|Title||Temporal evolution of cellular heterogeneity during the progression to advanced AR-negative prostate cancer.|
|Publication Type||Journal Article|
|Year of Publication||2021|
|Authors||Brady 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|
|Date Published||2021 06 07|
|Keywords||Adenocarcinoma, 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 Journal||Nat Commun|
|PubMed Central ID||PMC8185096|
|Grant List||P50 CA211024 / CA / NCI NIH HHS / United States |
R01 CA230913 / CA / NCI NIH HHS / United States
Andrea Sboner, Ph.D. Brian Robinson, M.D. David Rickman, Ph.D. Francesca Khani, M.D. Massimo Loda, M.D. Nicholas Brady, Ph.D.