Head and neck squamous cell carcinoma (HNSCC) is associated with poor survival despite therapeutic
advances. We previously reported that cancer-associated fibroblasts (CAFs) facilitate tumor growth and
metastasis. In addition, we reported a higher rate of secretory autophagy in CAFs that is associated with
secretion of tumor promoting factors. In preliminary studies, we demonstrate that signaling in CAFs results in
activation of STAT3, which in turn then activates SOX2. This suppresses mTOR signaling and induces
secretory autophagy. The consequence of this autophagic process is the secretion of various cytokines and
chemokines, which in turn affects HNSCC. Based on these data, we hypothesize that secretory
autophagy in CAFs results in cytokine release that facilitates HNSCC growth and impacts
response to therapy. We will test this hypothesis in 3 Specific Aims. In Aim 1, we will elucidate the
mechanism of secretory autophagy in fibroblasts. In Aim 2, we will characterize the role of CAF-secretory
autophagy on HNSCC. Finally, in Aim 3, we will determine the therapeutic potential of mitigating autophagy.
These studies are significant in that they will help elucidate the role of stromal autophagy in tumor progression
and enable the development of more effective therapeutic approaches for HNSCC.