Secretory autophagy in cancer-associated fibroblasts promotes head and neck cancer progression and offers a novel therapeutic target

Jacob New, Levi Arnold, Megha Ananth, Sameer Alvi, Mackenzie Thornton, Lauryn Werner, Ossama Tawfik, Hongying Dai, Yelizaveta Shnayder, Kiran Kakarala, Terance T. Tsue, Douglas A. Girod, Wen Xing Ding, Shrikant Anant, Sufi Mary Thomas

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Despite therapeutic advancements, there has been little change in the survival of patients with head and neck squamous cell carcinoma (HNSCC). Recent results suggest that cancer-associated fibroblasts (CAF) drive progression of this disease. Here, we report that autophagy is upregulated in HNSCC-associated CAFs, where it is responsible for key pathogenic contributions in this disease. Autophagy is fundamentally involved in cell degradation, but there is emerging evidence that suggests it is also important for cellular secretion. Thus, we hypothesized that autophagy-dependent secretion of tumor-promoting factors by HNSCC-associated CAFs may explain their role in malignant development. In support of this hypothesis, we observed a reduction in CAF-facilitated HNSCC progression after blocking CAF autophagy. Studies of cell growth media conditioned after autophagy blockade revealed levels of secreted IL6, IL8, and other cytokines were modulated by autophagy. Notably, when HNSCC cells were cocultured with normal fibroblasts, they upregulated autophagy through IL6, IL8, and basic fibroblast growth factor. In a mouse xenograft model ofHNSCC, pharmacologic inhibition of Vps34, a key mediator of autophagy, enhanced the antitumor efficacy of cisplatin. Our results establish an oncogenic function for secretory autophagy in HNSCC stromal cells that promotes malignant progression.

Original languageEnglish (US)
Pages (from-to)6679-6691
Number of pages13
JournalCancer Research
Volume77
Issue number23
DOIs
StatePublished - Dec 1 2017

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Autophagy
Head and Neck Neoplasms
Therapeutics
Interleukin-8
Interleukin-6
Cancer-Associated Fibroblasts
Fibroblast Growth Factor 2
Stromal Cells
Conditioned Culture Medium
Heterografts
Cisplatin
Disease Progression
Carcinoma, squamous cell of head and neck
Fibroblasts
Cytokines
Survival
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Secretory autophagy in cancer-associated fibroblasts promotes head and neck cancer progression and offers a novel therapeutic target. / New, Jacob; Arnold, Levi; Ananth, Megha; Alvi, Sameer; Thornton, Mackenzie; Werner, Lauryn; Tawfik, Ossama; Dai, Hongying; Shnayder, Yelizaveta; Kakarala, Kiran; Tsue, Terance T.; Girod, Douglas A.; Ding, Wen Xing; Anant, Shrikant; Thomas, Sufi Mary.

In: Cancer Research, Vol. 77, No. 23, 01.12.2017, p. 6679-6691.

Research output: Contribution to journalArticle

New, J, Arnold, L, Ananth, M, Alvi, S, Thornton, M, Werner, L, Tawfik, O, Dai, H, Shnayder, Y, Kakarala, K, Tsue, TT, Girod, DA, Ding, WX, Anant, S & Thomas, SM 2017, 'Secretory autophagy in cancer-associated fibroblasts promotes head and neck cancer progression and offers a novel therapeutic target', Cancer Research, vol. 77, no. 23, pp. 6679-6691. https://doi.org/10.1158/0008-5472.CAN-17-1077
New, Jacob ; Arnold, Levi ; Ananth, Megha ; Alvi, Sameer ; Thornton, Mackenzie ; Werner, Lauryn ; Tawfik, Ossama ; Dai, Hongying ; Shnayder, Yelizaveta ; Kakarala, Kiran ; Tsue, Terance T. ; Girod, Douglas A. ; Ding, Wen Xing ; Anant, Shrikant ; Thomas, Sufi Mary. / Secretory autophagy in cancer-associated fibroblasts promotes head and neck cancer progression and offers a novel therapeutic target. In: Cancer Research. 2017 ; Vol. 77, No. 23. pp. 6679-6691.
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