Head and neck squamous cell carcinoma (HNSCC) affects 40,000 patients annually and is associated with <50% 5-year survival. There is an urgent need to better understand the biology of the disease in order to develop more effective therapeutic approaches. HNSCC tumors are dysplastic with up to 80% fibroblasts. We recently reported that tumor-associated fibroblasts (TAFs) make HNSCC more aggressive. Furthermore, we reported that TAFs produce hepatocyte growth factor (HGF), which binds to the c-Met receptor expressed on HNSCC to drive aggressiveness. Although we did not detect HGF secretion from HNSCC cell lines, we reported that paracrine activation of c-Met by TAF-secreted HGF facilitates HNSCC progression. Reciprocal signaling between the tumor and stroma has been reported in several cancers to facilitate tumor growth, invasion and resistance to therapy. Recent studies have shown that c-Met activation promotes glycolysis. Although highly glycolytic, the mechanisms regulating HNSCC glycolysis remain unknown. We show that TAF-secreted HGF through c-Met activation on HNSCC (a) induces aerobic glycolysis accompanied by lactate production, and b) regulates expression of basic fibroblast growth factor (bFGF). Studies have shown that HNSCC tumors have high lactate levels resulting from increased glycolysis, and this correlates with reduced survival. Our data demonstrate that TAF-secreted HGF increases key glycolytic enzymes including hexokinase II. Furthermore, HGF increases glycolysis and lactate production from HNSCC. We demonstrate that HGF also increases levels of the bidirectional lactate transporter, monocarboxylate transporter 1 (MCT1). We demonstrate that MCT1 levels are increased in both HNSCC and TAFs under co-culture conditions. In addition, HGF stimulation increases levels of MCT1 in HNSCC indicating a possible mechanism whereby HNSCC remove the excess lactate generated during glycolysis. The mechanisms whereby HNSCC tumors survive highly acidic conditions remain unknown. Since MCT1 levels are increased in TAFs as well, we sought to determine if TAFs utilize the lactate as a carbon source to generate energy. Indeed, we found that bFGF secreted by HNSCC, binds to its cognate FGF receptor (FGFR) on TAFs to facilitate latate utilization through mitochondrial oxidative phosphorylation (OXPHOS). Thus there exists a metabolic symbiosis between HNSCC and TAFs that contribute to tumor growth. Through these studies, we delineate the mechanisms of glycolysis regulation in HNSCC and demonstrate that inhibition of the cross-talk between HNSCC and TAFs can be used as a novel therapeutic approach.

Citation Format: Dhruv Kumar, Jacob New, Vikalp Vishwakarma, Hemant Chavan, Partha Kasturi, Sufi M. Thomas. Mitigating tumor-stroma metabolic symbiosis for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2970. doi:10.1158/1538-7445.AM2017-2970