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. van 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; Henry W. Long

doi:10.1038/s41467-021-26042-z

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 BeltranFrancesca Khani, Mark Pomerantz, Alessandra Dall’Agnese, Jett Crowdis, Eliezer M. van 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^*, Henry W. Long^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Article number	5775
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-26042-z
Publication status	Published - 1 Dec 2021

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Cejas, P., Xie, Y., Font-Tello, A., Lim, K., Syamala, S., Qiu, X., Tewari, A. K., Shah, N., Nguyen, H. M., Patel, R. A., Brown, L., Coleman, I., Hackeng, W. M., Brosens, L., Dreijerink, K. M. A., Ellis, L., Alaiwi, S. A., Seo, J-H., Baca, S., ... Long, H. W. (2021). Subtype heterogeneity and epigenetic convergence in neuroendocrine prostate cancer. Nature Communications, 12(1), [5775]. https://doi.org/10.1038/s41467-021-26042-z

@article{5da8a815c25c4d23b725253346cc020b,

title = "Subtype heterogeneity and epigenetic convergence in neuroendocrine prostate cancer",

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.",

author = "Paloma Cejas and Yingtian Xie and Alba Font-Tello and Klothilda Lim and Sudeepa Syamala and Xintao Qiu and Tewari, {Alok K.} and Neel Shah and Nguyen, {Holly M.} and Patel, {Radhika A.} and Lisha Brown and Ilsa Coleman and Hackeng, {Wenzel M.} and Lodewijk Brosens and Dreijerink, {Koen M. A.} and Leigh Ellis and Alaiwi, {Sarah Abou} and Ji-Heui Seo and Sylvan Baca and Himisha Beltran and Francesca Khani and Mark Pomerantz and Alessandra Dall{\textquoteright}Agnese and Jett Crowdis and {van Allen}, {Eliezer M.} and Joaquim Bellmunt and Colm Morrisey and Nelson, {Peter S.} and James DeCaprio and Anna Farago and Nicholas Dyson and Benjamin Drapkin and Liu, {X. Shirley} and Matthew Freedman and Haffner, {Michael C.} and Eva Corey and Myles Brown and Long, {Henry W.}",

note = "Funding Information: P.C. acknowledges funding from the Ministry of Economy and Competitiveness, Insti-tuto de Salud Carlos III (Institute of Health Carlos III)—PI18-01604. H.W.L., M.B., E.C., and P.S.N. acknowledge support from NIH grant P01 CA163227-06A1. C.M. and P.S.N. acknowledge P50 CA097186-16A1, whereas P.S.N. also acknowledges support from W81XWH-17-1-0415. N.J.D., B.J.D., and A.F.F. are supported by U01CA220323 (N.J.D.). Publisher Copyright: {\textcopyright} 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = dec,

day = "1",

doi = "10.1038/s41467-021-26042-z",

language = "English",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

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, SA, 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, Liu, XS, Freedman, M, Haffner, MC, Corey, E, Brown, M & Long, HW 2021, 'Subtype heterogeneity and epigenetic convergence in neuroendocrine prostate cancer', Nature Communications, vol. 12, no. 1, 5775. https://doi.org/10.1038/s41467-021-26042-z

TY - JOUR

T1 - Subtype heterogeneity and epigenetic convergence in neuroendocrine prostate cancer

AU - Cejas, Paloma

AU - Xie, Yingtian

AU - Font-Tello, Alba

AU - Lim, Klothilda

AU - Syamala, Sudeepa

AU - Qiu, Xintao

AU - Tewari, Alok K.

AU - Shah, Neel

AU - Nguyen, Holly M.

AU - Patel, Radhika A.

AU - Brown, Lisha

AU - Coleman, Ilsa

AU - Hackeng, Wenzel M.

AU - Brosens, Lodewijk

AU - Dreijerink, Koen M. A.

AU - Ellis, Leigh

AU - Alaiwi, Sarah Abou

AU - Seo, Ji-Heui

AU - Baca, Sylvan

AU - Beltran, Himisha

AU - Khani, Francesca

AU - Pomerantz, Mark

AU - Dall’Agnese, Alessandra

AU - Crowdis, Jett

AU - van Allen, Eliezer M.

AU - Bellmunt, Joaquim

AU - Morrisey, Colm

AU - Nelson, Peter S.

AU - DeCaprio, James

AU - Farago, Anna

AU - Dyson, Nicholas

AU - Drapkin, Benjamin

AU - Liu, X. Shirley

AU - Freedman, Matthew

AU - Haffner, Michael C.

AU - Corey, Eva

AU - Brown, Myles

AU - Long, Henry W.

N1 - Funding Information: P.C. acknowledges funding from the Ministry of Economy and Competitiveness, Insti-tuto de Salud Carlos III (Institute of Health Carlos III)—PI18-01604. H.W.L., M.B., E.C., and P.S.N. acknowledge support from NIH grant P01 CA163227-06A1. C.M. and P.S.N. acknowledge P50 CA097186-16A1, whereas P.S.N. also acknowledges support from W81XWH-17-1-0415. N.J.D., B.J.D., and A.F.F. are supported by U01CA220323 (N.J.D.). Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/12/1

Y1 - 2021/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85116354103&partnerID=8YFLogxK

U2 - 10.1038/s41467-021-26042-z

DO - 10.1038/s41467-021-26042-z

M3 - Article

C2 - 34599169

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5775

ER -

Subtype heterogeneity and epigenetic convergence in neuroendocrine prostate cancer

Abstract

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