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Abstract
Neuroendocrine prostate cancer is an aggressive variant of prostate cancer that may arise de novo or develop from pre-existing prostate adenocarcinoma as a mechanism of treatment resistance. The combined loss of tumor suppressors RB1, TP53, and PTEN are frequent in NEPC but also present in a subset of prostate adenocarcinomas. Most clinical and preclinical studies support a trans-differentiation process, whereby NEPC arises clonally from a prostate adenocarcinoma precursor during the course of treatment resistance. Here we highlight a case of NEPC with significant intra-patient heterogeneity observed across metastases. We further demonstrate how single-cell genomic analysis of circulating tumor cells combined with a phenotypic evaluation of cellular diversity can be considered as a window into tumor heterogeneity in patients with advanced prostate cancer.
Highlights
Cell-to-cell heterogeneity is a major driver of cancer evolution, progression, and drug resistance
We use single-cell genomic analysis of circulating tumor cells (CTCs) in this patient and additional patients to further explore the contribution of cellular diversity in Neuroendocrine prostate cancer (NEPC)
Based on his aggressive clinical presentation and pathologic features of both adenocarcinoma and NEPC, the patient was treated with androgen deprivation therapy (ADT), carboplatin and docetaxel chemotherapy
Summary
Cell-to-cell heterogeneity is a major driver of cancer evolution, progression, and drug resistance. NEPC may arise de novo or develop from prostate adenocarcinoma as a mechanism of treatment resistance[2,3] During this progression, mixed histologic features may be observed with both high-grade prostate adenocarcinoma and neuroendocrine carcinoma present. In NEPC, expression of the androgen receptor (AR) and prostate-specific antigen (PSA) are often negative; in some cases, in mixed cases or hybrid tumors with overlapping features, AR can be expressed with or without PSA1,2,4,5. In treatment-related NEPC, most clinical and preclinical studies support a trans-differentiation process where NEPC arises clonally from a prostate adenocarcinoma precursor[3,6] This trans-differentiation occurs through a process of lineage plasticity, whereby tumor cells lose their luminal prostate identity including AR signaling dependence, and can acquire a neuroendocrine lineage program. We use single-cell genomic analysis of circulating tumor cells (CTCs) in this patient and additional patients to further explore the contribution of cellular diversity in NEPC
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