Biology and Biomedical Sciences: Molecular Genetics and Genomics
Date of Award
Doctor of Philosophy (PhD)
Chair and Committee
Sheila A Stewart
Age is the number one risk factor for the development of cancer. While accumulation of epithelial cell mutations is a driving factor for this risk, the role that the tumor microenvironment plays in this process is now well established. Indeed, seminal work has shown that tumorigenic cells unable to grow in xenografts can form tumors when supportive stromal cells are present. Work by many laboratories has demonstrated that a wide variety of cells including endothelial cells, immune cells, the extracellular matrix and fibroblasts can all assume a pro-tumorigenic phenotype.
Like cancer-associated fibroblasts (CAFs), senescent cells promote all stages of tumor development and progression. We and others have demonstrated that senescent fibroblasts have an altered expression profile known as the senescence-associated secretory phenotype (SASP). The SASP is composed of pro-angiogenic, pro-inflammatory, pro-growth and extracellular matrix remodeling proteins. Through the SASP, senescent cells promote all stages of tumorigenesis. Interestingly, senescent fibroblasts accumulate in human tissues with age, making them potential players in increasing cancer incidences.
Given the profound impact the SASP has on nearly every step in the tumorigenic process it is important to understand how it is regulated. Furthermore, identification of SASP regulatory pathways will identify targets for anti-cancer therapies aimed at inhibiting the pro-tumorigenic microenvironment. I have investigated the regulation of the SASP on several different levels. My work has uncovered a novel transcriptional regulator of SASP factor expression, c-myb. I have also identified a post-transcriptional regulatory network composed of p38MAPK and the RNA-binding protein AUF1, which regulates SASP mRNA stability and sustains SASP expression after the induction of senescence. Finally, I have demonstrated that p38MAPK is a viable stromal-specific therapeutic target for the inhibition of tumor-promoting microenvironments in general, not just those containing senescent fibroblasts. Indeed, cancer-associated fibroblasts (CAFs), which promote tumor growth through an altered gene expression profile similar to the SASP, are dependent upon p38MAPK activity. Inactivation of p38MAPK using an orally administered small molecule inhibitor results in significant blunting of both senescent fibroblast-driven and CAF-driven epithelial cell growth.
Oster Alspach, Elise, "Regulation and inhibition of pro-tumorigenic microenvironments" (2014). All Theses and Dissertations (ETDs). 1330.