Targeting Autophagy in the Tumor Stroma to Eradicate Breast Cancer
Abstract
Cancer associated fibroblasts (CAFs) are a major stromal cell type in breast tumors and produce several inflammatory cytokines required for breast cancer progression. Stromal fibroblasts modulate breast cancer cell behavior through diverse mechanisms, including the synthesis of pro-inflammatory cytokines, as well as remodeling of the extracellular matrix (ECM). Overall, the cell biological mechanisms controlling the pro-tumor functions of stromal fibroblasts, including CAFs, remain poorly understood. This proposal seeks to understand, how autophagy, a tightly regulated lysosomal degradation process, modulates the tumor-promoting properties of stromal fibroblasts. During the first year of this proposal, we have optimized the conditions to isolate both normal mammary gland fibroblasts as well as tumor derived CAFs. Furthermore, we have successfully these fibroblasts into the mammary fat pad of syngeneic recipient mice in combination with polyoma middle T (PyMT) breast cancer cells. Our pilot studies indicate that PyMT tumor growth is impaired in the presence of autophagy deficient, but not autophagy-competent fibroblasts, providing initial support for the hypothesis that autophagy in stromal fibroblasts is essential for breast cancer progression. In addition, we have uncovered that autophagy-deficient fibroblasts exhibit reduced secretion of multiple pro-inflammatory cytokines in vitro as well as exhibit reduced contractility in type I collagen in vitro. In the upcoming year, we will validate these results and determine whether and how changes in cytokine secretion and ECM remodeling impact breast cancer progression in vivo.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2013
- Accession Number
- ADA599963
Entities
People
- Jayanta Debnath
Organizations
- University of California, San Francisco