Autophagy in Head and Neck Cancer Associated Fibroblasts
View/ Open
Issue Date
2018-05-31Author
New, Jacob
Publisher
University of Kansas
Format
173 pages
Type
Dissertation
Degree Level
Ph.D.
Discipline
Anatomy & Cell Biology
Rights
Copyright held by the author.
Metadata
Show full item recordAbstract
Head and neck squamous cell carcinoma (HNSCC) is a devastating disease. Despite therapeutic advancements, little change in 5-year survival has been made for patients with HNSCC. To improve therapy, a better understanding of the underlying biology is needed. Recent results suggest that cancer-associated fibroblasts (CAFs) drive disease progression. CAFs comprise the most abundant microenvironment cell type in HNSCC, and robustly support the cancer. Yet, little is understood of the underlying biology of CAFs. We sought to investigate the biological mechanisms mediating CAF-facilitated HNSCC progression. To our surprise, CAFs demonstrate significant upregulation of autophagy compared to normal fibroblasts (NFs) from cancer-free patients. Autophagy is fundamentally involved in cell degradation, but emerging evidence suggests a role for autophagy in 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. Assessment of CAF-conditioned media after autophagy blockade revealed levels of secreted IL-6 and IL-8, and other cytokines to be modulated by autophagy. We identify that HNSCC induces fibroblast autophagy through basic fibroblast growth factor, IL-6, and IL-8. Although autophagy is implicated in other cancers, little is known about autophagy inhibition in HNSCC. Thus, we assessed the therapeutic potential of targeting autophagy in HNSCC preclinical models. In a CAF-HNSCC mouse xenograft model, pharmacologic inhibition of Vps34, a key mediator of autophagy, enhanced the antitumor efficacy of cisplatin. Our results establish an oncogenic function of autophagy-dependent secretion in HNSCC stromal cells that promotes malignant progression.
Collections
- Dissertations [4701]
- KU Med Center Dissertations and Theses [464]
Items in KU ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.
We want to hear from you! Please share your stories about how Open Access to this item benefits YOU.