000199:Actins / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002630:Chemotactic Factors / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism*; D005353:Fibronectins; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D000199:Actins; D014408:Biomarkers, Tumor; D002630:Chemotactic Factors; D016207:Cytokines; C067625:FN1 protein, human; D005353:Fibronectins; D016328:NF-kappa B; D016212:Transforming Growth Factor beta; D019344:Lactic Acid; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein