Abstract A28: N-Myc drives small cell neuroendocrine cancer initiated from human prostate basal cells

Human small cell prostate carcinoma (SCPC) represents up to 25% of lethal castration-resistant prostate cancer. Molecular characterization of a panel of SCPCs recently identified frequent genomic amplification of both MYCN and AURKA. The oncogenic function of N-Myc has been characterized in many cancer types but its role in the initiation of human SCPC has not been defined. To investigate the function of N-Myc in human prostate transformation, we utilized a tissue regeneration model of human prostate cancer. Human prostate basal epithelial cells were isolated from benign primary prostate tissue from four independent human donors, infected with lentiviruses expressing the oncogenes N-Myc and activated (myristoylated) AKT1, mixed with mouse urogenital sinus mesenchyme, and grafted subcutaneously in immunodeficient NOD-SCID-IL2Rγnull mice. Palpable tumors were appreciated within 2-3 months and histological evaluation revealed regions of mixed high-grade adenocarcinoma and small cell carcinoma. The small cell carcinoma histology showed typical findings of high nuclear-to-cytoplasmic ratio, nuclear molding, stippled chromatin, and frequent mitotic and apoptotic features. Immunohistochemical analysis demonstrated low to absent androgen receptor (AR) staining in both the adenocarcinoma and small cell carcinoma. Further, we found heterogeneous staining for neuroendocrine markers including neural cell adhesion molecule 1, chromogranin A, synaptophysin, thyroid transcription factor 1, and forkhead box A2 in the regions of small cell carcinoma in support of the histological diagnosis. To assess the androgen dependence of tumor growth, regenerated N-Myc and activated AKT1 tumors derived from the lentiviral infection of primary human prostate basal cells were passaged in either intact or castrate immunodeficient mice. Tumors were propagated both in the presence and absence of androgens and showed a small but progressive enrichment of the small cell carcinoma over the adenocarcinoma with successive passage in castrate hosts. Molecular profiling by RNA-Seq of three regenerated N-Myc and activated AKT1 tumors showed a significant resemblance to a subset of human SCPC clinical specimens. Further, the adenocarcinoma and small cell carcinoma components of each tumor were remarkably similar at the transcriptional level despite their differences in histological appearance. In conclusion, we have established a novel model of human small cell prostate cancer arising from benign human prostate basal cells. Overexpression of N-Myc and activated AKT1 in basal cells produces tumors that recapitulate the histology, immunophenotype, and transcriptional profile of human SCPC. These findings support a direct role for N-Myc in the neuroendocrine transformation of basal cells in the human prostate. Further studies are ongoing to elucidate the mechanisms by which N-Myc induces a neuroendocrine differentiation program in prostate cancer. Citation Format: John K. Lee, Bryan A. Smith, John W. Phillips, Jungwook Park, Tanya I. Stoyanova, Robert Baertsch, Artem Sokolov, Colleen Mathis, Donghui Cheng, Joshua M. Stuart, Jiaoti Huang, Owen N. Witte. N-Myc drives small cell neuroendocrine cancer initiated from human prostate basal cells. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A28.