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A slow-cycling LGR5 tumour population mediates basal cell carcinoma relapse after therapy

Author

Listed:
  • Adriana Sánchez-Danés

    (Université Libre de Bruxelles)

  • Jean-Christophe Larsimont

    (Université Libre de Bruxelles)

  • Mélanie Liagre

    (Université Libre de Bruxelles)

  • Eva Muñoz-Couselo

    (Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona
    Universitat Autònoma de Barcelona)

  • Gaëlle Lapouge

    (Université Libre de Bruxelles)

  • Audrey Brisebarre

    (Université Libre de Bruxelles)

  • Christine Dubois

    (Université Libre de Bruxelles)

  • Mariano Suppa

    (Erasme Hospital, Université Libre de Bruxelles)

  • Vijayakumar Sukumaran

    (Université Libre de Bruxelles)

  • Véronique del Marmol

    (Erasme Hospital, Université Libre de Bruxelles)

  • Josep Tabernero

    (Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona
    Universitat Autònoma de Barcelona)

  • Cédric Blanpain

    (Université Libre de Bruxelles
    WELBIO, Université Libre de Bruxelles)

Abstract

Basal cell carcinoma (BCC) is the most frequent cancer in humans and results from constitutive activation of the Hedgehog pathway1. Several Smoothened inhibitors are used to treat Hedgehog-mediated malignancies, including BCC and medulloblastoma2. Vismodegib, a Smoothened inhibitor, leads to BCC shrinkage in the majority of patients with BCC3, but the mechanism by which it mediates BCC regression is unknown. Here we used two genetically engineered mouse models of BCC4 to investigate the mechanisms by which inhibition of Smoothened mediates tumour regression. We found that vismodegib mediates BCC regression by inhibiting a hair follicle-like fate and promoting the differentiation of tumour cells. However, a small population of tumour cells persists and is responsible for tumour relapse following treatment discontinuation, mimicking the situation found in humans5. In both mouse and human BCC, this persisting, slow-cycling tumour population expresses LGR5 and is characterized by active Wnt signalling. Combining Lgr5 lineage ablation or inhibition of Wnt signalling with vismodegib treatment leads to eradication of BCC. Our results show that vismodegib induces tumour regression by promoting tumour differentiation, and demonstrates that the synergy between Wnt and Smoothened inhibitors is a clinically relevant strategy for overcoming tumour relapse in BCC.

Suggested Citation

  • Adriana Sánchez-Danés & Jean-Christophe Larsimont & Mélanie Liagre & Eva Muñoz-Couselo & Gaëlle Lapouge & Audrey Brisebarre & Christine Dubois & Mariano Suppa & Vijayakumar Sukumaran & Véronique del M, 2018. "A slow-cycling LGR5 tumour population mediates basal cell carcinoma relapse after therapy," Nature, Nature, vol. 562(7727), pages 434-438, October.
    • Handle: RePEc:nat:nature:v:562:y:2018:i:7727:d:10.1038_s41586-018-0603-3
    DOI: 10.1038/s41586-018-0603-3
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    Citations

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    Cited by:

    1. Daniel Haensel & Sadhana Gaddam & Nancy Y. Li & Fernanda Gonzalez & Tiffany Patel & Jeffrey M. Cloutier & Kavita Y. Sarin & Jean Y. Tang & Kerri E. Rieger & Sumaira Z. Aasi & Anthony E. Oro, 2022. "LY6D marks pre-existing resistant basosquamous tumor subpopulations," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Daniel Haensel & Bence Daniel & Sadhana Gaddam & Cory Pan & Tania Fabo & Jeremy Bjelajac & Anna R. Jussila & Fernanda Gonzalez & Nancy Yanzhe Li & Yun Chen & JinChao Hou & Tiffany Patel & Sumaira Aasi, 2023. "Skin basal cell carcinomas assemble a pro-tumorigenic spatially organized and self-propagating Trem2+ myeloid niche," Nature Communications, Nature, vol. 14(1), pages 1-22, December.

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