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 analyze 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 exhibits a more complex tumor structure with subtypes coexisting as separate sub-populations 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.
Highlights
Neuroendocrine carcinomas (NEC) are tumors expressing markers of neuronal differentiation that can arise at different anatomic sites but have strong histological and clinical similarities
To investigate the impact of chromatin accessibility in determining the NEC phenotype, we profiled the epigenetic landscape of NECs arising in various anatomic locations using assay for transposaseaccessible chromatin with high-throughput sequencing (ATACseq) and RNA sequencing (RNA-seq) applied to patient-derived xenograft (PDX) models of NEPC12, SCLC13, and Merkel Cell Carcinoma (MCC), as well as Gastrointestinal NEC (GINEC) clinical samples (Supplementary Table 1)
As NEC can emerge from a preexisting AD, as typified by NEPC5 and occasionally by SCLC6, we hypothesized that those histologies are extremes of a spectrum of tumor progression
Summary
Neuroendocrine carcinomas (NEC) are tumors expressing markers of neuronal differentiation that can arise at different anatomic sites but have strong histological and clinical similarities. With a particular focus on treatment emergent neuroendocrine prostate cancer (NEPC), we analyze 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. NEC comprises a group of tumors that can have features of small-cell carcinoma and show expression of neuroendocrine (NE) markers including SYP, CHGA, and INSM12 Given these common characteristics, NECs constitute a unique clinicopathological entity despite their distinct anatomical origins[1]. SCLC has been subclassified based on the differential expression of the basic helix-loop-helix (bHLH) transcription factors (TFs) ASCL1 and NEUROD17 These neuronal lineage TFs (LTFs) have been implicated in the maturation of resident NE cells of the lung[8,9]. The observed intratumoral heterogeneity of clinical NEPC samples has therapeutic implications
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