Turku Centre for Biotechnology

University of Turku


Cell Adhesion and Cancer

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.

Filopodia and Myosin-X in Cancer Cell Invasion

Introduction:Cell invasion through the stroma and the formation of metastases is the principal cause of death in patients with solid tumours. Our aim is to understand the specific pro-invasive cellular machinery that facilitate cancer cell migration and invasion.

Filopodia are actin-rich microspikes that project out from the cell cytoplasm and extend beyond the lamellipodia or the leading edge in migrating cells. Myosin-X (also known as Myo10) is the unconventional member of the myosin family of actin motor proteins as it contains plekstrin homolgy domains (PH) that are absent in all other family members. Mysoin-X is ubiquitously expressed in mammalian tissues and transports cargo to filopodial tips and regulates filopodia formation.

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