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Extraction of a Stromal Metastatic Gene Signature in Breast Cancer via Spatial Profiling

ABSTRACT: The identification of molecular characteristics that define metastatic disease is a primary research focus across numerous types of malignancies. Understanding the mechanisms that drive metastatic foci, which diverge significantly from the biology of primary tumors, and identifying new biomarkers specifically associated with metastatic disease, is of critical importance in oncology. Consequently, the characterization of the stroma associated with metastatic foci has been largely unexplored and remains an area requiring significant investigation. We identified a detailed transcriptional profile of the stromal compartment within primary tumors and corresponding metastatic foci using spatially resolved approaches. The identified stromal Met signature may serve as a prognostic biomarker and provide insights into the molecular mechanisms underlying the metastatic potential of the tumor microenvironment.

ORGANISM(S): Mus musculus

PROVIDER: GSE273439 | GEO | 2024/08/04

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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Extraction of a Stromal Metastatic Gene Signature in Breast Cancer via Spatial Profiling

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