Trans-differentiation from adenocarcinoma to small cell neuroendocrine (SCN) cancer is an adverse consequence of treatment escape in various cancers, including prostate, lung, and bladder cancers (Balanis and Sheu et al., <a href="https://pubmed.ncbi.nlm.nih.gov/31287989/">PMID 31287989</a>). Expression of dominant negative <a href="https://www.ncbi.nlm.nih.gov/gene/7157">p53</a> (TP53DN), <a href="https://www.ncbi.nlm.nih.gov/gene/207">myr</a><a href="https://www.ncbi.nlm.nih.gov/gene/207">A</a><a href="https://www.ncbi.nlm.nih.gov/gene/207">kt1</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/5925">R</a><a href="https://www.ncbi.nlm.nih.gov/gene/5925">B1</a>-shRNA, <a href="https://www.ncbi.nlm.nih.gov/gene/4609">c-Myc</a>, and <a href="https://www.ncbi.nlm.nih.gov/gene/596">Bcl2</a>(PARCB forward transformation) using human naïve prostate basal epithelial cells recapitulated both transcriptional and histological characteristics of small cell neuroendocrine prostate cancer (NEPC) (Park et al., <a href="https://pubmed.ncbi.nlm.nih.gov/30287662/">PMID 30287662</a>). To study the temporal transcriptional landscape during this trans-differentiation process, we conducted a time course study using a PARCB model by integrating multi-omics sequencing, including bulk RNA-sequencing and ATAC-sequencing on samples taken at different time point, as well as single cell RNA sequencing on serial xenograft tumors. We found a common SCN pathway that resulted in two distinct end states defined by mutually exclusive expression of <a href="https://www.ncbi.nlm.nih.gov/gene/429">ASCL1</a> and <a href="https://www.ncbi.nlm.nih.gov/gene/430">ASCL2</a>. Further investigation using CUT&#x26;RUN sequencing identified <a href="https://www.ncbi.nlm.nih.gov/gene/7023">TFAP4 </a>as a potential epigenetic regulator of both proteins. Our study reveals temporal and transcriptional changes from prostate adenocarcinoma to NEPC trans-differentiation.

Temporal Evolution Reveals Bifurcated Lineages in Aggressive Neuroendocrine Small Cell Prostate Cancer Trans-Differentiation

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