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During the invasion, individual cancer cells modulate the morphodynamics of protrusions to optimize their migration efficiency. However, it remains unclear how protrusion fluctuations govern the invasion of more complex multi\u2010cellular structures, such as tumors, and their correlation with the tumor metastatic potential. Herein, a reductionist approach based on 3D tumor cell micro\u2010spheroids with different invasion capabilities is used as a model to decipher the role of tumor\u2010associated fluctuating protrusions in cancer progression. To quantify fluctuations, a set of key biophysical parameters that precisely correlate with the invasive potential of tumors is defined. It is shown that different pharmacological drugs and cytokines are capable of modulating protrusion activity, significantly altering protrusion fluctuations, and tumor invasiveness. This correlation is used to define a novel quantitative invasion index encoding the key biophysical parameters of fluctuations and the relative levels of cell\u2010cell\/matrix interactions, which is capable of assessing the tumor's metastatic capability solely based on its magnitude. Overall, this study provides new insights into how protrusion fluctuations regulate tumor cell invasion, suggesting that they may be employed as a novel early indicator, or biophysical signature, of the metastatic potential of tumors.<\/jats:p>","DOI":"10.1002\/adbi.202101019","type":"journal-article","created":{"date-parts":[[2021,7,4]],"date-time":"2021-07-04T00:40:51Z","timestamp":1625359251000},"source":"Crossref","is-referenced-by-count":16,"title":["Tumor\u2010Associated Protrusion Fluctuations as a Signature of Cancer Invasiveness"],"prefix":"10.1002","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7930-2535","authenticated-orcid":false,"given":"David","family":"Caballero","sequence":"first","affiliation":[{"name":"3B's Research Group I3Bs \u2013 Research Institute on Biomaterials Biodegradables and Biomimetics University of Minho Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine  Barco Guimar\u00e3es 4805\u2010017 Portugal"},{"name":"ICVS\/3B's PT Government Associate Laboratory  Braga Guimar\u00e3es 4805\u2010017 Portugal"}]},{"given":"Virginia","family":"Brancato","sequence":"additional","affiliation":[{"name":"3B's Research Group I3Bs \u2013 Research Institute on Biomaterials Biodegradables and Biomimetics University of Minho Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine  Barco Guimar\u00e3es 4805\u2010017 Portugal"},{"name":"ICVS\/3B's PT Government Associate Laboratory  Braga Guimar\u00e3es 4805\u2010017 Portugal"}]},{"given":"Ana C.","family":"Lima","sequence":"additional","affiliation":[{"name":"3B's Research Group I3Bs \u2013 Research Institute on Biomaterials Biodegradables and Biomimetics University of Minho Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine  Barco Guimar\u00e3es 4805\u2010017 Portugal"},{"name":"ICVS\/3B's PT Government Associate Laboratory  Braga Guimar\u00e3es 4805\u2010017 Portugal"}]},{"given":"Catarina M.","family":"Abreu","sequence":"additional","affiliation":[{"name":"3B's Research Group I3Bs \u2013 Research Institute on Biomaterials Biodegradables and Biomimetics University of Minho Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine  Barco Guimar\u00e3es 4805\u2010017 Portugal"},{"name":"ICVS\/3B's PT Government Associate Laboratory  Braga Guimar\u00e3es 4805\u2010017 Portugal"}]},{"given":"Nuno M.","family":"Neves","sequence":"additional","affiliation":[{"name":"3B's Research Group I3Bs \u2013 Research Institute on Biomaterials Biodegradables and Biomimetics University of Minho Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine  Barco Guimar\u00e3es 4805\u2010017 Portugal"},{"name":"ICVS\/3B's PT Government Associate Laboratory  Braga Guimar\u00e3es 4805\u2010017 Portugal"}]},{"given":"Vitor M.","family":"Correlo","sequence":"additional","affiliation":[{"name":"3B's Research Group I3Bs \u2013 Research Institute on Biomaterials Biodegradables and Biomimetics University of Minho Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine  Barco Guimar\u00e3es 4805\u2010017 Portugal"},{"name":"ICVS\/3B's PT Government Associate Laboratory  Braga Guimar\u00e3es 4805\u2010017 Portugal"}]},{"given":"Joaquim M.","family":"Oliveira","sequence":"additional","affiliation":[{"name":"3B's Research Group I3Bs \u2013 Research Institute on Biomaterials Biodegradables and Biomimetics University of Minho Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine  Barco Guimar\u00e3es 4805\u2010017 Portugal"},{"name":"ICVS\/3B's PT Government Associate Laboratory  Braga Guimar\u00e3es 4805\u2010017 Portugal"}]},{"given":"Rui L.","family":"Reis","sequence":"additional","affiliation":[{"name":"3B's Research 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