Jason D. Weber, Ph.D.
Project Overview:
Can we identify, early on, why some breast cancers become life-threatening metastasis?
This question has remained at the top of the list for many clinicians, researchers, and patients. Metastasis of cancer cells from the breast to distal target organs is the single-most important cause of mortality in women with breast cancer. One of the most challenging aspects of eradicating breast cancer and increasing the survival rates of women with breast cancer is the prevention and/or treatment of metastasis. Arguably, breast cancers that do not metastasize become a far more manageable form of the disease. Recent next generation sequencing studies have confirmed that TP53 and CDKN2A gene mutations are the most frequent alterations in breast carcinomas, occurring in all subtypes of human breast cancer at varying rates. Our exciting new combined published and preliminary findings indicate that the activation of a common anti-viral signaling pathway is sufficient to drive enhance tumorigenesis and metastasis of breast cancer cells. This has led us to re-think the process of metastasis.
Could it be that aggressive metastasis is the result of the activation of an anti-viral pathway? That is, can tumor cells use this anti-viral pathway to escape their local environment and move throughout the body to distal organs?
We hypothesize that a common anti-viral regulatory pathway provides p53/CDKN2A-mutant mammary tumor cells with a tremendous advantage in vivo and therefore, serves as a driver for growth and metastasis.
To test this hypothesis, we propose to de-construct this pathway in highly metastatic cells that harbor TP53/CDKN2A mutations AND exhibit an activation of this pathway. Furthermore, we will determine whether we can trigger metastasis in TP53 mutant cells through the activation of this anti-viral pathway. Our experiments will cover both in vitro and in vivo aspects of growth, invasion, and metastasis using established human breast cancer cells and primary mouse mammary epithelial cells. Our combined expertise in tumor suppressors and oncogenes along with our unlimited access to primary human tumor samples at Washington University gives us tremendous leverage in successfully obtaining large amounts of patient tumors to perform our analysis. Identification of required signaling components in aggressive TP53/CDKN2A mutant breast cancers will lead to the discovery of novel drugs targeting the key genes and genetic pathways responsible for breast cancer metastasis. How fast can we get there? The anti-viral pathway we have uncovered already has targeted drug therapies, suggesting that our timeline to the clinic could be within two years.
