Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE

G Carmona; U Perera; C. Gillett; A Naba; A-L Law; V P Sharma; J. Wang; J Wyckoff; M Balsamo; F Mosis; M De Piano; J Monypenny; N Woodman; R E McConnell; G Mouneimne; M Van Hemelrijck; Y Cao; J Condeelis; R O Hynes; F  B Gertler; M Krause

doi:10.1038/onc.2016.47

Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE

G Carmona, U Perera, C. Gillett, A Naba, A-L Law, V P Sharma, J. Wang, J Wyckoff, M Balsamo, F Mosis, M De Piano, J Monypenny, N Woodman, R E McConnell, G Mouneimne, M Van Hemelrijck, Y Cao, J Condeelis, R O Hynes, F B GertlerM Krause

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Abstract

Cancer invasion is a hallmark of metastasis. The mesenchymal mode of cancer cell invasion is mediated by elongated membrane protrusions driven by the assembly of branched F-actin networks. How deregulation of actin regulators promotes cancer cell invasion is still enigmatic. We report that increased expression and membrane localization of the actin regulator Lamellipodin correlate with reduced metastasis-free survival and poor prognosis in breast cancer patients. In agreement, we find that Lamellipodin depletion reduced lung metastasis in an orthotopic mouse breast cancer model. Invasive 3D cancer cell migration as well as invadopodia formation and matrix degradation was impaired upon Lamellipodin depletion. Mechanistically, we show that Lamellipodin promotes invasive 3D cancer cell migration via both actin-elongating Ena/VASP proteins and the Scar/WAVE complex, which stimulates actin branching. In contrast, Lamellipodin interaction with Scar/WAVE but not with Ena/VASP is required for random 2D cell migration. We identified a phosphorylation-dependent mechanism that regulates selective recruitment of
these effectors to Lamellipodin: Abl-mediated Lamellipodin phosphorylation promotes its association with both Scar/WAVE and Ena/VASP, whereas Src-dependent phosphorylation enhances binding to Scar/WAVE but not to Ena/VASP. Through these selective, regulated interactions Lamellipodin mediates directional sensing of epidermal growth factor (EGF) gradients and invasive 3D migration of breast cancer cells. Our findings imply that increased Lamellipodin levels enhance Ena/VASP and Scar/WAVE activities
at the plasma membrane to promote 3D invasion and metastasis.

Original language	English
Pages (from-to)	5155–5169
Journal	Oncogene
Volume	35
Early online date	21 Mar 2016
DOIs	https://doi.org/10.1038/onc.2016.47
Publication status	Published - 29 Sept 2016

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Lamellipodin promotes invasive 3D_CARMONA_Accepted8February2016_GOLD VoR (CC BY)Final published version, 4.01 MBLicence: CC BY

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Carmona, G., Perera, U., Gillett, C., Naba, A., Law, A.-L., P Sharma, V., Wang, J., Wyckoff, J., Balsamo, M., Mosis, F., De Piano, M., Monypenny, J., Woodman, N., E McConnell, R., Mouneimne, G., Van Hemelrijck, M., Cao, Y., Condeelis, J., O Hynes, R., ... Krause, M. (2016). Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE. Oncogene, 35, 5155–5169. https://doi.org/10.1038/onc.2016.47

@article{d3fd7cabc3e7483bbf48db4c8e8f8643,

title = "Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE",

abstract = "Cancer invasion is a hallmark of metastasis. The mesenchymal mode of cancer cell invasion is mediated by elongated membrane protrusions driven by the assembly of branched F-actin networks. How deregulation of actin regulators promotes cancer cell invasion is still enigmatic. We report that increased expression and membrane localization of the actin regulator Lamellipodin correlate with reduced metastasis-free survival and poor prognosis in breast cancer patients. In agreement, we find that Lamellipodin depletion reduced lung metastasis in an orthotopic mouse breast cancer model. Invasive 3D cancer cell migration as well as invadopodia formation and matrix degradation was impaired upon Lamellipodin depletion. Mechanistically, we show that Lamellipodin promotes invasive 3D cancer cell migration via both actin-elongating Ena/VASP proteins and the Scar/WAVE complex, which stimulates actin branching. In contrast, Lamellipodin interaction with Scar/WAVE but not with Ena/VASP is required for random 2D cell migration. We identified a phosphorylation-dependent mechanism that regulates selective recruitment ofthese effectors to Lamellipodin: Abl-mediated Lamellipodin phosphorylation promotes its association with both Scar/WAVE and Ena/VASP, whereas Src-dependent phosphorylation enhances binding to Scar/WAVE but not to Ena/VASP. Through these selective, regulated interactions Lamellipodin mediates directional sensing of epidermal growth factor (EGF) gradients and invasive 3D migration of breast cancer cells. Our findings imply that increased Lamellipodin levels enhance Ena/VASP and Scar/WAVE activitiesat the plasma membrane to promote 3D invasion and metastasis.",

