Journal
CELL CYCLE
Volume 11, Issue 18, Pages 3403-3414Publisher
LANDES BIOSCIENCE
DOI: 10.4161/cc.21701
Keywords
migration stimulating factor (MSF); myofibroblast; metabolic coupling; tumor stroma; cancer-associated fibroblasts; aerobic glycolysis; TGF-beta signaling
Categories
Funding
- Breast Cancer Alliance (BCA)
- American Cancer Society (ACS)
- NIH/NCI [R01-CA-080250, R01-CA-098779, R01-CA-120876, R01-AR-055660, R01-CA-70896, R01-CA-75503, R01-CA-86072, R01-CA-107382]
- Susan G. Komen Breast Cancer Foundation
- Dr. Ralph and Marian C. Falk Medical Research Trust
- NIH/NCI Cancer Center Core grant [P30-CA-56036]
- Margaret Q. Landenberger Research Foundation
- Pennsylvania Department of Health
- Centre grant in Manchester from Breakthrough Breast Cancer in the UK
- European Research Council
- Breast Cancer Now [MAN-Q1] Funding Source: researchfish
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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-beta signaling. In addition, MSF activates the inflammation-associated transcription factor NF kappa B, 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/NF kappa B 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.
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