Wednesday, January 15, 2025
1/15/2025
SUMMARY Late stages of cancer metastasis involves the seeding of cancer cells at distant organs and the lethal outgrowth of seeded cells. In 2019, virtually all 31,620 prostate cancer (PCa) deaths in the United States were attributed to metastasis. Epithelial Mesenchymal Transition (EMT) is important for physiological development; however, EMT promotes migration, invasion, and seeding in multiple cancer types. In contrast, EMT inhibits proliferation and tumor outgrowth. SNAI1 and Twist1 are major EMT drivers that promote cancer cell seeding and inhibit cell proliferation and tumor outgrowth, in non-PCa. SNAI1 expression is detected in invasive primary and metastatic PCa. In contrast, the androgen receptor (AR) is a major driver of PCa cell proliferation and tumor outgrowth. Of note, AR activates, but SNAI1 represses, transcription of Cyclin D1 (a cell cycle driver). Both bind to an overlapping region of the ccnd1 (Cyclin D1) proximal promoter, suggesting direct competitive regulation of Cyclin D1 transcription. Given that outgrowth occurs at the end of the metastasis cascade, EMT is likely to occur transiently, early in PCa patients. In fact, vimentin (a marker of EMT) is highly expressed in PCa circulating tumor cells; however, vimentin is lowly expressed once seeded PCa cells grow into detectable metastases. While EMT and AR signaling have been independently investigated in PCa, how EMT and AR coordinate PCa metastasis remains unclear. Adhering to the transient nature of EMT in clinical PCa, a TetON-SNAI1 expression system was created, whereby transient expression of SNAI1 can be turned ON/OFF with doxycycline. Preliminary data shows that SNAI1 induces a mesenchymal morphology in PCa cells, suppresses cell growth, and upregulates mRNA of EMT markers such as vimentin and NPR2. However, AR signaling suppresses SNAI1’s ability to upregulate vimentin and NRP2 and downregulates Twist1 mRNA, independent of SNAI1 expression. Altogether, these data suggest that AR and SNAI1 have opposing roles in regulating EMT and proliferation; and are consistent with the late sequence of events that occur during PCa metastasis: i.e., seeding followed by outgrowth. Therefore, I hypothesize that SNAI1 mediates an anti-proliferative EMT-like invasion program to promote PCa seeding; subsequently, AR antagonizes SNAI1-mediated cyclin D1 repression to restore proliferation and promote metastatic outgrowth. The following aims are designed to address the central hypothesis. Aim1: Determine how AR impacts SNAI1’s ability to promote PCa invasion and metastatic seeding. Aim2: Determine how SNAI1 and AR regulate PCa proliferation. Aim3: Determine extent of AR and SNAI1 co- expression and activity in clinical PCa samples. Patients with aggressive PCa are treated with standard anti AR- signaling therapies; but will develop resistance within 2 years. Given the limited treatment options available for this group of patients, further study of SNAI1 and AR will help develop research models that are more clinically accurate and provide deeper insights for future therapeutic strategies.
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