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 language | English |
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Article number | 13297 |
Journal | Nature Communications |
Volume | 7 |
DOIs | |
Publication status | Published - 2016 |
MoE publication type | A1 Journal article-refereed |
Keywords
- breast cancer
- cell invasion
- integrins