Graduation Year
2025
Document Type
Dissertation
Degree
Ph.D.
Degree Name
Doctor of Philosophy (Ph.D.)
Degree Granting Department
Biology (Cell Biology, Microbiology, Molecular Biology)
Major Professor
Conor C. Lynch, Ph.D.
Committee Member
Alvaro Monteiro, Ph.D.
Committee Member
Lixin Wan, Ph.D.
Committee Member
Andriy Marusyk, Ph.D.
Committee Member
Julio A. Aguirre-Ghiso, Ph.D.
Committee Member
Rachelle W. Johnson, Ph.D.
Keywords
B Cells, Bone marrow, Metastasis, MMP2, PRDM16
Abstract
Metastatic disease is the primary driver of cancer-related mortality. In prostate cancer (PCa), patient survival decreases dramatically once the disease spreads to distant organs, with over 80% of metastases occurring in the bone. This dissemination is often followed by a clinically silent period of tumor dormancy that can last for years, creating a critical reservoir of cells poised for lethal relapse. A significant barrier to understanding and targeting this dormant phase has been the lack of robust experimental models. This thesis first addresses this challenge by establishing a novel stress-induced model of PCa dormancy, validated across multiple murine and human cell lines. We demonstrate that this dormant phenotype is sustained in vivo following intra-iliac artery delivery into the bone marrow and, critically, can be reversed to a proliferative state by tissue injury, mimicking clinical reactivation.
Using this model, transcriptomic analysis identified the transcription factor PRDM16 as a key intrinsic regulator commonly upregulated in dormant PCa cells. Functional studies confirmed that PRDM16 is essential for maintaining the dormant state both in vitro and in vivo. Clinically, higher PRDM16 expression correlated with reduced disease recurrence and inversely correlated with the E2F cell cycle program in disseminated tumor cells from patient bone marrow. Mechanistically, we show that PRDM16 directly binds the promoter region of the potent cell cycle repressor RB1.
Our transcriptomic data also revealed a distinct enrichment of extracellular matrix (ECM) regulators in dormant cells, implicating ECM remodeling as a central process. Subsequent functional screens identified Matrix Metalloproteinase 2 (MMP2) as a critical mediator. Pharmacological or genetic inhibition of MMP2 abrogated entry into dormancy and triggered cell death. Conversely, using an inducible shRNA system, we demonstrated that downregulating MMP2 in established dormant cells promoted reawakening and proliferation, suggesting a dynamic, context-dependent role for MMP2 in regulating the dormancy-reactivation switch.
Finally, leveraging our novel syngeneic model, we investigated how dormant cells interact with their microenvironment. Using spatial transcriptomics, we dissected the cellular landscape of the bone niche harboring dormant PCa cells, revealing significant alterations within the B cell compartment. This finding suggests that dormant cells are not passive but actively modulate their local immune microenvironment.
In conclusion, this work presents novel, clinically relevant models of PCa dormancy and identifies PRDM16 and MMP2 as distinct molecular regulators governing the maintenance and dynamic state-switching of dormant cells. Furthermore, it provides spatial resolution of potential dormant tumor-immune crosstalk in the bone, opening new avenues for therapeutic intervention against metastatic relapse.
Scholar Commons Citation
Nasr, Mostafa M., "Dissecting the Intrinsic and Extrinsic Regulators of Prostate Cancer Dormancy in the Bone Microenvironment" (2025). USF Tampa Graduate Theses and Dissertations.
https://digitalcommons.usf.edu/etd/11061
