A cell identity switch allows residual BCC to survive Hedgehog pathway inhibition
Abstract
Despite the efficacy of Hedgehog pathway inhibitors in the treatment of basal cell carcinoma (BCC)1, residual disease persists in some patients and may contribute to relapse when treatment is discontinued 2. Here, to study the effect of the Smoothened inhibitor vismodegib on tumour clearance, we have used a Ptch1-Trp53 mouse model of BCC 3 and found that mice treated with vismodegib harbour quiescent residual tumours that regrow upon cessation of treatment. Profiling experiments revealed that residual BCCs initiate a transcriptional program that closely resembles that of stem cells of the interfollicular epidermis and isthmus, whereas untreated BCCs are more similar to the hair follicle bulge. This cell identity switch was enabled by a mostly permissive chromatin state accompanied by rapid Wnt pathway activation and reprogramming of super enhancers to drive activation of key transcription factors involved in cellular identity. Accordingly, treatment of BCC with both vismodegib and a Wnt pathway inhibitor reduced the residual tumour burden and enhanced differentiation. Our study identifies a resistance mechanism in which tumour cells evade treatment by adopting an alternative identity that does not rely on the original oncogenic driver for survival.
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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 [46]
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 [46]
In basal cell carcinoma, comparison of genome-wide chromatin accessibility profiles in drug-naive and residual tumor cells after hedgehog pathway inhibition revealed that regions of increased chromatin accessibility in residual cells were enriched for transcription factor-binding motifs, including SOX family transcription factors that regulate stem and progenitor cell fate.
“In basal cell carcinoma (BCC), comparison of genome-wide chromatin accessibility profiles in drug-naive and residual tumor cells after hedgehog pathway inhibition revealed that regions of increased chromatin accessibility in residual cells were enriched for transcription factor-binding motifs, including SOX family transcription factors that regulate stem and progenitor cell fate [46].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [46]
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- Authors
- Biehs, B., Dijkgraaf, G. J. P., Piskol, R., Alicke, B., Boumahdi, S., Peale, F., Gould, S. E., & de Sauvage, F. J.
- Affiliations
- Genentech (US)
- Venue
- Nature
- Published
- 2018-10
- Volume
- 562
- Issue
- 7727
- Pages
- 429-433
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2895619213
- Cited by
- 137
- References
- 51
- Citations by year
- 2026: 4 · 2025: 15 · 2024: 15 · 2023: 18 · 2022: 18 · 2021: 31 · 2020: 16 · 2019: 17 · 2018: 3
- FWCI
- 6.05
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Health Sciences › Medicine › Epidemiology › Nonmelanoma Skin Cancer Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Keywords
- basal cell carcinoma, Hedgehog pathway inhibition, vismodegib, Smoothened inhibitors, treatment resistance, residual tumor, super-enhancers, chromatin state, hair follicle bulge, tumor recurrence, epidermal stem cells
- MeSH terms
- Smoothened Receptor, Epidermal Cells, Anilides, Animals, Basal Cell Carcinoma, Carcinoma, Basal Cell, Cell Differentiation, Humans, Pyridines, Skin Neoplasms, Stem Cells, Signal Transduction, Hair Follicle, Cell Proliferation, Mice, Hedgehog Proteins, Wnt Signaling Pathway
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