Left panel: Cell invasion movie (green, Life-Act; Red, fibronectin). Right panel: Microscopy image showing Myosin-X (GFP) decorating the tips of filopodia (Life-Act RFP).
murine models of cancer metastasis (see Publications; Arjonen et al. 2014). Disrupting the myosin-X integrin-binding domain (in the FERM domain, see diagram below) revealed that the ability of myosin-X to transport β₁ integrins to the filopodia tips is crucial for invasion. Moreover, a p53-mutant resulting in myosin-X overexpression promotes cell invasion.
(A) Functional domains of myosin-X. Myosin-X is composed of a motor domain, three IQ motifs, three PH domains (1a/b, 2 and 3), a myosin tail homology 4 (MyTH4) and a band 4.1, ezrin, radixin, moesin (FERM) domain important for protein binding. (B-D) Myosin-X activation. Full activation of myosin-X is dependent on PH domain-PIP3 interaction (C) and protein dimerisation (D).
We are now investigating the role of myosin-X in promoting cell invasion by screening for novel binding partners and by introducing specific mutations in different myosin-X domains. We are also continuing to gain a more in-depth understanding of filopodia and their regulators using a combination of mass-spectrometric, drug and siRNA screens, to identify novel regulators of filopodia formation. We are now in the process of validating and investigating the contribution of these filopodia-associated proteins to the metastatic process both in vitro and in vivo. and believe that this multi-pronged approach in studying filopodia and invasive machineries could underpin the development of valuable therapeutic strategies to target cancer cell metastases.
Our research: We recently observed that invasive cell migration is associated with the development of dense filopodia at the cell front and that myosin-X, a key regulator of filopodia formation, is required for cell invasion in 3D microenvironments and in vivo. Through analysis of breast cancer gene expression profiles we revealed that myosin-X is highly expressed in aggressive cancer subtypes. We further demonstrated that myosin-X is required for breast cancer cell invasion and tumour dissemination in multiple cancer cell lines and in