The role of clonal communication and heterogeneity in breast cancer

BMC Cancer

Ángel Diaz-Lagares¹  Roberto Piñeiro Cid¹  Rafael López-López²  Aitor Rodriguez-Casanova²  Pablo Hurtado Blanco³  Víctor Sebastian⁴  Ana Bribian⁵  Laura López-Mascaraque⁵  Luis Serrano⁶  María Lluch-Senar⁶  Samuel Miravet-Verde⁶  Josep Castellvi⁷  Eva Bejar Serrano⁸  Gemma Bande Vargas⁸  Ana Martín-Pardillos⁸  Stefan Hümmer⁸  Santiago Ramón y Cajal⁸  Pedro J. Guijarro⁸  Ángeles Valls Chiva⁸ 

[1]CIBERONC (Centro de Investigación Biomédica en Red de Cáncer)

[2]Cancer Epigenomics, Translational Medical Oncology (Oncomet), Health Research Institute of Santiago (IDIS), University Clinical Hospital of Santiago (CHUS)

[3]Cancer Modelling Lab, Roche-CHUS Joint Unit

[4]Department of Chemical Engineering, Aragon Institute of Nanoscience (INA), University of Zaragoza

[5]Department of Molecular, Cellular and Developmental Neurobiology, Instituto Cajal-CSIC

[6]EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), The Institute of Science and Technology

[7]Hospital Vall d’Hebron, Anatomía Patológica

[8]Translational Molecular Pathology Group, Vall d’Hebron Research Institute

关键词: Tumor;    Breast;    Cancer;    Metastasis;    Heterogeneity;    Clone;   

DOI  :  10.1186/s12885-019-5883-y

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown