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

Author

Listed:
  • Nicholas J. Brady

    (Weill Cornell Medicine)

  • Alyssa M. Bagadion

    (Weill Cornell Medicine)

  • Richa Singh

    (Weill Cornell Medicine)

  • Vincenza Conteduca

    (Dana Farber Cancer Institute)

  • Lucie Van Emmenis

    (Weill Cornell Medicine)

  • Elisa Arceci

    (Weill Cornell Medicine)

  • Hubert Pakula

    (Weill Cornell Medicine)

  • Ryan Carelli

    (Weill Cornell Medicine)

  • Francesca Khani

    (Weill Cornell Medicine
    Weill Cornell Medicine
    Weill Cornell Medicine
    Weill Cornell Medicine)

  • Martin Bakht

    (Dana Farber Cancer Institute)

  • Michael Sigouros

    (Weill Cornell Medicine)

  • Rohan Bareja

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • Andrea Sboner

    (Weill Cornell Medicine
    Weill Cornell Medicine
    Weill Cornell Medicine
    Weill Cornell Medicine)

  • Olivier Elemento

    (Weill Cornell Medicine
    Weill Cornell Medicine
    Weill Cornell Medicine
    Weill Cornell Medicine)

  • Scott Tagawa

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • David M. Nanus

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • Massimo Loda

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • Himisha Beltran

    (Dana Farber Cancer Institute)

  • Brian Robinson

    (Weill Cornell Medicine
    Weill Cornell Medicine
    Weill Cornell Medicine
    Weill Cornell Medicine)

  • David S. Rickman

    (Weill Cornell Medicine
    Weill Cornell Medicine)

Abstract

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.

Suggested Citation

  • Nicholas J. Brady & Alyssa M. Bagadion & Richa Singh & Vincenza Conteduca & Lucie Van Emmenis & Elisa Arceci & Hubert Pakula & Ryan Carelli & Francesca Khani & Martin Bakht & Michael Sigouros & Rohan , 2021. "Temporal evolution of cellular heterogeneity during the progression to advanced AR-negative prostate cancer," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23780-y
    DOI: 10.1038/s41467-021-23780-y
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    Cited by:

    1. Sukanya Panja & Mihai Ioan Truica & Christina Y. Yu & Vamshi Saggurthi & Michael W. Craige & Katie Whitehead & Mayra V. Tuiche & Aymen Al-Saadi & Riddhi Vyas & Shridar Ganesan & Suril Gohel & Frederic, 2024. "Mechanism-centric regulatory network identifies NME2 and MYC programs as markers of Enzalutamide resistance in CRPC," Nature Communications, Nature, vol. 15(1), pages 1-24, December.
    2. 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.
    3. Hubert Pakula & Mohamed Omar & Ryan Carelli & Filippo Pederzoli & Giuseppe Nicolò Fanelli & Tania Pannellini & Fabio Socciarelli & Lucie Van Emmenis & Silvia Rodrigues & Caroline Fidalgo-Ribeiro & Pie, 2024. "Distinct mesenchymal cell states mediate prostate cancer progression," Nature Communications, Nature, vol. 15(1), pages 1-21, December.

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