Journal
CANCER RESEARCH
Volume 77, Issue 23, Pages 6679-6691Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-17-1077
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Funding
- University of Kansas Cancer Center under CCSG [P30CA168524]
- NIH Clinical and Translational Science Award grant [UL1TR000001]
- KUMC Biomedical Research Training Program
- NIH/NIGMS COBRE [P30GM103326]
- NIH COBRE [P20GM104936, S10RR027564]
- KUMC Research Institute
- Smith Intellectual and Developmental Disabilities Research Center [NIH U54 HD 090216]
- [R01CA182872]
- [R01AA020518]
- [U01AA024733]
- [P20GM103549]
- [P30GM118247]
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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 of HNSCC, 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. (C) 2017 AACR.
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