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

ABSTRACT: Poor prognosis in cutaneous squamous cell carcinoma (cSCC) stems from poor 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 different subpopulations ranging from fully epithelial (E) to intermediate (EM) to fully mesenchymal (M) which was associated with the graded 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 towards TNF-induced cell death. Altogether we provide insights in cSCC heterogeneity and modes to target mesenchymal- metastasis inducing cells

ORGANISM(S): Mus musculus

PROVIDER: GSE265908 | GEO | 2024/10/22

REPOSITORIES: GEO

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Project description:Background Oral squamous cell carcinoma (OSCC), an HPV-negative head and neck cancer, frequently metastasizes to the regional lymph nodes but only occasionally beyond. Initial phases of metastasis are associated with an epithelial–mesenchymal transition (EMT), while the consolidation phase is associated with mesenchymal–epithelial transition (MET). This dynamic is referred to as epithelial–mesenchymal plasticity (EMP). While it is known that EMP is essential for cancer cell invasion and metastatic spread, less is known about the heterogeneity of EMP states and even less about the heterogeneity between primary and metastatic lesions. Methods To assess both the heterogeneity of EMP states in OSCC cells and their effects on stromal cells, we performed single-cell RNA sequencing (scRNAseq) of 5 primary tumors, 9 matching metastatic and 5 tumor-free lymph nodes and re-analyzed publicly available scRNAseq data of 9 additional primary tumors. For examining the cell type composition, we performed bulk transcriptome sequencing. Protein expression of selected genes were confirmed by immunohistochemistry. Results From the 23 OSCC lesions, the single cell transcriptomes of a total of 7263 carcinoma cells were available for in-depth analyses. We initially focused on one lesion to avoid confounding inter-patient heterogeneity and identified OSCC cells expressing genes characteristic of different epithelial and partial EMT stages. RNA velocity and the increase in inferred copy number variations indicated a progressive trajectory towards epithelial differentiation in this metastatic lesion, i.e., cells likely underwent MET. Extension to all samples revealed a less stringent but essentially similar pattern. Interestingly, MET cells show increased activity of the EMT-activator ZEB1. Immunohistochemistry confirmed that ZEB1 was co-expressed with the epithelial marker cornifin B in individual tumor cells. The lack of E-cadherin mRNA expression suggests this is a partial MET. Within the tumor microenvironment we found immunomodulating fibroblasts that were maintained in primary and metastatic OSCC. Conclusions This study reveals that EMP enables different partial EMT and epithelial phenotypes of OSCC cells, which are endowed with capabilities essential for the different stages of the metastatic process, including maintenance of cellular integrity. During MET, ZEB1 appears to be functionally active, indicating a more complex role of ZEB1 than mere induction of EMT.

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

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