TY - JOUR
T1 - Cancer-associated fibroblasts drive glycolysis in a targetable signaling loop implicated in head and neck squamous cell carcinoma progression
AU - Kumar, Dhruv
AU - New, Jacob
AU - Vishwakarma, Vikalp
AU - Joshi, Radhika
AU - Enders, Jonathan
AU - Lin, Fangchen
AU - Dasari, Sumana
AU - Gutierrez, Wade R.
AU - Leef, George
AU - Ponnurangam, Sivapriya
AU - Chavan, Hemantkumar
AU - Ganaden, Lydia
AU - Thornton, Mackenzie M.
AU - Dai, Hongying
AU - Tawfik, Ossama
AU - Straub, Jeffrey
AU - Shnayder, Yelizaveta
AU - Kakarala, Kiran
AU - Tsue, Terance Ted
AU - Girod, Douglas A.
AU - Van Houten, Bennett
AU - Anant, Shrikant
AU - Krishnamurthy, Partha
AU - Thomas, Sufi Mary
N1 - Publisher Copyright:
©2018 American Association for Cancer Research.
PY - 2018/7/15
Y1 - 2018/7/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-17-1076
DO - 10.1158/0008-5472.CAN-17-1076
M3 - Article
C2 - 29769197
AN - SCOPUS:85050671070
SN - 0008-5472
VL - 78
SP - 3769
EP - 3782
JO - Cancer Research
JF - Cancer Research
IS - 14
ER -