The role of clonal communication and heterogeneity in breast cancer

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• dc.contributor.author Martín-Pardillos, Ana
• dc.contributor.author Miravet Verde, Samuel, 1992-
• dc.contributor.author Serrano Pubull, Luis, 1982-
• dc.contributor.author Lluch-Senar, Maria 1982-
• dc.contributor.author Ramón y Cajal, Santiago
• dc.date.accessioned 2019-09-26T07:23:49Z
• dc.date.available 2019-09-26T07:23:49Z
• dc.date.issued 2019
• dc.description.abstract Background: Cancer is a rapidly evolving, multifactorial disease that accumulates numerous genetic and epigenetic alterations. This results in molecular and phenotypic heterogeneity within the tumor, the complexity of which is further amplified through specific interactions between cancer cells. We aimed to dissect the molecular mechanisms underlying the cooperation between different clones. Methods: We produced clonal cell lines derived from the MDA-MB-231 breast cancer cell line, using the UbC-StarTrack system, which allowed tracking of multiple clones by color: GFP C3, mKO E10 and Sapphire D7. Characterization of these clones was performed by growth rate, cell metabolic activity, wound healing, invasion assays and genetic and epigenetic arrays. Tumorigenicity was tested by orthotopic and intravenous injections. Clonal cooperation was evaluated by medium complementation, co-culture and co-injection assays. Results: Characterization of these clones in vitro revealed clear genetic and epigenetic differences that affected growth rate, cell metabolic activity, morphology and cytokine expression among cell lines. In vivo, all clonal cell lines were able to form tumors; however, injection of an equal mix of the different clones led to tumors with very few mKO E10 cells. Additionally, the mKO E10 clonal cell line showed a significant inability to form lung metastases. These results confirm that even in stable cell lines heterogeneity is present. In vitro, the complementation of growth medium with medium or exosomes from parental or clonal cell lines increased the growth rate of the other clones. Complementation assays, co-growth and co-injection of mKO E10 and GFP C3 clonal cell lines increased the efficiency of invasion and migration. Conclusions: These findings support a model where interplay between clones confers aggressiveness, and which may allow identification of the factors involved in cellular communication that could play a role in clonal cooperation and thus represent new targets for preventing tumor progression.
• dc.description.sponsorship SRYC acknowledges support from Fondo de Investigaciones Sanitarias (FIS; PI17/02247 and PI14/01320), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC; CB16/12/00363) and Generalitat de Catalunya (AGAUR; 2017 SGR 1799 and 2014 SGR 1131). AMP is funded by a FP7 Marie Sklodowska-Curie COFUND program under Grant Agreement n° 267128 (INCOMED program). ADL is funded by a “Juan Rodés” contract (JR17/00016) from ISCIII. Funding bodies have provided funding to to cover experimental and publication expenses.
• dc.format.mimetype application/pdf
• dc.identifier.citation Martín-Pardillos A, Valls Chiva Á, Bande Vargas G, Hurtado Blanco P, Piñeiro Cid R, Guijarro PJ et al. The role of clonal communication and heterogeneity in breast cancer. BMC Cancer. 2019;19(1):666. DOI: 10.1186/s12885-019-5883-y
• dc.identifier.doi http://dx.doi.org/10.1186/s12885-019-5883-y
• dc.identifier.issn 1471-2407
• dc.identifier.uri http://hdl.handle.net/10230/42333
• dc.language.iso eng
• dc.publisher BioMed Central
• dc.relation.ispartof BMC Cancer. 2019;19(1):666
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/267128
• dc.rights © The Author(s). 2019. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Tumor
• dc.subject.keyword Breast
• dc.subject.keyword Cancer
• dc.subject.keyword Metastasis
• dc.subject.keyword Heterogeneity
• dc.subject.keyword Clone
• dc.subject.keyword Communication
• dc.subject.keyword Cooperation
• dc.subject.keyword MDA-MB-231
• dc.title The role of clonal communication and heterogeneity in breast cancer
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion