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 Beltran, Francesca Khani, Mark Pomerantz, Alessandra Dall’Agnese, Jett Crowdis, Eliezer M. 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 () and Henry W. Long ()
Additional contact information
Paloma Cejas: Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School
Yingtian Xie: Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School
Alba Font-Tello: Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School
Klothilda Lim: Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School
Sudeepa Syamala: Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School
Xintao Qiu: Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School
Alok K. Tewari: Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School
Neel Shah: Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School
Holly M. Nguyen: University of Washington
Radhika A. Patel: Fred Hutchinson Cancer Research Center
Lisha Brown: University of Washington
Ilsa Coleman: Fred Hutchinson Cancer Research Center
Wenzel M. Hackeng: Utrecht University
Lodewijk Brosens: Utrecht University
Koen M. A. Dreijerink: Amsterdam UMC
Leigh Ellis: Broad Institute of MIT and Harvard
Sarah Abou Alaiwi: Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School
Ji-Heui Seo: Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School
Sylvan Baca: Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School
Himisha Beltran: Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School
Francesca Khani: New York Presbyterian Hospital
Mark Pomerantz: Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School
Alessandra Dall’Agnese: Whitehead Institute for Biomedical Research
Jett Crowdis: Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School
Eliezer M. Allen: Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School
Joaquim Bellmunt: Beth Israel Deaconess Medical Center and PSMAR-IMIM Lab. Harvard Medical School
Colm Morrisey: University of Washington
Peter S. Nelson: Fred Hutchinson Cancer Research Center
James DeCaprio: Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School
Anna Farago: Massachusetts General Hospital Cancer Center
Nicholas Dyson: Massachusetts General Hospital Cancer Center
Benjamin Drapkin: Nancy B. and Jake L. Hamon Center for Therapeutic Oncology Research
X. Shirley Liu: Dana-Farber Cancer Institute
Matthew Freedman: Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School
Michael C. Haffner: Fred Hutchinson Cancer Research Center
Eva Corey: University of Washington
Myles Brown: Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School
Henry W. Long: Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-26042-z

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