L-type calcium channels regulate filopodia stability and cancer cell invasion downstream of integrin signalling

Guillaume Jacquemet (Corresponding Author), Habib Baghirov, Maria Georgiadou, Harri Sihto, Emilia Peuhu, Pierre Cettour-Janet, Tao He, Merja Perälä, Pauliina Kronqvist, Heikki Joensuu, Johanna Ivaska (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

32 Citations (Scopus)

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.
Original languageEnglish
Article number13297
JournalNature Communications
Volume7
DOIs
Publication statusPublished - 2016
MoE publication typeA1 Journal article-refereed

Fingerprint

L-Type Calcium Channels
Pseudopodia
Integrins
calcium
cancer
Cells
Neoplasms
adhesion
Adhesion
Chemical activation
Talin
activation
protease
Calpain
Calcium Channel Blockers
mounting
Focal Adhesions
Mountings
entry
inhibitors

Keywords

  • breast cancer
  • cell invasion
  • integrins

Cite this

Jacquemet, G., Baghirov, H., Georgiadou, M., Sihto, H., Peuhu, E., Cettour-Janet, P., ... Ivaska, J. (2016). L-type calcium channels regulate filopodia stability and cancer cell invasion downstream of integrin signalling. Nature Communications, 7, [13297]. https://doi.org/10.1038/ncomms13297
Jacquemet, Guillaume ; Baghirov, Habib ; Georgiadou, Maria ; Sihto, Harri ; Peuhu, Emilia ; Cettour-Janet, Pierre ; He, Tao ; Perälä, Merja ; Kronqvist, Pauliina ; Joensuu, Heikki ; Ivaska, Johanna. / L-type calcium channels regulate filopodia stability and cancer cell invasion downstream of integrin signalling. In: Nature Communications. 2016 ; Vol. 7.
@article{b1154e7e23a04c08be866a6a3b557507,
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.",
keywords = "breast cancer, cell invasion, integrins",
author = "Guillaume Jacquemet and Habib Baghirov and Maria Georgiadou and Harri Sihto and Emilia Peuhu and Pierre Cettour-Janet and Tao He and Merja Per{\"a}l{\"a} and Pauliina Kronqvist and Heikki Joensuu and Johanna Ivaska",
year = "2016",
doi = "10.1038/ncomms13297",
language = "English",
volume = "7",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

}

Jacquemet, G, Baghirov, H, Georgiadou, M, Sihto, H, Peuhu, E, Cettour-Janet, P, He, T, Perälä, M, Kronqvist, P, Joensuu, H & Ivaska, J 2016, 'L-type calcium channels regulate filopodia stability and cancer cell invasion downstream of integrin signalling', Nature Communications, vol. 7, 13297. https://doi.org/10.1038/ncomms13297

L-type calcium channels regulate filopodia stability and cancer cell invasion downstream of integrin signalling. / Jacquemet, Guillaume (Corresponding Author); Baghirov, Habib; Georgiadou, Maria; Sihto, Harri; Peuhu, Emilia; Cettour-Janet, Pierre; He, Tao; Perälä, Merja; Kronqvist, Pauliina; Joensuu, Heikki; Ivaska, Johanna (Corresponding Author).

In: Nature Communications, Vol. 7, 13297, 2016.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - L-type calcium channels regulate filopodia stability and cancer cell invasion downstream of integrin signalling

AU - Jacquemet, Guillaume

AU - Baghirov, Habib

AU - Georgiadou, Maria

AU - Sihto, Harri

AU - Peuhu, Emilia

AU - Cettour-Janet, Pierre

AU - He, Tao

AU - Perälä, Merja

AU - Kronqvist, Pauliina

AU - Joensuu, Heikki

AU - Ivaska, Johanna

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

KW - breast cancer

KW - cell invasion

KW - integrins

U2 - 10.1038/ncomms13297

DO - 10.1038/ncomms13297

M3 - Article

VL - 7

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 13297

ER -