Dissecting the Functions of Autophagy in Breast Cancer Associated Fibroblasts
Abstract
Autophagy has emerged as a tumor cell survival mechanism in response to various stresses such as hypoxia and chemotherapy. As a result, there is rising interest in autophagy inhibition as an adjuvant cancer treatment. Given that carcinomas evolve with an inflammatory, desmoplastic stroma with significant numbers of cancer associated fibroblasts (CAFs), one can predict that autophagy is also induced in in these cells, allowing for their adaptation and function within tumor microenvironments. How autophagy inhibition in CAFs impacts tumorigenesis remains unclear. This proposal seeks to understand how stromal fibroblast specific ATG deletion effects mammary tumor progression, and seeks to determine the mechanisms by which this stromal deletion influences mammary epithelial cell fate and behavior. During the first year of this proposal, we generated a compound transgenic mouse model of mammary cancer (MMTV-PyMT) harboring genetic deletion of Atg12 in stromal fibroblasts using the fibroblast specific promoter FSP1 to drive Cre recombinase. We have characterized mammary tumor growth, metastasis and survival in these mice on mixed background. Our results suggest a trend toward reduced tumor burden and decreased metastasis in mice with autophagy deletion in stromal fibroblasts. We are currently obtaining larger sized cohorts for these studies. Also, this year, we have optimized the isolation and infection of both mouse mammary fibroblasts and CAFs for in vitro and in vivo analyses. In the upcoming year, we will investigate the mechanism by which autophagy deletion in stromal fibroblasts reduces mammary tumor progression.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2014
- Accession Number
- ADA613416
Entities
People
- Jennifer A. Rudnick
Organizations
- University of California, San Francisco