AUTHOR=Sun Xianting , Fang Jianchen , Ye Fen , Zhang Shuxian , Huang Honghui , Hou Jian , Wang Ting 

TITLE=Diffuse Large B-Cell Lymphoma Promotes Endothelial-to-Mesenchymal Transition via WNT10A/Beta-Catenin/Snail Signaling

JOURNAL=Frontiers in Oncology

VOLUME=Volume 12 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.871788

DOI=10.3389/fonc.2022.871788

ISSN=2234-943X

ABSTRACT=Diffuse large B cell lymphoma (DLBCL) is one type of highly heterogeneous lymphoid malignancy with 30~40% patients experiencing treatment failure. Novel risk stratification and therapeutic approaches for DLBCL were urgently needed. Endothelial-to-mesenchymal transition (EndMT) which contributes to tumor angiogenesis, metastasis, drug resistance and cancer-associated fibroblasts generation has been detected in the microenvironment of many types of cancers. However, the existence of EndMT in hematological malignancies microenvironment remains unknown. Here, we identified the existence of EndMT in DLBCL-associated endothelial cells and the clinical relevance of EndMT markers in DLBCL, which was associated with advanced clinical stage and poor prognosis. In vitro experiments confirmed that DLBCL cells stimulated angiogenesis and EndMT of HUVECs. We further unveiled the molecular mechanisms underlying this process. We demonstrated that WNT10A, a WNT-family member overexpressed in DLBCL tissues and correlated with clinical features in DLBCL, promoted EndMT through glycogen synthase kinase 3β (GSK3β)/β-catenin/snail signaling. WNT10A inhibited the binding of GSK3β to β-catenin/snail, resulting in β-catenin and snail nuclear accumulation and target genes transcription. Silencing β-catenin and snail respectively attenuated WNT10A-induced angiogenesis and EndMT. Interplay between β-catenin-dependent and snail-dependent signaling was also confirmed in this study. Collectively, considering the significance of EndMT which has been previously described in tumor progression, these findings indicated that EndMT markers and WNT10A may serve as novel predictors of clinical outcome and identified the WNT10A/GSK3β/β-catenin/snail pathway as a potential therapeutic target in DLBCL.