Prostate epithelial cell of origin determines cancer differentiation state in an organoid transformation assay

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 113; no. 16; pp. 4482 - 4487
• Main Authors: Park, Jung Wook, Lee, John K., Phillips, John W., Huang, Patrick, Cheng, Donghui, Huang, Jiaoti, Witte, Owen N.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 19.04.2016; National Acad Sciences
• Subjects: Animals; Antigens; Bioassays; Biological Sciences; Cancer; Cell Differentiation; Cell Line, Tumor; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cells; Epithelial Cells - metabolism; Epithelial Cells - pathology; Genetic engineering; Heterografts; Humans; Kallikreins - biosynthesis; Kallikreins - genetics; Lentivirus; Male; Mice; Mice, SCID; Neoplasm Transplantation; Organoids - metabolism; Organoids - pathology; Prostate - metabolism; Prostate - pathology; Prostate-Specific Antigen - biosynthesis; Prostate-Specific Antigen - genetics; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proto-Oncogene Proteins c-akt - biosynthesis; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-myc - biosynthesis; Proto-Oncogene Proteins c-myc - genetics; PTEN Phosphohydrolase - biosynthesis; PTEN Phosphohydrolase - genetics; Receptors, Androgen - biosynthesis; Receptors, Androgen - genetics; Rodents; Transduction, Genetic; cancer differentiation; cells of origin; human prostate cancer; luminal cell; oragnoid culture
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1603645113

The cell of origin for prostate cancer remains a subject of debate. Genetically engineered mouse models have demonstrated that both basal and luminal cells can serve as cells of origin for prostate cancer. Using a human prostate regeneration and transformation assay, our group previously demonstrated that basal cells can serve as efficient targets for transformation. Recently, a subpopulation of multipotent human luminal cells defined by CD26 expression that retains progenitor activity in a defined organoid culture was identified. We transduced primary human prostate basal and luminal cells with lentiviruses expressing c-Myc and activated AKT1 (myristoylated AKT1 or myrAKT1) to mimic the MYC amplification and PTEN loss commonly detected in human prostate cancer. These cells were propagated in organoid culture before being transplanted into immunodeficient mice. We found that c-Myc/myrAKT1–transduced luminal xenografts exhibited histological features of well-differentiated acinar adenocarcinoma, with strong androgen receptor (AR) and prostate-specific antigen (PSA) expression. In contrast, c-Myc/myrAKT1–transduced basal xenografts were histologically more aggressive, with a loss of acinar structures and low/absent AR and PSA expression. Our findings imply that distinct subtypes of prostate cancer may arise from luminal and basal epithelial cell types subjected to the same oncogenic insults. This study provides a platform for the functional evaluation of oncogenes in basal and luminal epithelial populations of the human prostate. Tumors derived in this fashion with defined genetics can be used in the preclinical development of targeted therapeutics.