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

TitleTemporal evolution of cellular heterogeneity during the progression to advanced AR-negative prostate cancer.
Publication TypeJournal Article
Year of Publication2021
AuthorsBrady NJ, Bagadion AM, Singh R, Conteduca V, Van Emmenis L, Arceci E, Pakula H, Carelli R, Khani F, Bakht M, Sigouros M, Bareja R, Sboner A, Elemento O, Tagawa S, Nanus DM, Loda M, Beltran H, Robinson B, Rickman DS
JournalNat Commun
Date Published2021 06 07
KeywordsAdenocarcinoma, Animals, Carcinoma, Neuroendocrine, Cell Line, Tumor, Disease Progression, Gene Expression Regulation, Neoplastic, Humans, Male, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, N-Myc Proto-Oncogene Protein, Organ Culture Techniques, Prognosis, Prostate, Prostatic Neoplasms, Receptors, Androgen, Retinoblastoma Protein

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.

Alternate JournalNat Commun
PubMed ID34099734
PubMed Central IDPMC8185096
Grant ListP50 CA211024 / CA / NCI NIH HHS / United States
R01 CA230913 / CA / NCI NIH HHS / United States
Related Faculty: 
Andrea Sboner, Ph.D. Brian Robinson, M.D. David Rickman, Ph.D. Francesca Khani, M.D. Massimo Loda, M.D. Nicholas Brady, Ph.D.

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