Abstract 4991: RET and integrins cooperate in cell-microenvironment response

Abstract

Abstract The RET receptor tyrosine kinase is expressed in neural crest-derived cell types, where it is activated by soluble ligands of the Glial Cell-derived Neurotrophic Factor (GDNF) family and signals through multiple downstream pathways, contributing to cell growth, survival, and migration during embryonic development. In addition to its normal developmental roles, oncogenic mutations or aberrant expression of RET are also linked to tumour spread and metastasis in multiple human tumour types. Thus, a consistent feature of RET involvement in these disease processes is its contribution to directional cell motility. We have previously shown that RET-mediated cell-adhesion and migration requires multiple members of the integrin family of cell adhesion molecules, including integrin β1 (ITGB1) and β3 (ITGB3) subunits, however the regulation of cell migration and invasion by RET and integrins has not been explored. In this study, we showed that GDNF-mediated RET activation induced rapid ITGB1 and ITGB3 activation with transiently increased cell adhesion, followed by enhanced cell protrusion formation and reduced adhesion typical of more migratory cells. In addition, we showed that directional cell migration in response to GDNF requires the presence of both extracellular matrix and a GDNF concentration gradient. Our data also suggest that ITGB1 and ITGB3 play complementary but non-compensatory roles in the initiation of RET-mediated cell migration and invasion, and that the inhibition of either ITGB1 or ITGB3 resulted in impaired migration and invasion in both 2D and 3D culture conditions. We have also shown that multiple signaling pathways downstream of RET are involved in these processes and that these pathways contribute differently to migration in 2D vs 3D microenvironments. These data highlight the ability of tumour cells to leverage different signaling pathways to mediate cell migration and invasion downstream of RET, and reveal ways in which cooperation between RET and integrins might affect aspects of tumour progression. Our data, together with other studies which have shown combination therapy targeting integrins and RTKs to be more effective than monotherapy, suggest that adjuvant treatment with agents targeting integrin function may further enhance therapeutic options for tumours where RET is expressed. Citation Format: Eric Lian, Mathieu J.F. Crupi, Jessica G. Cockburn, Simona M. Wagner, Anirudh Goel, Lois M. Mulligan. RET and integrins cooperate in cell-microenvironment response. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4991. doi:10.1158/1538-7445.AM2015-4991