To date, a comprehensive characterization of the dynamic landscape of lncRNAs during the neuroendocrine transdifferentiation (NEtD) process has not been performed. A temporal analysis of the PDX-based NEtD model has for the first time provided this dynamic landscape. TFBS analysis identified NEPC-related TF motifs present within the NEtD lncRNA sequences, suggesting functional roles for these lncRNAs in NEPC pathogenesis. Furthermore, select NEtD lncRNAs appear to be associated with metastasis and patients receiving ADT. Treatment-related metastasis is a clinical consequence of NEPC tumours. Top candidate lncRNAs FENDRR, H19, LINC00514, LINC00617, and SSTR5-AS1 identified in this study are implicated in the development of NEPC.
researchers present here for the first time a genome-wide catalogue of NEtD lncRNAs that characterize the transdifferentiation process and a robust NEPC lncRNA patient expression signature. To accomplish this, they carried out the largest integrative study that applied a PDX NEtD model to clinical samples. These NEtD and NEPC lncRNAs are strong candidates for clinical biomarkers and therapeutic targets and warrant further investigation.
Xenograft model of neuroendocrine transdifferentiation,
phenotype – driven integration, and NEtD associated lncRNAs
(A) Schematic depicting the time points at which xenograft tumours were collected along the transdifferentiation of AD to NEPC (adapted from Akamatsu et al., 2015 24 ). (B) Phenotypes that align to various time points from above xenograft model and group – wise comparisons analyzed for clinical samples. (C) Four isolated expression profiles (grey triangles) from select time points in A (light grey circles) with appropria te clinical group – wise comparisons overlaid and integrated. Unsupervised hierarchical clustering with NEtD lncRNAs (Class I – Deactivated – Black bars, Class II – Activated – Orange bars, and Class III – Persistent – Red bars) identified from integration o utlined in (C) . D istinct clusters of AD and NEPC clinical samples are observed in the (D) VPC and (E) WCM cohorts. Class IV – Transient lncRNAs were excluded from the clustering due to the lack of clinical samples that would represent this intermediate state.