A slow-cycling LGR5 tumour population mediates basal cell carcinoma relapse after therapy
Open accessAbstract
Basal cell carcinoma (BCC) is the most frequent cancer in humans and results from constitutive activation of the Hedgehog pathway 1. Several Smoothened inhibitors are used to treat Hedgehog-mediated malignancies, including BCC and medulloblastoma 2. Vismodegib, a Smoothened inhibitor, leads to BCC shrinkage in the majority of patients with BCC 3, but the mechanism by which it mediates BCC regression is unknown. Here we used two genetically engineered mouse models of BCC 4 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 humans 5. 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.
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In vivo models have shown similar drug-tolerant slow-cycling persister cells.
“In vivo models have shown similar drug-tolerant slow-cycling persister cells.”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [47]
Drug-tolerant quiescent residual cells in basal cell carcinoma can cause relapse after treatment is stopped.
“Drug-tolerant quiescent residual cells in basal cell carcinoma (BCC) can cause relapse after treatment is stopped [46,47].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [47]
A slow-cycling LGR5+ tumor population promotes basal cell carcinoma (BCC) relapse after treatment with the Hedgehog pathway Smoothened inhibitor vismodegib in both mouse and human BCC.
“Sánchez-Danés et al. found that a slow-cycling LGR5+ tumor population promotes basal cell carcinoma (BCC) relapse after treatment with the Hedgehog (Hh) pathway Smoothened inhibitor vismodegib in both mouse and human BCC [47].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [47]
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- Authors
- Sánchez-Danés, A., Larsimont, J.-C., Liagre, M., Muñoz-Couselo, E., Lapouge, G., Brisebarre, A., Dubois, C., Suppa, M., Sukumaran, V., del Marmol, V., Tabernero, J., & Blanpain, C.
- Affiliations
- Université Libre de Bruxelles (BE)
- Universitat Autònoma de Barcelona (ES)
- Corresponding author
- Blanpain, Cédric
- ORCID
- Venue
- Nature
- Published
- 2018-10
- Volume
- 562
- Issue
- 7727
- Pages
- 434-438
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6295195
- OpenAlex
- W2895563925
- Cited by
- 139
- References
- 35
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 13 · 2023: 19 · 2022: 15 · 2021: 25 · 2020: 25 · 2019: 19 · 2018: 3
- FWCI
- 6.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion, other-oa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Epidemiology › Nonmelanoma Skin Cancer Studies
- Keywords
- basal cell carcinoma, vismodegib, Smoothened inhibitors, Lgr5, Wnt signaling, tumor recurrence, tumor differentiation, Hedgehog signaling, combination therapy
- MeSH terms
- Patched-1 Receptor, Smoothened Receptor, Anilides, Animals, Basal Cell Carcinoma, Cell Differentiation, Disease Models, Animal, Female, Humans, Male, Neoplasm Recurrence, Local, Pyridines, Recurrence, Skin Neoplasms, Hair Follicle, Cell Lineage, Withholding Treatment, Receptors, G-Protein-Coupled, Wnt Proteins, Mice, Hedgehog Proteins, Secondary Prevention, Wnt Signaling Pathway
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