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Translational Therapeutics

Cytochrome P450 1B1 polymorphism drives cancer cell stemness and patient outcome in head-and-neck carcinoma

Subjects

Abstract

Background

Cytochrome P450 1B1 (CYP1B1) is mostly expressed in tumours and displays unusual properties. Its two polymorphic forms were differently associated with anticancer drug sensitivity. We decipher here the role of this polymorphism in anticancer drug efficacy in vitro, in vivo and in the clinical setting.

Methods

From head-and-neck squamous cell carcinoma cell lines not expressing CYP1B1, we generated isogenic derivatives expressing the two forms. Proliferation, invasiveness, stem cell characteristics, sensitivity to anticancer agents and transcriptome were analysed. Tumour growth and chemosensitivity were studied in vivo. A prospective clinical trial on 121 patients with advanced head-and-neck cancers was conducted, and a validation-retrospective study was conducted.

Results

Cell lines expressing the variant form displayed high rates of in vitro proliferation and invasiveness, stemness features and resistance to DNA-damaging agents. In vivo, tumours expressing the variant CYP1B1 had higher growth rates and were markedly drug-resistant. In the clinical study, overall survival was significantly associated with the genotypes, wild-type patients presenting a longer median survival (13.5 months) than the variant patients (6.3 months) (p = 0.0166).

Conclusions

This frequent CYP1B1 polymorphism is crucial for cancer cell proliferation, migration, resistance to chemotherapy and stemness properties, and strongly influences head-and-neck cancer patients’ survival.

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Fig. 1: Proliferation and migration capacity of the isogenic CYP1B1 cell lines.
Fig. 2: Cytotoxicity profiles of the isogenic cell lines.
Fig. 3: In vivo tumour growth of isogenic cell lines in immunodeficient mice.
Fig. 4: Drug-induced tumour growth inhibition of CAL27-derived isogenic cell lines in immunodeficient mice.
Fig. 5: Stemness characteristics of CAL27 CYP1B1-WT and CYP1B1-VAR cells.
Fig. 6: Survival curves of advanced head-and-neck cancer patients treated with chemotherapy plus cetuximab.

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Acknowledgements

We are grateful to Dr Laurence Bresson-Bepoldin and Dr Frédéric Delom for their kind support during the preparation of the paper. We are indebted to Prof Jean-Pierre Delord for his implication in the clinical validation study.

Author information

Affiliations

Authors

Contributions

V.L.M. and J.R. designed the experiments and evaluated and interpreted the results. V.L.M. and A.La generated the isogenic cell lines. V.L.M. conducted most of the experiments and supervised those realised by younger scientists, M.C. and L.B.B. C.A. and D.F. realised part of the in vitro experiments. E.R. conducted all in vivo experiments. A.P. conducted the original prospective clinical trial that was analysed and validated by S.M.P. A.M. and A.Lu identified the patients and samples of the retrospective clinical validation study. V.L.M. and J.R. conceived and designed the project, planned the experiments, prepared the figures and wrote the paper with the help of D.F.

Corresponding author

Correspondence to Jacques Robert.

Ethics declarations

Ethics approval and consent to participate

CAL27 and CAL33 HNSCC cell lines were kindly provided by Dr J.L. Fischel (Centre Antoine Lacassagne, Nice, France, where they were initially obtained). They were authenticated by Azur Génétique (Nice, France) as identical to the corresponding DSMZ cell lines (report reference AGLC-14-00225). The study was approved by the local ethical committee (Comité de Protection des Personnes de Bordeaux), and written informed consent was provided by all the participants after a full explanation of the study was given to them. This study was performed in accordance with the Declaration of Helsinki and was registered under ref. NCT-01827956.

Consent to publish

Not applicable.

Data availability

Raw results of the RNA-seq are available on the Annotare platform (ArrayExpress accession #E-MTAB-8512).

Competing interests

The authors declare no competing interests.

Funding information

This work was made possible through grants from the Ligue Nationale contre le Cancer (comité des Landes) and from GEFLUC-Aquitaine.

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Morvan, V.L., Richard, É., Cadars, M. et al. Cytochrome P450 1B1 polymorphism drives cancer cell stemness and patient outcome in head-and-neck carcinoma. Br J Cancer 123, 772–784 (2020). https://doi.org/10.1038/s41416-020-0932-5

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