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Decoding MUC1 and AR axis in a radiation-induced neuroendocrine prostate cancer cell-subpopulation unveils novel
Catarina Macedo-Silva1, Ângela Albuquerque-Castro1, Iris Carriço1,2
1Cancer Biology & Epigenetics Group, IPO Porto Research Center (CI-IPOP) / CI-IPOP@ RISE, Portuguese Oncology Institute of Porto (IPO Porto) / Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC), R. Dr. António Bernardino de Almeida, Porto, Portugal.
Abstract:
Despite the initial efficacy of radiotherapy (RT) in treating prostate adenocarcinoma (PCa), disease progression can lead to the emergence of neuroendocrine prostate cancer (NEPC) - a highly aggressive malignancy for which standard therapies are mostly ineffective. Although oncogenic MUC1-C is a leading driver of NEPC and of PCa lineage plasticity, its putative role in response to RT, including RT-induced neuroendocrine transdifferentiation (tNED), has not been explored. We thus aimed to explore the interplay between androgen receptor (AR) signaling and MUC1 in PCa progression to NEPC. Firstly, using a radioresistant PCa cell line (22Rv1-RR), we demonstrated that epigenetic suppression of AR signaling led to MUC1/MUC1-C upregulation, which seems to be activated through γSTAT3. MUC1 activation is positively associated with increased expression of neuroendocrine-related markers, including CD56, chromogranin A, synaptophysin, and INSM transcriptional repressor 1 (INSM1). In NEPC tissues and compared to prostate adenocarcinoma, MUC1 was upregulated and negatively correlated with AR, which was suppressed. Finally, proteomic analyses revealed that MUC1 activation upon RT selective pressure led to the acquisition of stemness features, induction of epithelial to mesenchymal transition, and enhancement of basal cell-like traits. Notably, MUC1 knockdown significantly boosted response to RT in both 22Rv1-RR and DU145 cell lines. Moreover, AR-induced overexpression in PC3 cell lines entailed MUC1 downregulation, resulting in attenuated neuroendocrine traits and radioresistance, as well as impaired cell migration and invasion capabilities. Collectively, these results highlight MUC1 as a promising radiosensitization target and may ultimately help overcome therapy resistance and NEPC progression.
Insights
MUC1-C drives neuroendocrine prostate cancer (NEPC) after radiotherapy. Targeting MUC1-C enhances treatment response and overcomes resistance, offering a new strategy against aggressive prostate cancer.
Area of Science:
- Oncology
- Cancer Biology
- Molecular Urology
Background:
- Radiotherapy (RT) is initially effective for prostate adenocarcinoma (PCa) but can lead to aggressive neuroendocrine prostate cancer (NEPC).
- Oncogenic MUC1-C drives NEPC and PCa plasticity, but its role in RT response and RT-induced neuroendocrine transdifferentiation (tNED) is unexplored.
- Understanding the interplay between androgen receptor (AR) signaling and MUC1 is crucial for NEPC progression.
Purpose of the Study:
- To investigate the role of MUC1 in PCa progression to NEPC, particularly in response to RT.
- To explore the relationship between AR signaling and MUC1 in the context of NEPC development.
- To identify MUC1 as a potential target for radiosensitization in prostate cancer.
Main Methods:
- Utilized a radioresistant PCa cell line (22Rv1-RR) to study AR signaling suppression and MUC1 upregulation.
- Analyzed NEPC and PCa tissues to assess MUC1 and AR expression.
- Performed proteomic analyses to evaluate MUC1's impact on cellular traits.
- Conducted MUC1 knockdown and AR-overexpression experiments in PCa cell lines (22Rv1-RR, DU145, PC3).
Main Results:
- Epigenetic suppression of AR signaling in radioresistant PCa cells led to MUC1/MUC1-C upregulation, associated with neuroendocrine marker expression.
- MUC1 was upregulated and negatively correlated with AR in NEPC tissues compared to PCa.
- MUC1 activation upon RT pressure induced stemness, epithelial-to-mesenchymal transition, and basal cell traits.
- MUC1 knockdown enhanced RT response, while AR overexpression downregulated MUC1, reducing neuroendocrine traits and radioresistance.
Conclusions:
- MUC1 plays a significant role in PCa progression to NEPC and resistance to RT.
- MUC1 activation is linked to neuroendocrine differentiation and acquisition of aggressive traits.
- MUC1 is a promising target for radiosensitization, potentially overcoming therapy resistance and NEPC progression.
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