Dissertation
Newly identified mediators and mechanisms promoting metastatic prostate cancer
Doctor of Philosophy (Ph.D.), Drexel University
Apr 2021
DOI:
https://doi.org/10.17918/00000703
Abstract
Prostate cancer is the second leading cause of cancer death in men, and virtually all deaths are caused by metastases. At diagnosis, prostate cancer is driven by the androgen receptor (AR), however, we have recently shown that prostate cancer skeletal metastases are heterogenous for AR expression, with ~30% of tumor cells lacking the AR (ARNeg). ARNeg tumor cells express Interleukin-1beta (IL-1[beta]), a pro-inflammatory cytokine, and CX3CR1, a chemokine receptor, and we provide the evidence for their crucial roles in metastasis initiation. We also demonstrate that the AR physically interacts with a consensus site within the IL-1[beta] promoter to mediate epigenetic transcriptional repression. Since the current standard-of-care for metastatic prostate cancer is androgen deprivation, blocking AR transcriptional activity will inevitably derepress IL-1[beta] expression, thus promoting tumor growth. Specifically, we show that the AR recruits the histone deacetylase HDAC4 to remove activating histone acetylation marks, therefore blocking downstream transcriptional activators from the promoter. Additionally, we found that ARNeg cells treated with the novel CX3CR1 antagonist FX-68 have impaired tumor seeding and progression. Interestingly, we identified a sub-population of ARNeg cells expressing high levels of CX3CR1 (CX3CR1High), constituting about 5% of the total population and highly expressing the master regulator pluripotency transcription factors POU5F1 and Nanog. We reveal that disseminated tumor cells responsible for tumor initiation are enriched for CX3CR1, POU5F1 (OCT4a), and Nanog. The CX3CR1High population displays stemness features in vitro and metastasis-initiation properties in vivo. In summary, these results shed light on two extremely promising new therapeutic targets for prostate cancer and reveal the mechanistic underpinning of their involvement in metastatic colonization and progression.
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Details
- Title
- Newly identified mediators and mechanisms promoting metastatic prostate cancer
- Creators
- Anthony Charles DiNatale
- Contributors
- Alessandro Fatatis (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- 175 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Pharmacology and Physiology; Drexel University
- Other Identifier
- 991015090549804721