The extracellular matrix dictates regional competence for tumour initiation

Nordin Bansaccal, Pauline Vieugue, Rahul Sarate, Yura Song, Esmeralda Minguijon, Yekaterina A. Miroshnikova, Dagmar Zeuschner, Amandine Collin, Justine Allard, Dan Engelman, Anne-Lise Delaunois, Mélanie Liagre, Leona Groote, Evy Timmerman, Delphi Haver, Francis Impens, Isabelle Salmon, Sara A. Wickström, Alejandro Sifrim and Cédric Blanpain ()
Additional contact information
Nordin Bansaccal: Université Libre de Bruxelles
Pauline Vieugue: Université Libre de Bruxelles
Rahul Sarate: Université Libre de Bruxelles
Yura Song: Université Libre de Bruxelles
Esmeralda Minguijon: CUB Hôpital Erasme, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles (ULB)
Yekaterina A. Miroshnikova: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
Dagmar Zeuschner: Max Planck Institute for Molecular Biomedicine
Amandine Collin: Université Libre de Bruxelles (ULB)
Justine Allard: Université Libre de Bruxelles (ULB)
Dan Engelman: Université Libre de Bruxelles
Anne-Lise Delaunois: Université Libre de Bruxelles
Mélanie Liagre: Université Libre de Bruxelles
Leona Groote: Université Libre de Bruxelles
Evy Timmerman: Ghent University
Delphi Haver: Ghent University
Francis Impens: Ghent University
Isabelle Salmon: CUB Hôpital Erasme, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles (ULB)
Sara A. Wickström: Max Planck Institute for Molecular Biomedicine
Alejandro Sifrim: KU Leuven
Cédric Blanpain: Université Libre de Bruxelles

Nature, 2023, vol. 623, issue 7988, 828-835

Abstract: Abstract The skin epidermis is constantly renewed throughout life1,2. Disruption of the balance between renewal and differentiation can lead to uncontrolled growth and tumour initiation3. However, the ways in which oncogenic mutations affect the balance between renewal and differentiation and lead to clonal expansion, cell competition, tissue colonization and tumour development are unknown. Here, through multidisciplinary approaches that combine in vivo clonal analysis using intravital microscopy, single-cell analysis and functional analysis, we show how SmoM2—a constitutively active oncogenic mutant version of Smoothened (SMO) that induces the development of basal cell carcinoma—affects clonal competition and tumour initiation in real time. We found that expressing SmoM2 in the ear epidermis of mice induced clonal expansion together with tumour initiation and invasion. By contrast, expressing SmoM2 in the back-skin epidermis led to a clonal expansion that induced lateral cell competition without dermal invasion and tumour formation. Single-cell analysis showed that oncogene expression was associated with a cellular reprogramming of adult interfollicular cells into an embryonic hair follicle progenitor (EHFP) state in the ear but not in the back skin. Comparisons between the ear and the back skin revealed that the dermis has a very different composition in these two skin types, with increased stiffness and a denser collagen I network in the back skin. Decreasing the expression of collagen I in the back skin through treatment with collagenase, chronic UV exposure or natural ageing overcame the natural resistance of back-skin basal cells to undergoing EHFP reprogramming and tumour initiation after SmoM2 expression. Altogether, our study shows that the composition of the extracellular matrix regulates how susceptible different regions of the body are to tumour initiation and invasion.

Date: 2023
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DOI: 10.1038/s41586-023-06740-y

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