74911 20200117221635.0 doi 10.1038/s41598-018-30683-4 sideral 107493 ART-2018-107493 eng (orcid)0000-0002-4220-105X Plou, J. From individual to collective 3D cancer dissemination: roles of collagen concentration and TGF-ß 2018 Access copy available to the general public Unrestricted Cancer cells have the ability to migrate from the primary (original) site to other places in the body. The extracellular matrix affects cancer cell migratory capacity and has been correlated with tissue-specific spreading patterns. However, how the matrix orchestrates these behaviors remains unclear. Here, we investigated how both higher collagen concentrations and TGF-ß regulate the formation of H1299 cell (a non-small cell lung cancer cell line) spheroids within 3D collagen-based matrices and promote cancer cell invasive capacity. We show that at low collagen concentrations, tumor cells move individually and have moderate invasive capacity, whereas when the collagen concentration is increased, the formation of cell clusters is promoted. In addition, when the concentration of TGF-ß in the microenvironment is lower, most of the clusters are aggregates of cancer cells with a spheroid-like morphology and poor migratory capacity. In contrast, higher concentrations of TGF-ß induced the formation of clusters with a notably higher invasive capacity, resulting in clear strand-like collective cell migration. Our results show that the concentration of the extracellular matrix is a key regulator of the formation of tumor clusters that affects their development and growth. In addition, chemical factors create a microenvironment that promotes the transformation of idle tumor clusters into very active, invasive tumor structures. These results collectively demonstrate the relevant regulatory role of the mechano-chemical microenvironment in leading the preferential metastasis of tumor cells to specific tissues with high collagen concentrations and TFG-ß activity. This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No H2020 737543-IMAGO info:eu-repo/grantAgreement/EC/H2020/737543/EU/Image Analysis Online Services for in-vitro experiments/IMAGO info:eu-repo/grantAgreement/EC/FP7/306571/EU/Predictive modelling and simulation in mechano-chemo-biology: a computer multi-approach/INSILICO-CELL info:eu-repo/grantAgreement/ES/MINECO/DPI2015-64221-C2-1-R info:eu-repo/semantics/openAccess by http://creativecommons.org/licenses/by/3.0/es/ 4.011 2018 MULTIDISCIPLINARY SCIENCES 14 / 69 = 0.203 2018 Q1 T1 1.414 2018 Multidisciplinary 2018 Q1 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion (orcid)0000-0003-2237-8859 Juste-Lanas, Y. Universidad de Zaragoza Olivares, V. Universidad de Zaragoza (orcid)0000-0002-3796-4482 del Amo, C. Universidad de Zaragoza (orcid)0000-0002-3784-1140 Borau, C. Universidad de Zaragoza (orcid)0000-0002-9864-7683 García-Aznar, J.M. Universidad de Zaragoza 1002 050 Universidad de Zaragoza Dpto. Bioq.Biolog.Mol. Celular Área Biología Celular 5004 605 Universidad de Zaragoza Dpto. Ingeniería Mecánica Área Mec.Med.Cont. y Teor.Est. 8, 1 (2018), 12723 [14 pp] Sci. rep. SCIENTIFIC REPORTS 2045-2322 5716940 http://zaguan.unizar.es/record/74911/files/texto_completo.pdf Versión publicada 114095 http://zaguan.unizar.es/record/74911/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:74911 articulos driver 2020-01-17-22:01:58 ARTICLE