RSPO2 promotes progression of ovarian cancer through dual receptor-mediated FAK/Src signaling activation

Rulu Pan; Yan Yu; Haiyan Zhu; Wenyi Zhang; Yuan Qin; Lin Ye; Juji Dai; Ren Huang; Xinyan Peng; Siqi Ye; Ziqi Lin; Shishun Huang; Shuyi Chong; Liting Lu; Xincheng Lu

doi:10.1016/j.isci.2022.105184

RSPO2 promotes progression of ovarian cancer through dual receptor-mediated FAK/Src signaling activation

iScience. 2022 Sep 23;25(10):105184. doi: 10.1016/j.isci.2022.105184. eCollection 2022 Oct 21.

Authors

Rulu Pan¹, Yan Yu², Haiyan Zhu³, Wenyi Zhang⁴, Yuan Qin¹, Lin Ye¹, Juji Dai⁵, Ren Huang¹, Xinyan Peng¹, Siqi Ye¹, Ziqi Lin¹, Shishun Huang¹, Shuyi Chong¹, Liting Lu¹, Xincheng Lu¹

Affiliations

¹ School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
² Clinical Laboratory, Yiwu Traditional Chinese Medicine Hospital, Yiwu 322000, China.
³ Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 200126, China.
⁴ Department of Radiotherapy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
⁵ Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.

Abstract

R-spondin 2 (RSPO2) drives the potentiation of Wnt signaling and is implicated in tumorigenesis in multiple cancers, but its role in ovarian cancer has not been investigated. Here, we reported that RSPO2 promoted the growth and metastasis of ovarian cancer through the activation of FAK/Src signaling cascades. RSPO2 enhanced the autophosphorylation of FAK and Src through a unique dual receptors mechanism. First, RSPO2-LGR4 interaction prevented the endocytic degradation of LGR4 and promoted LGR4-mediated translocation of Src to the plasma membrane. Second, RSPO2 directly bound to integrin β3 as a ligand and enhanced the stability of integrins, and both actions potentiated autoactivation of FAK and/or Src in ovarian cancer cells. RSPO2 expression was increased in ovarian tumors and was associated with poor prognosis in patients. Our study highlights the importance of RSPO2 in ovarian tumor progression and suggests that targeting RSPO2/FAK/Src cascades may constitute potential approaches to inhibit the progression of aggressive ovarian cancer.

Keywords: Cell biology; cancer.