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Subtype heterogeneity and epigenetic convergence in neuroendocrine prostate cancer

Author

Listed:
  • Paloma Cejas

    (Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School
    Dana-Farber Cancer Institute
    La Paz University Hospital)

  • Yingtian Xie

    (Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School
    Dana-Farber Cancer Institute)

  • Alba Font-Tello

    (Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School
    Dana-Farber Cancer Institute)

  • Klothilda Lim

    (Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School
    Dana-Farber Cancer Institute)

  • Sudeepa Syamala

    (Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School
    Dana-Farber Cancer Institute)

  • Xintao Qiu

    (Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School
    Dana-Farber Cancer Institute)

  • Alok K. Tewari

    (Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School
    Dana-Farber Cancer Institute
    Broad Institute of MIT and Harvard)

  • Neel Shah

    (Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School
    Dana-Farber Cancer Institute)

  • Holly M. Nguyen

    (University of Washington)

  • Radhika A. Patel

    (Fred Hutchinson Cancer Research Center)

  • Lisha Brown

    (University of Washington)

  • Ilsa Coleman

    (Fred Hutchinson Cancer Research Center)

  • Wenzel M. Hackeng

    (Utrecht University)

  • Lodewijk Brosens

    (Utrecht University)

  • Koen M. A. Dreijerink

    (Amsterdam UMC)

  • Leigh Ellis

    (Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute and Harvard Medical School)

  • Sarah Abou Alaiwi

    (Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School)

  • Ji-Heui Seo

    (Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School)

  • Sylvan Baca

    (Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School)

  • Himisha Beltran

    (Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School)

  • Francesca Khani

    (New York Presbyterian Hospital)

  • Mark Pomerantz

    (Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School)

  • Alessandra Dall’Agnese

    (Whitehead Institute for Biomedical Research)

  • Jett Crowdis

    (Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Eliezer M. Allen

    (Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Joaquim Bellmunt

    (Beth Israel Deaconess Medical Center and PSMAR-IMIM Lab. Harvard Medical School)

  • Colm Morrisey

    (University of Washington)

  • Peter S. Nelson

    (Fred Hutchinson Cancer Research Center)

  • James DeCaprio

    (Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School)

  • Anna Farago

    (Massachusetts General Hospital Cancer Center)

  • Nicholas Dyson

    (Massachusetts General Hospital Cancer Center)

  • Benjamin Drapkin

    (Nancy B. and Jake L. Hamon Center for Therapeutic Oncology Research
    University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

  • X. Shirley Liu

    (Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public Health)

  • Matthew Freedman

    (Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School
    Dana-Farber Cancer Institute)

  • Michael C. Haffner

    (Fred Hutchinson Cancer Research Center
    Fred Hutchinson Cancer Research Center
    University of Washington)

  • Eva Corey

    (University of Washington)

  • Myles Brown

    (Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School
    Dana-Farber Cancer Institute)

  • Henry W. Long

    (Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School
    Dana-Farber Cancer Institute)

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.

Suggested Citation

  • 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. , 2021. "Subtype heterogeneity and epigenetic convergence in neuroendocrine prostate cancer," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26042-z
    DOI: 10.1038/s41467-021-26042-z
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    Citations

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    Cited by:

    1. Varadha Balaji Venkadakrishnan & Adam G. Presser & Richa Singh & Matthew A. Booker & Nicole A. Traphagen & Kenny Weng & Nathaniel C. E. Voss & Navin R. Mahadevan & Kei Mizuno & Loredana Puca & Osasena, 2024. "Lineage-specific canonical and non-canonical activity of EZH2 in advanced prostate cancer subtypes," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Goutam Chakraborty & Kasmira Gupta & Natasha Kyprianou, 2023. "Epigenetic mechanisms underlying subtype heterogeneity and tumor recurrence in prostate cancer," Nature Communications, Nature, vol. 14(1), pages 1-4, December.
    3. Alessia Cacciatore & Dheeraj Shinde & Carola Musumeci & Giada Sandrini & Luca Guarrera & Domenico Albino & Gianluca Civenni & Elisa Storelli & Simone Mosole & Elisa Federici & Alessio Fusina & Marta I, 2024. "Epigenome-wide impact of MAT2A sustains the androgen-indifferent state and confers synthetic vulnerability in ERG fusion-positive prostate cancer," Nature Communications, Nature, vol. 15(1), pages 1-25, December.
    4. Shaghayegh Nouruzi & Dwaipayan Ganguli & Nakisa Tabrizian & Maxim Kobelev & Olena Sivak & Takeshi Namekawa & Daksh Thaper & Sylvan C. Baca & Matthew L. Freedman & Adeleke Aguda & Alastair Davies & Ami, 2022. "ASCL1 activates neuronal stem cell-like lineage programming through remodeling of the chromatin landscape in prostate cancer," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    5. Thomas C. Westbrook & Xiangnan Guan & Eva Rodansky & Diana Flores & Chia Jen Liu & Aaron M. Udager & Radhika A. Patel & Michael C. Haffner & Ya-Mei Hu & Duanchen Sun & Tomasz M. Beer & Adam Foye & Rah, 2022. "Transcriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced lineage plasticity," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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