Abstract 2720: The GPC3 metastasis suppressor induces the activation of p38 MAPK signaling pathway promoting dormancy at the secondary organ

Abstract GPC3 is a proteoglycan involved in the control of proliferation and survival, which has been linked to cancer. In this respect, we previously demonstrated that normal breast tissues exhibit high levels of GPC3, while its expression is diminished in tumors. However, the role of the GPC3 downregulation in breast tumor progression and its molecular and cellular operational mechanisms are not fully understood. In this study we showed that GPC3 reverts the epithelial-to-mesenchymal transition (EMT) underwent by mammary tumor cells, blocks metastatic dissemination and induces dormancy at secondary site. Using genetically modified murine breast cancer cell sublines, we demonstrated that the phospho-Erk/phospho-p38 ratio is lower in GPC3 reexpressing cells, while p21, p27 and SOX2 levels are higher, suggesting a dormant phenotype. In vivo metastasis assays confirmed that GPC3 reexpressing cells reduce their metastatic ability. Interestingly, the presence of dormant cells was evidenced in the lungs of inoculated mice. Dormant cells could reactivate their proliferative capacity, remain viable as well as tumorigenic, but they reentered in dormancy upon reaching secondary site. We also proved that GPC3 inhibits metastasis through the p38 MAPK signaling pathway activation. The in vivo treatment with a pharmacological inhibitor of p38 induced an increase in cell invasion of orthotopic tumors reexpressing GPC3, as well as in spontaneous and experimental metastatic dissemination. In conclusion, our study shows that GPC3 returns mesenchymal-like breast cancer cells to an epithelial phenotype, impairing in vivo metastasis and inducing tumor dormancy through p38 MAPK signaling activation. These results help to identify the genetic determinants of dormancy and suggest the translational potential of research focusing in GPC3. Citation Format: Magali Delgado Pastore, Macarena Guereño, Ana C. Lugones, Maria G. Peters. The GPC3 metastasis suppressor induces the activation of p38 MAPK signaling pathway promoting dormancy at the secondary organ [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2720.