Dissecting the Functions of Autophagy in Breast Cancer-Associated Fibroblasts
Annual rept. 15 Sep 2014-14 Sep 2015
CALIFORNIA UNIV SAN FRANCISCO
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Interactions between cancer cells and their associated stroma can influence the initiation, progression, and overall prognosis of breast cancer. The most predominant stromal cell type implicated in breast cancer progression is the mammary fibroblast. These cells, which normally provide structural integrity and extracellular matrix remodeling required for proper mammary gland development, transition to an activated state now referred to as cancer associated fibroblasts, CAFs to promote breast tumor growth and survival. However, the cellintrinsic mechanisms regulating mammary fibroblast activation remain poorly understood. We sought to determine if autophagy regulates the tumor suppressive or tumor promoting behavior of mammary fibroblasts. To do so, we utilized an immunocompetent, cleared mouse mammary gland transplantation model to engraft autophagy deficient or autophagy competent fibroblasts into their native microenvironment. Fat pads primed with autophagy deficient fibroblasts show reduced recruitment of CD3 cells. Moreover, these fat pads fail to support PyMT tumor growth as compared to fat pads primed with autophagy competent fibroblasts. The tumor suppressive behavior of autophagy deficient fibroblasts is contingent upon an intact adaptive immune response, as this phenotype is masked in immunodeficient mice. We are currently investigating how fibroblast specific autophagy competency modulates the tumor microenvironment in a manner permissible for tumor growth. Our data suggests stromal autophagy contributes to the development and progression of mammary tumors, and advocates for the use of autophagy inhibitors as an adjuvant therapy in treating both early and late stage breast cancers.
- Anatomy and Physiology
- Medicine and Medical Research