We have extensively studied chromatin states in cancer. Currently, we have increased the resolution to a single-cell (sc) level for the investigation of clinical samples. sc technology can reveal intra-tumor heterogeneity. Here we show heterogeneity in terms of the expression of ASCL1 and NEUROD1 transcription factors in Neuroendocrine Prostate cancer. The sc-ATAC-seq analysis show chromatin accessibility at distinct loci for both subtypes and can be used to investigate the transcriptional program activated for each subtype. In addition, the reads resulting from scATAC-seq can be used to infer copy number variation (CNV) profile to investigate the genetic-epigenetic interplay existing in NEPC.
a) Representative immunostaining of a NEPC liver metastasis showing intratumor heterogeneity in terms of ASCL1 and NEUROD1 staining. (b) sc-ATAC-seq analysis of the same liver met in (a) showing differentially accessibility at promoters of ASCL1 or NEUROD1 gene signature (c) CNV inference from scATAC-seq data. (d) tSNE plot of scATAC-seq data colored by the cluster each cell was partitioned into by the inferred CNV alterations. Those three genetic clusters correspond to NEUROD1 (blue), ASCL1 (green), and normal cells (gray) as defined by scATAC-seq analysis.
Reference: Cejas P, Xie Y, Font-Tello A, Tewari A, Lim K, Syamala S, Qiu X, Nguyen HM, Haffner MC, Patel RA, Brown L, Coleman I, Brosens L, Hackeng WM, Dreijerink KMA, Ellis L, Van Allen EM, Bellmunt J, Nelson PS, DeCaprio J, Farago A, Dyson N, Drapkin B, Liu XS, Freedman M, Morrisey C, Corey E, Brown M and Long HW. Subtype Heterogeneity and Epigenetic Convergence in Neuroendocrine Prostate Cancer. Nat Commun 2021 Oct 1;12(1):5775