|Title||Subtype heterogeneity and epigenetic convergence in neuroendocrine prostate cancer.|
|Publication Type||Journal Article|
|Year of Publication||2021|
|Authors||Cejas P, Xie Y, Font-Tello A, Lim K, Syamala S, Qiu X, Tewari AK, Shah N, Nguyen HM, Patel RA, Brown L, Coleman I, Hackeng WM, Brosens L, Dreijerink KMA, Ellis L, Alaiwi SAbou, Seo J-H, Baca S, Beltran H, Khani F, Pomerantz M, Dall'Agnese A, Crowdis J, Van Allen EM, Bellmunt J, Morrisey C, Nelson PS, DeCaprio J, Farago A, Dyson N, Drapkin B, X Liu S, Freedman M, Haffner MC, Corey E, Brown M, Long HW|
|Date Published||2021 10 01|
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.
|Alternate Journal||Nat Commun|
|Grant List||P01 CA163227 / CA / NCI NIH HHS / United States |
P50 CA097186 / CA / NCI NIH HHS / United States
U01 CA220323 / CA / NCI NIH HHS / United States
Related Faculty:Francesca Khani, M.D.