Expression profiling by high throughput sequencing of tumors derived from human prostate epithelial cells transformed with the oncogenes N-Myc and myrAKT1.. Homo sapiens

MYCN amplification and overexpression are common in neuroendocrine prostate cancer (NEPC). However, the impact of aberrant N-Myc expression in prostate tumorigenesis and the cellular origin of NEPC have not been established. We define N-Myc and activated AKT1 as oncogenic components sufficient to transform human prostate epithelial cells to prostate adenocarcinoma and NEPC including the small cell prostate carcinoma (SCPC) variant with phenotypic and molecular features of aggressive, late-stage human disease. We directly show that prostate adenocarcinoma and NEPC can both arise from a common epithelial clone. Further, N-Myc is required for tumor maintenance and destabilization of N-Myc through Aurora A kinase inhibition reduces tumor burden. Our findings establish N-Myc as a driver of NEPC and a target for therapeutic intervention. Expression profiling by high throughput sequencing of experimentally generated human tumors with mixed NEPC and prostate adenocarcinoma. Overall design: Gene expression analysis of laser capture microdissected NEPC and adenocarcinoma from three independent engineered human tumors of mixed NEPC and prostate adenocarcinoma phenotype.

神经内分泌前列腺癌（neuroendocrine prostate cancer, NEPC）中常见MYCN扩增与过表达。然而，异常N-Myc表达在前列腺肿瘤发生中的作用，以及NEPC的细胞起源，尚未得到阐明。本研究将N-Myc与活化AKT1定义为可将人前列腺上皮细胞转化为前列腺腺癌及NEPC（包含携带侵袭性晚期人类疾病表型与分子特征的前列腺小细胞癌（small cell prostate carcinoma, SCPC）亚型）的致癌组分。我们直接证实，前列腺腺癌与NEPC均可起源于同一上皮克隆。进一步研究表明，N-Myc对肿瘤维持不可或缺，且通过Aurora A激酶（Aurora A kinase）抑制N-Myc稳定性可减轻肿瘤负荷。本研究结果确立了N-Myc作为NEPC驱动因子及治疗干预靶点的地位。本数据集通过高通量测序对实验构建的混合NEPC与前列腺腺癌的人类肿瘤开展表达谱分析。总体实验设计：对3株独立的混合NEPC与前列腺腺癌表型的工程化人类肿瘤中，经激光捕获显微切割获取的NEPC与腺癌组织进行基因表达分析。