The Rho GTPase Rnd1 suppresses mammary tumorigenesis and EMT by restraining Ras-MAPK signalling

Abstract

SUMMARY We identified the Rho-GTPase Rnd1 as a candidate metastasis suppressor through bioinformatics analysis and showed that its depletion disrupt epithelial adhesion and polarity, induced Epithelial-to-Mesenchymal Transition (EMT), and cooperated with deregulated expression of c-Myc or loss of p53 to cause neoplastic conversion. Mechanistic studies revealed that Rnd1 suppresses Ras signalling by activating the GAP domain of Plexin B1, which inhibits Rap1. Rap1 inhibition in turn led to derepression of p120-RasGAP, which was able to inhibit Ras. Inactivation of Rnd1 in mammary epithelial cells induced highly undifferentiated and invasive tumors in mice. Conversely, Rnd1 expression inhibited spontaneous and experimental lung colonization in mouse models of metastasis. Genomic studies indicated that gene deletion in combination with epigenetic silencing or, more rarely, point mutation inactivates RND1 in human breast cancer. These results reveal a previously unappreciated mechanism through which Rnd1 restrains activation of Ras-MAPK signaling and breast tumor initiation and progression.

Sema3e/Plexin D1 Modulates Immunological Synapse and Migration of Thymocytes by Rap1 Inhibition

“…Although an in vitro study demonstrated an involvement of plexins and Rap1 GAP (20) in neural morphogenesis and tumor metastasis (20,44), other reports ruled out the involvement of Rap1 in sema3e/plexin D1 signaling because Rap1 activation was not detected in thymocytes (24). The failure of Choi and colleagues (24) to detect Rap1 activation at 30 min after chemokine stimulation was likely due to the fact that Rap1 activation had returned to basal levels.…”

Plexin-B1 signalling promotes androgen receptor translocation to the nucleus

“…18 Activation of the Rap1-GAP activity of plexin-B1 inhibits Ras-MAPK activity in triple-negative breast cancer. 19 The mechanism by which plexin-B1 contributes to cancer progression in each cancer type is therefore dependent on cellular context and on which plexin-B1 signalling pathways predominate in the tumour cell. 20 Plexin-B1 has also been implicated in prostate cancer: somatic missense mutations in the plexin-B1 gene and overexpression of the protein occur in prostate tumours.…”

Distinctive properties of metastasis-initiating cells

“…After tumor cells escape the primary site, the epigenome is subjected to microenvironmental signal modulation, conferring cellular plasticity and adaptability to new and inhospitable conditions (Seftor et al 2006;Hendrix et al 2007;Tam and Weinberg 2013). Indeed, multiple studies have unveiled evidence of specific epigenetic pathways involved in the metastatic progression of different cancer types (Cunha et al 2014;Gu et al 2015;Okada et al 2015;Tang et al 2015). Therefore, the combination of genetic and epigenetic events during the course of metastasis likely determines the acquisition of MIC traits.…”