Modeling African American prostate adenocarcinoma by inducing defined genetic alterations in organoids
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Kenji Unno1, Meejeon Roh1, Young A. Yoo1, Yousef Al-Shraideh1, Lu Wang2, Larisa Nonn3 and Sarki A. Abdulkadir1,2,4
1Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
2Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
3Department of Pathology, University of Illinois at Chicago, Chicago, IL 60612, USA
4The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Sarki A. Abdulkadir, email: email@example.com
Keywords: prostate cancer, organoid culture, malignant transformation, cancer development, African American
Received: February 15, 2017 Accepted: March 16, 2017 Published: April 19, 2017
Genomic studies are rapidly identifying genetic alterations in human cancer, but functional validation of such alterations has been slow. Here, using human prostate cancer as a model, we have assessed the feasibility of engineering defined genetic alterations in well-known cancer driver genes to transform benign prostate epithelial organoids derived from African American men. Benign human prostate organoids were transduced with lentiviruses expressing MYC, shPTEN, shTP53 and AR, alone and in various combinations, to recapitulate prostate cancer development. Organoids expressing MYC, shPTEN, shTP53 and AR (denoted MPPA); MYC, shPTEN and shTP53 (MPP); or MYC (M) were significantly larger, had higher proliferation rates and demonstrated pathologically transformed morphology compared to organoids transduced with control lentivirus. Alterations in MYC, PTEN and TP53 also affected the rate of organoid basal-to-luminal differentiation in vitro. MPPA and MPP organoids expressed the clinical prostate cancer marker AMACR and developed prostate adenocarcinoma when grafted under the renal capsule in mice. These data indicate that genetic alterations commonly observed in human prostate cancer can be rapidly modeled in human organoid culture. Prostate cancer organoids provide a useful pre-clinical model for the evaluation of new candidate cancer genes, cancer disparities, and potentially for testing of novel therapeutic agents.
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