Activating Mutation of SHP2 Establishes a Tumorigenic Phonotype Through Cell-Autonomous and Non-Cell-Autonomous Mechanisms

• Main Authors: Lei Dong, Da Han, Xinyi Meng, Mengchuan Xu, Chuwen Zheng, Qin Xia
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2021-03-01
• Series: Frontiers in Cell and Developmental Biology
• Subjects: SHP2 mutation; tumor; cell-autonomous/non-cell autonomous mechanisms; SHP2 inhibition; tumor microenvironment
• Online Access: https://www.frontiersin.org/articles/10.3389/fcell.2021.630712/full

Gain-of-function mutation of SHP2 is a central regulator in tumorigenesis and cancer progression through cell-autonomous mechanisms. Activating mutation of SHP2 in microenvironment was identified to promote cancerous transformation of hematopoietic stem cell in non-autonomous mechanisms. It is interesting to see whether therapies directed against SHP2 in tumor or microenvironmental cells augment antitumor efficacy. In this review, we summarized different types of gain-of-function SHP2 mutations from a human disease. In general, gain-of-function mutations destroy the auto-inhibition state from wild-type SHP2, leading to consistency activation of SHP2. We illustrated how somatic or germline mutation of SHP2 plays an oncogenic role in tumorigenesis, stemness maintenance, invasion, etc. Moreover, the small-molecule SHP2 inhibitors are considered as a potential strategy for enhancing the efficacy of antitumor immunotherapy and chemotherapy. We also discussed the interconnection between phase separation and activating mutation of SHP2 in drug resistance of antitumor therapy.