Mer Tyrosine Kinase Regulates Disseminated Prostate Cancer Cellular Dormancy

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Prostate cancer (PCa) recurrence is often linked to disseminated tumor cells (DTCs).
• The TAM receptor tyrosine kinases (TYRO3, AXL, MERTK) are implicated in PCa dormancy, but individual roles are unclear.

Purpose of the Study:

• To elucidate the specific mechanisms by which individual TAM receptors, particularly MERTK, regulate PCa dormancy and recurrence.
• To investigate the molecular pathways involved in MERTK-mediated dormancy escape.

Main Methods:

• Short hairpin RNA (shRNA) and small interfering RNA (siRNA) were used to knockdown MERTK, AXL, or TYRO3 in PCa cells.
• Analysis included cell cycle progression (G1/G0 arrest), protein phosphorylation (p-Erk1/2, p-p38), expression of key proteins (p27, NR2F1, SOX2, NANOG), histone methylation (H3K9me3, H3K27me3), and in vivo metastasis models (intra-cardiac injection mouse xenograft).
• The effect of MERTK knockdown was assessed in vitro and in subcutaneous xenografts, and the role of MAP kinases was evaluated using a p38 inhibitor (SB203580).

Main Results:

• MERTK knockdown, unlike AXL or TYRO3, induced G1/G0 cell cycle arrest, increased p27, NR2F1, SOX2, and NANOG expression, and elevated histone methylation (H3K9me3, H3K27me3).
• Knockdown of MERTK significantly increased metastasis-free survival in a mouse model, while not affecting tumor growth in vitro or subcutaneously.
• The observed effects of MERTK on cell cycle and histone methylation were reversible by a p38 inhibitor, highlighting the involvement of MAP kinases.

Conclusions:

• MERTK actively promotes prostate cancer dormancy escape through a mechanism dependent on MAP kinases.
• This process involves regulation of the cell cycle, expression of cell cycle inhibitors like p27, pluripotency transcription factors, and epigenetic modifications via histone methylation.
• MERTK's role appears specific to dormancy regulation rather than primary tumor growth, suggesting targeted therapeutic potential for preventing recurrence.