author = "G Carmona and U Perera and C. Gillett and A Naba and A-L Law and {P Sharma}, V and J. Wang and J Wyckoff and M Balsamo and F Mosis and {De Piano}, M and J Monypenny and N Woodman and {E McConnell}, R and G Mouneimne and {Van Hemelrijck}, M and Y Cao and J Condeelis and {O Hynes}, R and Gertler, {F B} and M Krause",

year = "2016",

month = sep,

day = "29",

doi = "10.1038/onc.2016.47",

language = "English",

volume = "35",

pages = "5155–5169",

journal = "Oncogene",

issn = "0950-9232",

publisher = "Springer Nature [academic journals on nature.com]",

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Carmona, G, Perera, U, Gillett, C, Naba, A, Law, A-L, P Sharma, V, Wang, J, Wyckoff, J, Balsamo, M, Mosis, F , De Piano, M , Monypenny, J, Woodman, N, E McConnell, R, Mouneimne, G, Van Hemelrijck, M, Cao, Y, Condeelis, J, O Hynes, R, Gertler, FB & Krause, M 2016, 'Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE', Oncogene, vol. 35, pp. 5155–5169. https://doi.org/10.1038/onc.2016.47

TY - JOUR

T1 - Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE

AU - Carmona, G

AU - Perera, U

AU - Gillett, C.

AU - Naba, A

AU - Law, A-L

AU - P Sharma, V

AU - Wang, J.

AU - Wyckoff, J

AU - Balsamo, M

AU - Mosis, F

AU - De Piano, M

AU - Monypenny, J

AU - Woodman, N

AU - E McConnell, R

AU - Mouneimne, G

AU - Van Hemelrijck, M

AU - Cao, Y

AU - Condeelis, J

AU - O Hynes, R

AU - Gertler, F B

AU - Krause, M

PY - 2016/9/29

Y1 - 2016/9/29

N2 - Cancer invasion is a hallmark of metastasis. The mesenchymal mode of cancer cell invasion is mediated by elongated membrane protrusions driven by the assembly of branched F-actin networks. How deregulation of actin regulators promotes cancer cell invasion is still enigmatic. We report that increased expression and membrane localization of the actin regulator Lamellipodin correlate with reduced metastasis-free survival and poor prognosis in breast cancer patients. In agreement, we find that Lamellipodin depletion reduced lung metastasis in an orthotopic mouse breast cancer model. Invasive 3D cancer cell migration as well as invadopodia formation and matrix degradation was impaired upon Lamellipodin depletion. Mechanistically, we show that Lamellipodin promotes invasive 3D cancer cell migration via both actin-elongating Ena/VASP proteins and the Scar/WAVE complex, which stimulates actin branching. In contrast, Lamellipodin interaction with Scar/WAVE but not with Ena/VASP is required for random 2D cell migration. We identified a phosphorylation-dependent mechanism that regulates selective recruitment ofthese effectors to Lamellipodin: Abl-mediated Lamellipodin phosphorylation promotes its association with both Scar/WAVE and Ena/VASP, whereas Src-dependent phosphorylation enhances binding to Scar/WAVE but not to Ena/VASP. Through these selective, regulated interactions Lamellipodin mediates directional sensing of epidermal growth factor (EGF) gradients and invasive 3D migration of breast cancer cells. Our findings imply that increased Lamellipodin levels enhance Ena/VASP and Scar/WAVE activitiesat the plasma membrane to promote 3D invasion and metastasis.

AB - Cancer invasion is a hallmark of metastasis. The mesenchymal mode of cancer cell invasion is mediated by elongated membrane protrusions driven by the assembly of branched F-actin networks. How deregulation of actin regulators promotes cancer cell invasion is still enigmatic. We report that increased expression and membrane localization of the actin regulator Lamellipodin correlate with reduced metastasis-free survival and poor prognosis in breast cancer patients. In agreement, we find that Lamellipodin depletion reduced lung metastasis in an orthotopic mouse breast cancer model. Invasive 3D cancer cell migration as well as invadopodia formation and matrix degradation was impaired upon Lamellipodin depletion. Mechanistically, we show that Lamellipodin promotes invasive 3D cancer cell migration via both actin-elongating Ena/VASP proteins and the Scar/WAVE complex, which stimulates actin branching. In contrast, Lamellipodin interaction with Scar/WAVE but not with Ena/VASP is required for random 2D cell migration. We identified a phosphorylation-dependent mechanism that regulates selective recruitment ofthese effectors to Lamellipodin: Abl-mediated Lamellipodin phosphorylation promotes its association with both Scar/WAVE and Ena/VASP, whereas Src-dependent phosphorylation enhances binding to Scar/WAVE but not to Ena/VASP. Through these selective, regulated interactions Lamellipodin mediates directional sensing of epidermal growth factor (EGF) gradients and invasive 3D migration of breast cancer cells. Our findings imply that increased Lamellipodin levels enhance Ena/VASP and Scar/WAVE activitiesat the plasma membrane to promote 3D invasion and metastasis.

U2 - 10.1038/onc.2016.47

DO - 10.1038/onc.2016.47

M3 - Article

SN - 0950-9232

VL - 35

SP - 5155

EP - 5169

JO - Oncogene

JF - Oncogene

ER -

Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE

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