Cancer-associated fibroblasts drive glycolysis in a targetable signaling loop implicated in head and neck squamous cell carcinoma progression

Dhruv Kumar, Jacob New, Vikalp Vishwakarma, Radhika Joshi, Jonathan Enders, Fangchen Lin, Sumana Dasari, Wade R. Gutierrez, George Leef, Sivapriya Ponnurangam, Hemantkumar Chavan, Lydia Ganaden, Mackenzie M. Thornton, Hongying Dai, Ossama Tawfik, Jeffrey Straub, Yelizaveta Shnayder, Kiran Kakarala, Terance Ted Tsue, Douglas A. GirodBennett Van Houten, Shrikant Anant, Partha Krishnamurthy, Sufi Mary Thomas

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3769-3782
Number of pages14
JournalCancer Research
Volume78
Issue number14
DOIs
StatePublished - Jul 15 2018
Externally publishedYes

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Glycolysis
Lactic Acid
Cancer-Associated Fibroblasts
Carcinoma, squamous cell of head and neck
Squamous Cell Neoplasms
Symbiosis
Oxidative Phosphorylation
Head and Neck Neoplasms
Up-Regulation
Carbon

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Cancer-associated fibroblasts drive glycolysis in a targetable signaling loop implicated in head and neck squamous cell carcinoma progression. / Kumar, Dhruv; New, Jacob; Vishwakarma, Vikalp; Joshi, Radhika; Enders, Jonathan; Lin, Fangchen; Dasari, Sumana; Gutierrez, Wade R.; Leef, George; Ponnurangam, Sivapriya; Chavan, Hemantkumar; Ganaden, Lydia; Thornton, Mackenzie M.; Dai, Hongying; Tawfik, Ossama; Straub, Jeffrey; Shnayder, Yelizaveta; Kakarala, Kiran; Tsue, Terance Ted; Girod, Douglas A.; Van Houten, Bennett; Anant, Shrikant; Krishnamurthy, Partha; Thomas, Sufi Mary.

In: Cancer Research, Vol. 78, No. 14, 15.07.2018, p. 3769-3782.

Research output: Contribution to journalArticle

Kumar, D, New, J, Vishwakarma, V, Joshi, R, Enders, J, Lin, F, Dasari, S, Gutierrez, WR, Leef, G, Ponnurangam, S, Chavan, H, Ganaden, L, Thornton, MM, Dai, H, Tawfik, O, Straub, J, Shnayder, Y, Kakarala, K, Tsue, TT, Girod, DA, Van Houten, B, Anant, S, Krishnamurthy, P & Thomas, SM 2018, 'Cancer-associated fibroblasts drive glycolysis in a targetable signaling loop implicated in head and neck squamous cell carcinoma progression', Cancer Research, vol. 78, no. 14, pp. 3769-3782. https://doi.org/10.1158/0008-5472.CAN-17-1076
Kumar, Dhruv ; New, Jacob ; Vishwakarma, Vikalp ; Joshi, Radhika ; Enders, Jonathan ; Lin, Fangchen ; Dasari, Sumana ; Gutierrez, Wade R. ; Leef, George ; Ponnurangam, Sivapriya ; Chavan, Hemantkumar ; Ganaden, Lydia ; Thornton, Mackenzie M. ; Dai, Hongying ; Tawfik, Ossama ; Straub, Jeffrey ; Shnayder, Yelizaveta ; Kakarala, Kiran ; Tsue, Terance Ted ; Girod, Douglas A. ; Van Houten, Bennett ; Anant, Shrikant ; Krishnamurthy, Partha ; Thomas, Sufi Mary. / Cancer-associated fibroblasts drive glycolysis in a targetable signaling loop implicated in head and neck squamous cell carcinoma progression. In: Cancer Research. 2018 ; Vol. 78, No. 14. pp. 3769-3782.
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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

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.

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