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

作者：Dhruv Kumar, Jacob New, Vikalp Vishwakarma, Radhika Joshi, Jonathan David Enders, Fangchen Lin, Sumana Dasari, Wade R. Gutierrez, George C. Leef, Sivapriya Ponnurangam, Hemantkumar D. Chavan, Lydia Ganaden, Mackenzie M. Thornton, Hongying Daisy Dai, Ossama Tawfik, Jeffrey M. Straub, Yelizaveta Shnayder, Kiran Kakarala, Terance Ted Tsue, Douglas A. Girod, Bennett Van Houten, Shrikant Anant, Partha C. Krishnamurthy, Sufi Mary Thomas · 发表于：Cancer Research · 年份：2018 · DOI：10.1158/0008-5472.can-17-1076 · 被引用次数：182 · 研究领域：Fibroblast Growth Factor Research、Cancer, Hypoxia, and Metabolism、Metabolism, Diabetes, and Cancer

Abstract 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.