Abstract 5020: A patient-derived organoid model of neuroendocrine prostate cancer transdifferentiation informing the role of the BAF complex component ARID1A
Authors: Beshiri Mike L. , Tice Caitlin M. , Sowalsky Adam G. , Tran Crystal , Karzai Fatima , Dahut William , Kelly Kathy 
Published: August 2018

Abstract
Metastatic castration-resistant prostate cancer (mCRPC) is a genetically and phenotypically heterogeneous disease. Resistance to contemporary androgen-deprivation therapy (ADT) is inevitable, and occurs via several different mechanisms. One of these is lineage plasticity leading to transdifferentiation of AR-positive adenocarcinoma (ACPC) to the neuroendocrine (NEPC) subtype. The modern era of second-generation ADT has seen a significant increase in the percentage of NEPC, yet little is known about the genetic and epigenetic drivers of this phenotype. Using modified organoid media conditions that we previously developed, we have established a set of mCRPC organoid lines derived from four biopsies (two samples before and two after carboplatin + etoposide treatment, 1 year apart) of a single patient tumor that capture the genetic and phenotypic heterogeneity of the original metastatic tumor. Genomic and histologic analysis show that the original patient tumor is composed of both adenocarcinoma and neuroendocrine subpopulations that are maintained in the organoids at a ratio of approximately 1:4, respectively. The two subpopulations share a common ancestor and a putative early driver event in the homozygous loss of CDKN1B, but our analysis of clonal evolution indicates that the majority NEPC population did not transdifferentiate directly from the minority ACPC population in the metastasis, but rather in the primary tumor or in a prior metastatic lesion. The ACPC subpopulation contains a high copy gain of an upstream regulatory region of the AR gene and is genetically distinct from the NEPC population that lacks this alteration, but uniquely contains a truncating mutation in the ARID1A gene. ARID1A is frequently mutated and/or deleted in several different cancer types. It has been found to be altered in ~2% of prostate cancer patients, but its role is not understood. It is a key component of the BAF complex, which is a known regulator of neural development. Immunofluourescent staining of our organoid cells shows that mutant ARID1A correlates with the NEPC population. Using single-cell RNA-seq and principle component clustering analysis, we have identified five different transcriptionally defined populations: one population that corresponds to the genetically defined ACPC population and four additional transcriptionally defined populations that represent different states of differentiation of the NEPC component, as determined by expression of lineage markers. A full understanding of this model with respect to differentiation of the NEPC population and the specific role of ARID1A in the process will inform the development of mechanism-based treatments to inhibit NEPC formation.
Citation Format: Mike L. Beshiri, Caitlin M. Tice, Adam G. Sowalsky, Crystal Tran, Fatima Karzai, William Dahut, Kathy Kelly. A patient-derived organoid model of neuroendocrine prostate cancer transdifferentiation informing the role of the BAF complex component ARID1A [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5020.