Subtype Heterogeneity and Epigenetic Convergence in Neuroendocrine Prostate Cancer

Abstract

Neuroendocrine carcinomas (NEC) are tumors expressing markers of neuronal differentiation that can arise at different anatomic sites but have strong histological and clinical similarities. Here we report the chromatin landscapes of a range of human NECs and show convergence to the activation of a common epigenetic program. With a particular focus on treatment emergent neuroendocrine prostate cancer (NEPC), we analyzed cell lines, patient-derived xenograft (PDX) models and human clinical samples to show the existence of two distinct NEPC subtypes based on the expression of the neuronal transcription factors ASCL1 and NEUROD1. While in cell lines and PDX models these subtypes are mutually exclusive, single cell analysis of human clinical samples exhibit a more complex tumor structure with subtypes coexisting as separate subpopulations within the same tumor. These tumor sub-populations differ genetically and epigenetically contributing to intra- and inter-tumoral heterogeneity in human metastases. Overall our results provide a deeper understanding of the shared clinicopathological characteristics shown by NECs. Furthermore, the intratumoral heterogeneity of human NEPCs suggests the requirement of simultaneous targeting of coexisting tumor populations as a therapeutic strategy.

Assessment of Androgen Receptor splice variant-7 as a biomarker of clinical response in castration-sensitive prostate cancer

“…Tissues were then incubated with anti-AR-V7 antibody (RM7 RevMAb) at 1 in 50 at 37°C for 1 hr in antibody diluent (Ventana). Primary antibody complexes were detected using the UltraVision Quanto Detection System (Thermo Fisher) as described previously (58). Tissues were counterstained with hematoxylin, mounted and imaged on a Ventana DP 200 Slide Scanner (Roche).…”

Progression of prostate cancer reprograms MYC-mediated lipid metabolism via lysine methyltransferase 2A

“…Nonetheless, these data suggest that at least in a subset of primary PCa, increased expression of KMT2A may contribute to tumor development, and that its expression in relationship to MYC activity modulates cancer progression. To assess this relationship in advanced disease, we examined gene expression profiles from WTS of two additional cohorts: a panel of metastatic prostate cancer patient derived xenografts (LuCaP PDX series, N = 25, [23,[29][30][31][32]) and the West Coast Dream Team-Prostate Cancer Foundation (WCDT-PCF) cohort of metastatic castration-resistant prostate cancer (mCRPC, N = 99, [8]). As depicted in Fig.…”

“…Transcriptomes from the Stand Up To Cancer West Coast Dream Team-Prostate Cancer Foundation metastatic castration resistant prostate cancer (WCDT-PCF mCRPC) cohort [41] were downloaded from the NCI Genomic Data Commons (https://gdc.cancer.gov) via access to dbGaP phs001648. Transcriptomes from the LuCaP [23,[29][30][31] series of patient-derived xenografts (PDXs) were downloaded from GEO using accession numbers GSE113741, GSE156292, and GSE126078. Downloaded FASTQ files were processed through the nextflow nf-core/rnaseq (v3.5) pipeline (https://github.com/nf-core/rnaseq).…”

The origin and dynamics of cellular heterogeneity vary across lineage subtypes of castrate resistant prostate cancer

“…These lineage-plastic subtypes of mCRPC are not static or homogeneous - multiple subpopulations can exist in a patient tumor, yet the dynamic relationship of the subpopulation structure is not well understood (Cejas et al, 2021; Labrecque et al, 2019). Epigenetic mechanisms underlying lineage-plasticity in cancer can instill resistance without genetic clonal selection (Fennell et al, 2021) and minor subpopulations that are not easily detected in bulk may command an outsized role in growth and resistance (Sharma et al, 2010).…”

“…A significant barrier in the field continues to be a lack of representative preclinical models. PDX models of NEPC are available but do not represent the intra-tumoral heterogeneity observed in patients, and are just one genetically-defined subtype (Cejas et al, 2021). AR + /NE + combined lineage patient-derived models present a singular kind of resource to study the dynamic interplay between the two lineage states.…”