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Cancer-Associated Fibroblasts Drive Glycolysis in a Targetable Signaling Loop Implicated in Head and Neck Squamous Cell Carcinoma Progression.

Dhruv KumarJacob NewVikalp VishwakarmaRadhika JoshiJonathan EndersFangchen LinSumana DasariWade R GutierrezGeorge LeefSivapriya PonnurangamHemantkumar ChavanLydia GanadenMackenzie M ThorntonHongying DaiOssama TawfikJeffrey StraubYelizaveta ShnayderKiran KakaralaTerance Ted TsueDouglas A GirodBennett Van HoutenShrikant AnantPartha KrishnamurthySufi Mary Thomas
Published in: Cancer research (2018)
Despite aggressive therapies, head and neck squamous cell carcinoma (HNSCC) is associated with a less than 50% 5-year survival rate. Late-stage HNSCC frequently consists of up to 80% cancer-associated fibroblasts (CAF). We previously reported that CAF-secreted HGF facilitates HNSCC progression; however, very little is known about the role of CAFs in HNSCC metabolism. Here, we demonstrate that CAF-secreted HGF increases extracellular lactate levels in HNSCC via upregulation of glycolysis. CAF-secreted HGF induced basic FGF (bFGF) secretion from HNSCC. CAFs were more efficient than HNSCC in using lactate as a carbon source. HNSCC-secreted bFGF increased mitochondrial oxidative phosphorylation and HGF secretion from CAFs. Combined inhibition of c-Met and FGFR significantly inhibited CAF-induced HNSCC growth in vitro and in vivo (P < 0.001). Our cumulative findings underscore reciprocal signaling between CAF and HNSCC involving bFGF and HGF. This contributes to metabolic symbiosis and a targetable therapeutic axis involving c-Met and FGFR.Significance: HNSCC cancer cells and CAFs have a metabolic relationship where CAFs secrete HGF to induce a glycolytic switch in HNSCC cells and HNSCC cells secrete bFGF to promote lactate consumption by CAFs. Cancer Res; 78(14); 3769-82. ©2018 AACR.
Keyphrases
  • stress induced
  • induced apoptosis
  • signaling pathway
  • cell cycle arrest
  • high glucose
  • tyrosine kinase
  • drug induced
  • squamous cell carcinoma
  • long non coding rna
  • extracellular matrix
  • endoplasmic reticulum stress