title: Prostate epithelial cell of origin determines cancer differentiation state in an organoid transformation assay.
abstract: 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 theMYCamplification andPTENloss 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.
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095;
authors.forename: Jung Wook
authors.initials: JW
authors.lastname: Park
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90095;
authors.forename: John K
authors.initials: JK
authors.lastname: Lee
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095;
authors.forename: John W
authors.initials: JW
authors.lastname: Phillips
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095;
authors.forename: Patrick
authors.initials: P
authors.lastname: Huang
authors.affiliation: Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095;
authors.forename: Donghui
authors.initials: D
authors.lastname: Cheng
authors.affiliation: Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095;
authors.forename: Jiaoti
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; Howard Hughes Medical Institute, University of California, Los Angeles, CA 90095 owenwitte@mednet.ucla.edu.
authors.forename: Owen N
authors.initials: ON
authors.lastname: Witte
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D064593:Heterografts; D006801:Humans; D007610:Kallikreins / Q000096:biosynthesis / Q000235:genetics; D016086:Lentivirus; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009940:Organoids / Q000378:metabolism / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000235:genetics; D011467:Prostate / Q000378:metabolism* / Q000473:pathology; D017430:Prostate-Specific Antigen / Q000096:biosynthesis / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000235:genetics; D014161:Transduction, Genetic
chemical_list: C410798:AR protein, human; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D011944:Receptors, Androgen; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen
keywords: cancer differentiation; cells of origin; human prostate cancer; luminal cell; oragnoid culture