Patient derived organoids to model rare prostate cancer phenotypes

Abstract

A major hurdle in the study of rare tumors is a lack of existing preclinical models. Neuroendocrine prostate cancer is an uncommon and aggressive histologic variant of prostate cancer that may arise de novo or as a mechanism of treatment resistance in patients with pre-existing castration-resistant prostate cancer. There are few available models to study neuroendocrine prostate cancer. Here, we report the generation and characterization of tumor organoids derived from needle biopsies of metastatic lesions from four patients. We demonstrate genomic, transcriptomic, and epigenomic concordance between organoids and their corresponding patient tumors. We utilize these organoids to understand the biologic role of the epigenetic modifier EZH2 in driving molecular programs associated with neuroendocrine prostate cancer progression. High-throughput organoid drug screening nominated single agents and drug combinations suggesting repurposing opportunities. This proof of principle study represents a strategy for the study of rare cancer phenotypes.

Role of Specialized Composition of SWI/SNF Complexes in Prostate Cancer Lineage Plasticity

“…We did not observe a significant association between the SMARCA4 knock-down signature and PTEN genomic status in CRPC-Adeno and CRPC-NE cohorts (not shown). We did, however, observe that SMARCA4 knock-down failed to impair proliferation of WCM154 cells, a PTEN-competent CRPC-NE organoid line 30 . Conversely, knock-down of BAF155 (SMARCC1) inhibited WCM154 cell growth as well as growth of adenocarcinoma cell lines (Supplementary Fig.…”

“…Moreover, mouse models with Trp53 and Rb1 genomic loss show lineage plasticity but epigenetic therapy can re-sensitize those tumors towards ARSi treatment 12 . In patient cohorts, CRPC-NE are characterized by an overexpression of several epigenetic regulators (such as EZH2) and a specific DNA methylation profile 4,14,30 . Overall, these data support the idea that PCa progression through lineage plasticity is regulated by epigenetic changes in a specific genomic context 13,55 .…”

“…WCM154 and WCM155 CRPC-NE cell lines have been previously established and were maintained in two-dimensional monolayer culture according to the previously described protocol 30 . LNCaP-AR cells were a kind gift from Dr. Sawyers and Dr. Mu (Memorial Sloan Kettering Cancer Center) and were cultured as previously described 13 .…”

Patient-derived xenografts and organoids model therapy response in prostate cancer

“…Patient-derived xenografts (PDX) are used to address intra-tumor characteristics and drug response since they model the original tumor in a more representative manner than other models such as two-dimensional cell culture [4]. Various PDX study programs have evaluated the take of various PDX models of primary and metastatic PCa [5][6][7], with the use of different immunocompromised strains, sites of implantations (subrenal [8], subcutaneous [9], orthotopic [5], intrafemoral [10]), grafting of biopsies, cells, circulatory tumor cells [11] and patient-derived organoids [9,12]. Nonetheless, the few PCa PDXs which are available and suitable for characterizing androgen dependency in PCa are predominantly from metastasis [13] (e.g.…”

Self‐Assembling Peptide Gels for 3D Prostate Cancer Spheroid Culture

“…To render the Q11 system more amenable to 3D cell encapsulation, we developed bQ13, and we investigated bQ13 gels in the context of human prostate cancer cell culture. Ex vivo cultured prostate cancer organoids from both primary tumor cells and cell lines are receiving considerable interest, both for modeling the phenotypes of various forms of the disease and evaluating therapeutics . The vast majority of these studies have employed Matrigel, despite speculations that minor components may variably influence phenotype or drug responses .…”