Reprogramming of stromal fibroblasts by SNAI2 contributes to tumor desmoplasia and ovarian cancer progression

Molecular Cancer

Research

Kecheng Huang¹  Sen Xu¹  Xin Yang¹  Dan Liu¹  Junbo Hu¹  Gang Chen¹  Sixiang Long¹  Chaoyang Sun¹  Xiaoting Li¹  Qinglei Gao¹  Xiao Wei¹  Ding Ma¹  Zongyuan Yang¹  Ping Jin¹  Ya Wang¹  Li Meng² 

[1] Cancer Biology Research Center (Key laboratory of the ministry of education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Anv., 430030, Wuhan, Hubei, China;Department of hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China;

关键词: SNAI2;    Stromal fibroblast;    Reprogram;    Stiffness;    Ovarian cancer;   

DOI  :  10.1186/s12943-017-0732-6

 received in 2017-05-29, accepted in 2017-10-13,  发布年份 2017

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© The Author(s). 2017