A MYC Family Switch: L-MYC Drives and Maintains Neuroendocrine Lineage Programs in Prostate Cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Neuroendocrine prostate cancer (NEPC) is an aggressive subtype resistant to therapy.
• NEPC arises from lineage plasticity after androgen receptor (AR) pathway inhibition.
• The role of MYCL (L-MYC) in NEPC development was previously unclear.

Purpose of the Study:

• Investigate the role of MYCL in NEPC pathogenesis.
• Determine the relationship between MYCL expression and neuroendocrine differentiation.
• Elucidate the regulatory mechanisms and functional consequences of MYCL in NEPC.

Main Methods:

• Analysis of MYCL expression in NEPC patient samples and cell lines.
• Correlation analysis with neuroendocrine and adenocarcinoma-associated genes.
• Functional studies involving MYCL overexpression and knockdown.
• Epigenetic landscape assessment and upstream regulator identification.

Main Results:

• MYCL is selectively upregulated in NEPC, while MYC and MYCN are downregulated, indicating a MYC family switch.
• MYCL expression correlates with neuroendocrine markers (ASCL1, INSM1) and inversely with adenocarcinoma markers.
• MYCL activation is linked to a permissive epigenetic landscape, not genomic amplification.
• MYCL overexpression promotes neuroendocrine reprogramming and suppresses AR signaling; MYCL knockdown reverses these effects.

Conclusions:

• MYCL acts as a lineage-specific regulator driving neuroendocrine identity in advanced prostate cancer.
• A conserved neuroendocrine transcriptional axis involving ASCL1, INSM1, and MYCL is established.
• MYCL plays a critical role in the plasticity and progression of NEPC.