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In part, this is accomplished by cells adjusting their migration mode to one that is best suited to the environment. Melanoma cells have been shown to be particularly plastic, frequently using both mesenchymal and amoeboid (bleb-based) modes of migration. It has been demonstrated that 2D confinement will promote the transition from mesenchymal to bleb-based migration. However, if melanoma cells similarly transition to bleb-based migration in response to 3D confinement, such as within narrow channels, is unknown. Here, using micro-fabricated channels, we demonstrate that metastatic, A375-M2, melanoma cells adopt features of both mesenchymal and bleb-based migration. In narrow (8\u00a0\u00b5m; height and width) channels coated with fibronectin,\u2009~\u200950% of melanoma cells were found to use either mesenchymal or bleb-based migration modes. In contrast, the inhibition of Src family kinases or coating channels with BSA, completely eliminated any features of mesenchymal migration. Detailed comparisons of migration parameters revealed that blebbing cells, particularly in the absence of adhesions, were faster than mesenchymal cells. In contrast to what has been previously shown under conditions of 2D confinement, pharmacologically inhibiting Arp2\/3 promoted a fast filopodial-based mode of migration. Accordingly, we report that melanoma cells adopt a unique range of phenotypes under conditions of 3D confinement.<\/jats:p>","DOI":"10.1038\/s41598-021-97348-7","type":"journal-article","created":{"date-parts":[[2021,9,7]],"date-time":"2021-09-07T06:03:12Z","timestamp":1630994592000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Melanoma cells adopt features of both mesenchymal and amoeboid migration within confining channels"],"prefix":"10.1038","volume":"11","author":[{"given":"Sairisheel R.","family":"Gabbireddy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl W.","family":"Vosatka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aram J","family":"Chung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy S.","family":"Logue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,7]]},"reference":[{"key":"97348_CR1","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1002\/1878-0261.12019","volume":"11","author":"P Pandya","year":"2017","unstructured":"Pandya, P., Orgaz, J. L. & Sanz-Moreno, V. Modes of invasion during tumour dissemination. Mol. Oncol. 11, 5\u201327 (2017).","journal-title":"Mol. Oncol."},{"key":"97348_CR2","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1038\/nrc.2016.123","volume":"17","author":"CD Paul","year":"2017","unstructured":"Paul, C. D., Mistriotis, P. & Konstantopoulos, K. Cancer cell motility: Lessons from migration in confined spaces. Nat. Rev. Cancer 17, 131 (2017).","journal-title":"Nat. Rev. Cancer"},{"key":"97348_CR3","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1016\/j.cell.2015.01.007","volume":"160","author":"YJ Liu","year":"2015","unstructured":"Liu, Y. J. et al. Confinement and low adhesion induce fast amoeboid migration of slow mesenchymal cells. Cell 160, 659\u2013672 (2015).","journal-title":"Cell"},{"key":"97348_CR4","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1186\/s13046-018-0742-2","volume":"37","author":"A Chilla","year":"2018","unstructured":"Chilla, A. et al. Mature and progenitor endothelial cells perform angiogenesis also under protease inhibition: The amoeboid angiogenesis. J. Exp. Clin. Cancer Res. 37, 74 (2018).","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"97348_CR5","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1038\/ncb3134","volume":"17","author":"M Bergert","year":"2015","unstructured":"Bergert, M. et al. Force transmission during adhesion-independent migration. Nat. Cell Biol. 17, 524\u2013529 (2015).","journal-title":"Nat. Cell Biol."},{"key":"97348_CR6","doi-asserted-by":"crossref","unstructured":"Logue, J. S. et al. Erk regulation of actin capping and bundling by Eps8 promotes cortex tension and leader bleb-based migration. Elife 4 (2015).","DOI":"10.7554\/eLife.08314"},{"key":"97348_CR7","doi-asserted-by":"crossref","unstructured":"Logue, J. S., Cartagena-Rivera, A. X. & Chadwick, R. S. c-Src activity is differentially required by cancer cell motility modes. Oncogene (2018).","DOI":"10.1038\/s41388-017-0071-5"},{"key":"97348_CR8","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1038\/ncb2775","volume":"15","author":"M Tozluoglu","year":"2013","unstructured":"Tozluoglu, M. et al. Matrix geometry determines optimal cancer cell migration strategy and modulates response to interventions. Nat. Cell Biol. 15, 751\u2013762 (2013).","journal-title":"Nat. Cell Biol."},{"key":"97348_CR9","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1016\/j.cell.2015.01.008","volume":"160","author":"V Ruprecht","year":"2015","unstructured":"Ruprecht, V. et al. Cortical contractility triggers a stochastic switch to fast amoeboid cell motility. Cell 160, 673\u2013685 (2015).","journal-title":"Cell"},{"key":"97348_CR10","doi-asserted-by":"publisher","unstructured":"Logue, J., Chadwick, R. & Waterman, C. A simple method for precisely controlling the confinement of cells in culture (2018). https:\/\/doi.org\/10.1038\/protex.2018.033.","DOI":"10.1038\/protex.2018.033"},{"key":"97348_CR11","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1016\/j.cell.2014.02.052","volume":"157","author":"KM Stroka","year":"2014","unstructured":"Stroka, K. M. et al. Water permeation drives tumor cell migration in confined microenvironments. Cell 157, 611\u2013623 (2014).","journal-title":"Cell"},{"key":"97348_CR12","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1083\/jcb.201302132","volume":"202","author":"WC Hung","year":"2013","unstructured":"Hung, W. C. et al. Distinct signaling mechanisms regulate migration in unconfined versus confined spaces. J. Cell Biol. 202, 807\u2013824 (2013).","journal-title":"J. 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