Abstract
BackgroundMolecular profiling in ovarian cancer (OC) revealed that the desmoplasia subtype presented the poorest prognosis, highlighting the contribution of stromal fibroblasts in tumor progression. This study aimed to investigate the molecular characteristics of SNAI2 driving the transcriptional reprogramming of fibroblasts within tumors.MethodsSNAI2 expression was evaluated in microdissected profiles of various cancers and in various molecular subtypes of OC. Gene set enrichment analysis (GSEA) and single sample GSEA (ssGSEA) were performed to explore the correlation between SNAI2 and stromal fibroblast activation. The SNAI2 defined signature in the mesenchymal OC subtype was identified through an integrative analysis of the TCGA and the Tothill datasets. The predictive value of this signature was validated in independent datasets. SNAI2 expression alteration influence of tumor growth in primary CAFs was evaluated in 3D organotypic and murine xenograft models.ResultsWe demonstrated that SNAI2 was frequently activated in the tumor stroma, correlated with fibroblast activation and worse patient outcome in OC. SNAI2 transformed normal fibroblasts to a CAF-like state and boosted their tumor–supporting role in 3D organotypic culture and in OC xenograft model. SNAI2 drove a transcriptional signature in the mesenchymal subtype of OC that contributed to tumor desmoplasia, which fed back to increase SNAI2 expression and sustain fibroblast activation.ConclusionsOur results address the role of SNAI2 in reprogramming stromal fibroblasts. The identified SNAI2 mesenchymal signature has both a predictive value and biological relevance and might be a therapeutic target for stroma-oriented therapy against the desmoplasia OC subtype.
Highlights
Molecular profiling in ovarian cancer (OC) revealed that the desmoplasia subtype presented the poorest prognosis, highlighting the contribution of stromal fibroblasts in tumor progression
Snail family zinc finger 2 (SNAI2) is overexpressed in OC stroma and associated with poor survival To explore the expression pattern of SNAI2 in epithelial OC, we analyzed a microdissected profile of OC and found that SNAI2 was decreased in the tumor epithelium and was elevated in the tumor stroma, compared with their normal counterparts (Fig. 1a)
Our observations suggest that the inhibition of SNAI2 and the regulated mesenchymal signature to target stromal activation could be a potential approach in targeting the cooperative tumor stroma of OC
Summary
Molecular profiling in ovarian cancer (OC) revealed that the desmoplasia subtype presented the poorest prognosis, highlighting the contribution of stromal fibroblasts in tumor progression. Even though the reciprocal interactions between cancer cells and fibroblasts has been extensively described, it is still currently unclear how quiescent fibroblasts are reprogrammed into CAFs [12, 13]. In this scenario, a thorough understanding of the regulatory basis underlying fibroblast activation could aid in the development of stromal fibroblast-oriented strategies against the fibrotic subtype of OC
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