Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE
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...
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| Format: | Article |
| Language: | en_US |
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Springer Nature
2016
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| Online Access: | http://hdl.handle.net/1721.1/105260 https://orcid.org/0000-0001-5063-8502 https://orcid.org/0000-0001-7603-8396 https://orcid.org/0000-0003-3214-4554 |
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| author | Perera, U. Gillett, C. Law, A-L. Sharma, V. P. Wang, J. Mosis, F. De Piano, M. Monypenny, J. Woodman, N. Mouneimne, G. Van Hemelrijck, M. Cao, Y. Condeelis, J. Krause, M. Carmona, Guillaume Naba, Alexandra Wyckoff, Jeffrey Balsamo, Michele McConnell, Russell E. Hynes, Richard O. Gertler, Frank |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Perera, U. Gillett, C. Law, A-L. Sharma, V. P. Wang, J. Mosis, F. De Piano, M. Monypenny, J. Woodman, N. Mouneimne, G. Van Hemelrijck, M. Cao, Y. Condeelis, J. Krause, M. Carmona, Guillaume Naba, Alexandra Wyckoff, Jeffrey Balsamo, Michele McConnell, Russell E. Hynes, Richard O. Gertler, Frank |
| author_sort | Perera, U. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T15:44:39Z |
| format | Article |
| id | mit-1721.1/105260 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T15:44:39Z |
| publishDate | 2016 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | mit-1721.1/1052602022-10-02T03:49:23Z Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE Perera, U. Gillett, C. Law, A-L. Sharma, V. P. Wang, J. Mosis, F. De Piano, M. Monypenny, J. Woodman, N. Mouneimne, G. Van Hemelrijck, M. Cao, Y. Condeelis, J. Krause, M. Carmona, Guillaume Naba, Alexandra Wyckoff, Jeffrey Balsamo, Michele McConnell, Russell E. Hynes, Richard O. Gertler, Frank Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Carmona, Guillaume Naba, Alexandra Wyckoff, Jeffrey Balsamo, Michele McConnell, Russell E. Hynes, Richard O. Gertler, Frank 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. Virginia and D.K. Ludwig Fund for Cancer Research (Postdoctoral fellowship) King's College London (Overseas Research PhD Studentship (KORS)) National Cancer Institute (U.S.) (U54-CA112967) National Cancer Institute (U.S.) (U54-CA163109) Ludwig Center for Molecular Oncology at MIT David H. Koch Institute for Integrative Cancer Research at MIT (Support Grant P30-CA14051) National Cancer Institute (U.S.) (Koch Institute Support Grant P30-CA14051) Biotechnology and Biological Sciences Research Council (Great Britain) (BB/F011431/1) Biotechnology and Biological Sciences Research Council (Great Britain) (BB/J000590/1) Biotechnology and Biological Sciences Research Council (Great Britain) (BB/N000226/1) Wellcome Trust (London, England) (082907/Z/07/Z) 2016-11-08T17:27:25Z 2016-11-08T17:27:25Z 2016-03 2016-01 Article http://purl.org/eprint/type/JournalArticle 0950-9232 1476-5594 http://hdl.handle.net/1721.1/105260 Carmona, G., U. Perera, C. Gillett, A. Naba, A.-L. Law, V. P. Sharma, J. Wang, et al. “Lamellipodin Promotes Invasive 3D Cancer Cell Migration via Regulated Interactions with Ena/VASP and SCAR/WAVE.” Oncogene 35, no. 39 (March 21, 2016): 5155–5169. https://orcid.org/0000-0001-5063-8502 https://orcid.org/0000-0001-7603-8396 https://orcid.org/0000-0003-3214-4554 en_US http://dx.doi.org/10.1038/onc.2016.47 Oncogene Creative Commons Attribution 4.0 International License http://creativecommons.org/licenses/by/4.0/ application/pdf Springer Nature Nature |
| spellingShingle | Perera, U. Gillett, C. Law, A-L. Sharma, V. P. Wang, J. Mosis, F. De Piano, M. Monypenny, J. Woodman, N. Mouneimne, G. Van Hemelrijck, M. Cao, Y. Condeelis, J. Krause, M. Carmona, Guillaume Naba, Alexandra Wyckoff, Jeffrey Balsamo, Michele McConnell, Russell E. Hynes, Richard O. Gertler, Frank Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE |
| title | Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE |
| title_full | Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE |
| title_fullStr | Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE |
| title_full_unstemmed | Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE |
| title_short | Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE |
| title_sort | lamellipodin promotes invasive 3d cancer cell migration via regulated interactions with ena vasp and scar wave |
| url | http://hdl.handle.net/1721.1/105260 https://orcid.org/0000-0001-5063-8502 https://orcid.org/0000-0001-7603-8396 https://orcid.org/0000-0003-3214-4554 |
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