Graduation Date
Spring 12-18-2026
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Programs
Cancer Research
First Advisor
Raymond C. Bergan
Second Advisor
Jennifer Black
Third Advisor
Gloria E. Borgstahl
Fourth Advisor
Paul L. Sorgen
Abstract
Metastasis is the principal cause of death in patients with solid tumors, and cell migration is the process that allows tumor cells to leave the primary site and colonize distant organs. Selectively inhibiting migration, a strategy termed migrastasis, offers a way to interrupt metastasis formation. How migration is regulated at the molecular level, however, and whether it can be separated from the pathways that sustain cell survival, remains incompletely understood. Using the selective chemical probe, KBU2046, we investigated the mechanisms that selectively govern motility in human prostate cancer cells by integrating quantitative proteomic profiling with targeted genetic models. At the systems level, we found that migration is controlled through the spatial and temporal reorganization of intracellular transport and focal adhesion networks. Rather than degrading the core cytoskeletal machinery, this regulation redistributes trafficking components, including aftiphilin and integrin β5, and slows the turnover of focal adhesions, while the structural machinery and cell viability are preserved. We next identified the serine/threonine kinase Raf1 as a central node in this process. Genetic knockout demonstrated that the Raf1 protein is required for single-cell migration but not for proliferation. The antimigratory response depended on the presence of the Raf1 protein rather than on phosphorylation of its Ser338 residue. In the engineered Ser338 mutants, effects on collective migration were modest and preliminary. Together, these findings define a framework in which directed migration in prostate cancer cells is governed by the spatial organization of transport and adhesion machinery, coordinated through the Raf1 protein and its interacting partners. They further demonstrate that cell motility can be uncoupled from cell survival, establishing directed migration as a distinct and tractable process in metastatic disease.
Rights
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Recommended Citation
Chen, Weining, "Molecular and Spatial Regulation of Directed Cell Migration in Prostate Cancer: Defining the Role of the Raf1 Protein with the Chemical Probe KBU2046" (2026). Theses & Dissertations. 1112.
https://digitalcommons.unmc.edu/etd/1112