Temporal evolution of cellular heterogeneity during the progression to advanced AR-negative prostate cancer

Nicholas J. Brady, Alyssa M. Bagadion, Richa Singh, Vincenza Conteduca, Lucie Van Emmenis, Elisa Arceci, Hubert Pakula, Ryan Carelli, Francesca Khani, Martin Bakht, Michael Sigouros, Rohan Bareja, Andrea Sboner, Olivier Elemento, Scott Tagawa, David M. Nanus, Massimo Loda, Himisha Beltran, Brian Robinson and David S. Rickman ()
Additional contact information
Nicholas J. Brady: Weill Cornell Medicine
Alyssa M. Bagadion: Weill Cornell Medicine
Richa Singh: Weill Cornell Medicine
Vincenza Conteduca: Dana Farber Cancer Institute
Lucie Van Emmenis: Weill Cornell Medicine
Elisa Arceci: Weill Cornell Medicine
Hubert Pakula: Weill Cornell Medicine
Ryan Carelli: Weill Cornell Medicine
Francesca Khani: Weill Cornell Medicine
Martin Bakht: Dana Farber Cancer Institute
Michael Sigouros: Weill Cornell Medicine
Rohan Bareja: Weill Cornell Medicine
Andrea Sboner: Weill Cornell Medicine
Olivier Elemento: Weill Cornell Medicine
Scott Tagawa: Weill Cornell Medicine
David M. Nanus: Weill Cornell Medicine
Massimo Loda: Weill Cornell Medicine
Himisha Beltran: Dana Farber Cancer Institute
Brian Robinson: Weill Cornell Medicine
David S. Rickman: Weill Cornell Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract Despite advances in the development of highly effective androgen receptor (AR)-directed therapies for the treatment of men with advanced prostate cancer, acquired resistance to such therapies frequently ensues. A significant subset of patients with resistant disease develop AR-negative tumors that lose their luminal identity and display neuroendocrine features (neuroendocrine prostate cancer (NEPC)). The cellular heterogeneity and the molecular evolution during the progression from AR-positive adenocarcinoma to AR-negative NEPC has yet to be characterized. Utilizing a new genetically engineered mouse model, we have characterized the synergy between Rb1 loss and MYCN (encodes N-Myc) overexpression which results in the formation of AR-negative, poorly differentiated tumors with high metastatic potential. Single-cell-based approaches revealed striking temporal changes to the transcriptome and chromatin accessibility which have identified the emergence of distinct cell populations, marked by differential expression of Ascl1 and Pou2f3, during the transition to NEPC. Moreover, global DNA methylation and the N-Myc cistrome are redirected following Rb1 loss. Altogether, our data provide insight into the progression of prostate adenocarcinoma to NEPC.

Date: 2021
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DOI: 10.1038/s41467-021-23780-y

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