Transient Sox9 Expression Facilitates Resistance to Androgen-Targeted Therapy in Prostate Cancer

Area of Science:

• Oncology
• Developmental Biology
• Cancer Cell Biology

Background:

• Metastatic prostate cancer increasingly shows treatment resistance with androgen receptor-negative/low (AR-/Low) tumors.
• Tumor cell plasticity, involving Rb1/p53 loss and Sox2 overexpression, contributes to treatment resistance.
• The role of developmental transcription factor Sox9 in this process is not well understood.

Purpose of the Study:

• To explore the role of Sox9 in prostate cancer therapy response and tumor progression.
• To investigate Sox9's function in AR-/Low prostate cancer stem cell-like intermediates.
• To determine the link between Sox9 expression, NF-κB pathway activity, and clinical outcomes.

Main Methods:

• Analysis of unique prostate cancer cell models with AR-/Low stem cell-like features.
• Evaluation of human prostate cancer xenografts and tissue microarrays for Sox9 expression.
• Investigation of NF-κB pathway involvement in Sox9 overexpression.

Main Results:

• Prostate cancer stem cell-like intermediates exhibit reduced Rb1/p53 and overexpression of Sox2 and Sox9.
• Sox9 is essential for spheroid growth and increases invasiveness and neural features in prostate cancer cells.
• Sox9 is transiently upregulated during castration-induced progression and overexpressed in neoadjuvant hormone therapy (NHT)-treated tumors, predicting recurrence.

Conclusions:

• Developmentally reprogrammed prostate cancer models mirror advanced tumor features, including Sox9 overexpression.
• Sox9 marks a transitional state in prostate cancer cells undergoing therapeutic stress, facilitating resistance.
• Sox9 expression may serve as an indicator of NF-κB pathway activity in prostate cancer.