Endothelial deletion of SHP2 suppresses tumor angiogenesis and promotes vascular normalization

• Published in: Nature communications 2021-11, Vol.12 (1), p.6310-6310, Article 6310
• Main Authors: Xu, Zhiyong, Guo, Chunyi, Ye, Qiaoli, Shi, Yueli, Sun, Yihui, Zhang, Jie, Huang, Jiaqi, Huang, Yizhou, Zeng, Chunlai, Zhang, Xue, Ke, Yuehai, Cheng, Hongqiang
• Format: Article
• Language: English
• Subjects: 13/1; 13/109; 13/21; 13/44; 13/89; 13/95; 14/19; 14/63; 38/109; 38/77; 38/88; 38/90; 631/80/86/2368; 64; 64/110; 64/60; 692/4028/67/2328; 692/4028/67/327; 82/80; 96/106; 96/34; Angiogenesis; Animal models; Animals; Antiangiogenics; Apoptosis; c-Jun protein; Cell migration; Cell Proliferation; Cells, Cultured; Clonal deletion; Deletion; Disease Models, Animal; Endothelial cells; Endothelial Cells - metabolism; Endothelial Cells - pathology; Humanities and Social Sciences; Humans; Kinases; MAP kinase; Mice; Mice, Knockout; Microvasculature; multidisciplinary; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Neovascularization, Pathologic - metabolism; Perfusion; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - deficiency; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism; Protein-tyrosine kinase receptors; Science; Science (multidisciplinary); Signal Transduction; Signaling; SOXF Transcription Factors - metabolism; Transcription factors; Tumors; Tyrosine; Vascular endothelial growth factor; Vascular endothelial growth factor receptors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-26697-8

SHP2 mediates the activities of multiple receptor tyrosine kinase signaling and its function in endothelial processes has been explored extensively. However, genetic studies on the role of SHP2 in tumor angiogenesis have not been conducted. Here, we show that SHP2 is activated in tumor endothelia. Shp2 deletion and pharmacological inhibition reduce tumor growth and microvascular density in multiple mouse tumor models. Shp2 deletion also leads to tumor vascular normalization, indicated by increased pericyte coverage and vessel perfusion. SHP2 inefficiency impairs endothelial cell proliferation, migration, and tubulogenesis through downregulating the expression of proangiogenic SRY-Box transcription factor 7 (SOX7), whose re-expression restores endothelial function in SHP2-knockdown cells and tumor growth, angiogenesis, and vascular abnormalization in Shp2 -deleted mice. SHP2 stabilizes apoptosis signal-regulating kinase 1 (ASK1), which regulates SOX7 expression mediated by c-Jun. Our studies suggest SHP2 in tumor associated endothelial cells is a promising anti-angiogenic target for cancer therapy. SHP2 regulates pro-angiogenic VEGF-VEGFR signalling, but its role in tumour angiogenesis is unclear. Here the authors show that endothelial cell-specific deletion of SHP2 impairs tumour growth and angiogenesis in syngeneic mouse models through ASK1-c-JunSOX7 signalling axis.