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

Adriana Sánchez-Danés, Jean-Christophe Larsimont, Mélanie Liagre, Eva Muñoz-Couselo, Gaëlle Lapouge, Audrey Brisebarre, Christine Dubois, Mariano Suppa, Vijayakumar Sukumaran, Véronique del Marmol, Josep Tabernero and Cédric Blanpain ()
Additional contact information
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
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
Cédric Blanpain: Université Libre de Bruxelles

Nature, 2018, vol. 562, issue 7727, 434-438

Abstract: 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.

Keywords: Basal Cell Carcinoma (BCC); Vismodegib Treatment; Smoothened Inhibitor; Hair Follicle Stem Cells (HFSC); HFSC Marker (search for similar items in EconPapers)
Date: 2018
References: Add references at CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41586-018-0603-3 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:562:y:2018:i:7727:d:10.1038_s41586-018-0603-3

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-018-0603-3

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().