Subtype heterogeneity and epigenetic convergence in neuroendocrine prostate cancer

Paloma Cejas, Yingtian Xie, Alba Font-Tello, Klothilda Lim, Sudeepa Syamala, Xintao Qiu, Alok K. Tewari, Neel Shah, Holly M. Nguyen, Radhika A. Patel, Lisha Brown, Ilsa Coleman, Wenzel M. Hackeng, Lodewijk Brosens, Koen M. A. Dreijerink, Leigh Ellis, Sarah Abou Alaiwi, Ji-Heui Seo, Sylvan Baca, Himisha BeltranFrancesca Khani, Mark Pomerantz, Alessandra Dall’Agnese, Jett Crowdis, Eliezer M. van Allen, Joaquim Bellmunt, Colm Morrisey, Peter S. Nelson, James DeCaprio, Anna Farago, Nicholas Dyson, Benjamin Drapkin, X. Shirley Liu, Matthew Freedman, Michael C. Haffner, Eva Corey, Myles Brown, Henry W. Long

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41 Citations (Scopus)


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.
Original languageEnglish
Article number5775
JournalNature communications
Issue number1
Publication statusPublished - 1 Dec 2021

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