title: L-type calcium channels regulate filopodia stability and cancer cell invasion downstream of integrin signalling.
abstract: Mounting in vitro, in vivo and clinical evidence suggest an important role for filopodia in driving cancer cell invasion. Using a high-throughput microscopic-based drug screen, we identify FDA-approved calcium channel blockers (CCBs) as potent inhibitors of filopodia formation in cancer cells. Unexpectedly, we discover that L-type calcium channels are functional and frequently expressed in cancer cells suggesting a previously unappreciated role for these channels during tumorigenesis. We further demonstrate that, at filopodia, L-type calcium channels are activated by integrin inside-out signalling, integrin activation and Src. Moreover, L-type calcium channels promote filopodia stability and maturation into talin-rich adhesions through the spatially restricted regulation of calcium entry and subsequent activation of the protease calpain-1. Altogether we uncover a novel and clinically relevant signalling pathway that regulates filopodia formation in cancer cells and propose that cycles of filopodia stabilization, followed by maturation into focal adhesions, directs cancer cell migration and invasion.
authors.affiliation: Turku Centre for Biotechnology, University of Turku, FIN-20520 Turku, Finland.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Jacquemet
authors.affiliation: Turku Centre for Biotechnology, University of Turku, FIN-20520 Turku, Finland.
authors.forename: Habib
authors.initials: H
authors.lastname: Baghirov
authors.affiliation: Turku Centre for Biotechnology, University of Turku, FIN-20520 Turku, Finland.
authors.forename: Maria
authors.initials: M
authors.lastname: Georgiadou
authors.affiliation: Laboratory of Molecular Oncology, Translational Cancer Biology program, University of Helsinki, FIN-00290 Helsinki, Finland.
authors.forename: Harri
authors.identifier: 0000-0001-5265-5509
authors.initials: H
authors.lastname: Sihto
authors.affiliation: Turku Centre for Biotechnology, University of Turku, FIN-20520 Turku, Finland.
authors.forename: Emilia
authors.initials: E
authors.lastname: Peuhu
authors.affiliation: Turku Centre for Biotechnology, University of Turku, FIN-20520 Turku, Finland.
authors.forename: Pierre
authors.initials: P
authors.lastname: Cettour-Janet
authors.affiliation: VTT Medical Biotechnology, Technical Research Centre of Finland, FIN-20520 Turku, Finland.
authors.forename: Tao
authors.initials: T
authors.lastname: He
authors.affiliation: VTT Medical Biotechnology, Technical Research Centre of Finland, FIN-20520 Turku, Finland.
authors.forename: Merja
authors.initials: M
authors.lastname: Perälä
authors.affiliation: Department of Pathology, University of Turku and Turku University Hospital, FIN-20520 Turku, Finland.
authors.forename: Pauliina
authors.initials: P
authors.lastname: Kronqvist
authors.affiliation: Laboratory of Molecular Oncology, Translational Cancer Biology program, University of Helsinki, FIN-00290 Helsinki, Finland.|Department of Oncology, Helsinki University Hospital, FIN-00290 Helsinki, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Joensuu
authors.affiliation: Turku Centre for Biotechnology, University of Turku, FIN-20520 Turku, Finland.|Department of Biochemistry, University of Turku, FIN-20520 Turku, Finland.
authors.forename: Johanna
authors.identifier: 0000-0002-6295-6556
authors.initials: J
authors.lastname: Ivaska
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D002154:Calpain / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016023:Integrins / Q000502:physiology*; D051379:Mice; D009218:Myosins / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D011554:Pseudopodia / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D020746:Calcium Channels, L-Type; D016023:Integrins; C498718:MYO10 protein, human; D002154:Calpain; D009218:Myosins