ZEB2 drives intra-tumor heterogeneity and skin squamous cell carcinoma formation with distinct EMP transition states

Jeroen Verstappe; Nicolas Skrypek; Jordy De Coninck; Bieke Soen; Joachim Taminau; Marianthi Tatari; Kenneth Bruneel; Nele Loret; Kato De Clercq; Caroline Van den Broecke; Koen Van De Vijver; Jo Van Dorpe; Jody Haigh; Bram De Craene; Steven Goossens; Niels Vandamme; Geert Berx

doi:10.1016/j.isci.2024.111169

ZEB2 drives intra-tumor heterogeneity and skin squamous cell carcinoma formation with distinct EMP transition states

iScience. 2024 Oct 16;27(11):111169. doi: 10.1016/j.isci.2024.111169. eCollection 2024 Nov 15.

Authors

Jeroen Verstappe^{1

2}, Nicolas Skrypek^{1

2}, Jordy De Coninck^{1

2

3}, Bieke Soen^{1

2}, Joachim Taminau^{1

2}, Marianthi Tatari^{1

2}, Kenneth Bruneel^{1

2}, Nele Loret^{1

2}, Kato De Clercq^{1

2}, Caroline Van den Broecke^{4

5}, Koen Van De Vijver^{2

6

4

7}, Jo Van Dorpe^{2

4}, Jody Haigh^{8

9}, Bram De Craene^{1

2}, Steven Goossens^{2

10}, Niels Vandamme^{1

2

3

11}, Geert Berx^{1

2}

Affiliations

¹ Molecular and Cellular Oncology Laboratory, Department of Biomedical Molecular Biology, Ghent University, Technologiepark 71, 9052 Ghent, Belgium.
² Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
³ VIB Single Cell Core, VIB, Ghent-Leuven, Belgium.
⁴ Department of Pathology, Ghent Unviversity Hospital, Ghent, Belgium.
⁵ AZ Sint-Lucas Gent, Ghent, Belgium.
⁶ Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
⁷ Department of Pathology, Antwerp University Hospital, Antwerp, Belgium.
⁸ Department of Pharmacology and Therapeutics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
⁹ Paul Albrechtsen Research Institute, CancerCare Manitoba, Winnipeg, MB, Canada.
¹⁰ Department of Diagnostic Sciences, Ghent University, Ghent, Belgium.
¹¹ VIB-UGent Center for Inflammation Research, Technologiepark 71, 9052 Ghent, Belgium.

Abstract

About 5% of patients with cutaneous squamous cell carcinoma (cSCC) have a poor prognosis which is associated with a loss of tumor differentiation, invasion and metastasis, all of which are linked to the process of epithelial-to-mesenchymal plasticity (EMP). Here, we showed that the EMP-associated transcription factor ZEB2 drives cSCC heterogeneity which resembles biphasic carcinosarcoma-like tumors. Single cell RNA sequencing revealed distinct subpopulations ranging from fully epithelial (E) to intermediate (EM) to fully mesenchymal (M), associated with the gradual loss of cell surface markers EPCAM, CDH1, ITGB4, and CD200. Mesenchymal features were associated with a higher metastatic capacity and anoikis resistance, yet this comes with a sensitivity toward TNF-induced cell death. Altogether we provide insights in cSCC heterogeneity and modes to target mesenchymal-metastasis inducing cells.

Keywords: Cancer; Cell biology; Molecular biology.