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Date of Award
Doctor of Philosophy (PhD)
Tumorigenesis results from the convergence of cell autonomous mutations and corresponding stromal changes that promote tumor cell growth. Mutations and stromal changes both accumulate with age and together account for the dramatic increase in cancer incidence with age. One change that occurs with age is the accumulation of stromal senescent cells. Senescent stromal cells secrete pro-tumorigenic factors collectively termed the senescence-associated secretory phenotype (SASP). The SASP impacts every stage of tumorigenesis and is a promising therapeutic target. As such, it is important to understand how the SASP is regulated. Many but not all SASP factors are regulated transcriptionally by NF-kB and its upstream activator p38MAPK. However, many pro-tumorigenic SASP factors, including osteopontin (OPN), are not dependent on NF-κB or other canonical SASP regulators such as ATM, leaving the regulation of these factors an open question. Here, I report that the transcription factor c-Myb regulates OPN, IL-6, IL-8 and other SASP factors. The regulation of OPN is direct as c-Myb binds to the OPN promoter in senescent cells, and this binding is required for promoter activation. Further, OPN is also regulated by the known SASP regulator C/EBPβ. In response to senescence, the full-length activating C/EBPβ isoform LAP2 increases binding to the OPN, IL-6, and IL-8 promoters. Using a microarray and RNAi approach, we identified 57 additional putative c-Myb-dependent SASP factors and 125 additional putative C/EBPβ SASP factors. There is a high degree of overlap between c-Myb- and C/EBPβ-dependent factors. The importance of both c-Myb and C/EBPβ is underscored by our finding that the depletion of either factor reduces the ability of senescent fibroblasts to promote the growth of preneoplastic epithelial cells. Furthermore, I describe a post-transcriptional SASP mRNA stability regulator pathway. This pathway is dependent on p38MAPK, but is distinct from p38MAPK’s role in NF-κB transcription of SASP factors. In fully senescent fibroblasts, p38MAPK regulates the removal of mRNA-destabilizing protein AUF1 from the 3’-UTRs of numerous SASP factor mRNAs, resulting in increased mRNA stability. Given p38MAPK’s role in both transcriptional and post-transcriptional regulation of the SASP, we tested the ability of p38MAPK inhibitors to inhibit tumor growth. Treatment of mice with an orallyadministered p38MAPK inhibitor significantly decreased tumor growth in senescent fibroblast-supported xenograft models. Importantly, p38MAPK inhibition acts upon the microenvironment by removing stromal support of tumor growth. Interestingly, p38MAPK inhibition also inhibits the tumor promoting activities of cancer-associated fibroblasts (CAFs). CAFs have a secretory profile similar to senescent fibroblasts. This work indicates that p38MAPK inhibition is a viable therapeutic for targeting both senescent fibroblast and CAF stromal support of tumor cell growth.
Chair and Committee
Sheila A. Stewart
Kendall Blumer, Milan Chheda, Robert Mecham, Joshua Rubin,
Flanagan, Kevin, "Regulation of the Pro-Tumorigenic Senescence-Associated Secretory Phenotype" (2017). Arts & Sciences Electronic Theses and Dissertations. 1101.