As the fifth most common cancer worldwide, head and neck squamous cell carcinoma (HNSCC) is a leading global health burden. Despite therapeutic advancements, the survival rate has remained relatively unchanged for the last fifty years. To improve treatment and survival, there is a need to better understand the underlying biology of this disease. The tumor microenvironment’s role in promoting cancer progression and resistance to therapy has gathered great attention. In HNSCC, the predominant microenvironment cell type is tumor associated fibroblasts (TAFs). Studies in our lab and others have demonstrated the significant tumor promoting role of TAFs; however, little is understood of the underlying biology of TAFs. In this study, we identify that TAFs have upregulated an unconventional pathway of secretion: secretory autophagy. Although paradigmatically a degradation pathway, there has been a growing appreciation for a novel role of autophagy in cellular secretion. We hypothesized HNSCC induces secretory autophagy in the TAFs, modulating secreted factors responsible for tumor progression. We assessed the role of autophagy inhibition in alleviating TAF-facilitated HNSCC progression, and uncovered a significant reduction in proliferation, migration, and invasion of the cancer cells. This was achieved by both siRNA knockdown of Beclin-1, and therapeutic inhibition of the lysosome through chloroquine. We discovered that NFs placed in co-culture with HNSCC had a significantly upregulated level of autophagy marker LC3-II. By characterizing the role of known HNSCC secreted factors in inducing TAF autophagy, we identified basic fibroblast growth factor is responsible for the LC3-II accumulation. To understand which TAF factors are secreted by an autophagy dependent mechanism, we assessed TAF-conditioned media in the presence of autophagy knockdown. Key cytokines, such as IL-6 and IL-8, were identified as autophagy dependent. Rescue of these cytokines in autophagy inhibited TAF-conditioned media restored HNSCC migration. Although autophagy has been identified as upregulated in a variety of cancer types, no one has previously characterized the role of autophagy in HNSCC, and both early pre-clinical and clinical studies of autophagy inhibition as a cancer therapy have been limited by the lack of a specifically targeted inhibitor. We demonstrate a significant decrease in HNSCC progression in preclinical models by using a new and highly specific small molecule inhibitor of autophagy, SAR405, which inhibits Vps34, an upstream autophagy pathway kinase. In summary, we uncover a novel role for secretory autophagy in the tumor microenvironment which promotes tumor progression, and can be uniquely targeted for therapy.

Citation Format: Jacob New, Levi Arnold, Megha Ananth, Sameer Alvi, Wen-Xing Ding, Sufi M. Thomas. Secretory autophagy in tumor associated fibroblasts promotes head and neck squamous cell carcinoma progression and emerges as a novel therapeutic target [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 2977. doi:10.1158/1538-7445.AM2017-2977