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BMC Cancer. 2019 Jul 5;19(1):666. doi: 10.1186/s12885-019-5883-y.

The role of clonal communication and heterogeneity in breast cancer.

Author information

1
Translational Molecular Pathology Group, Vall d'Hebron Research Institute, Barcelona, Spain. ana.martin@vhir.org.
2
CIBERONC (Centro de Investigación Biomédica en Red de Cáncer), Madrid, Spain. ana.martin@vhir.org.
3
Translational Molecular Pathology Group, Vall d'Hebron Research Institute, Barcelona, Spain.
4
Cancer Modelling Lab, Roche-CHUS Joint Unit, Santiago de Compostela, Spain.
5
CIBERONC (Centro de Investigación Biomédica en Red de Cáncer), Madrid, Spain.
6
Cancer Epigenomics, Translational Medical Oncology (Oncomet), Health Research Institute of Santiago (IDIS), University Clinical Hospital of Santiago (CHUS), Santiago de Compostela, Spain.
7
Hospital Vall d'Hebron, Anatomía Patológica, Barcelona, Spain.
8
EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), The Institute of Science and Technology, Barcelona, Spain.
9
Universitat Pompeu Fabra (UPF), Barcelona, Spain.
10
Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
11
Department of Chemical Engineering, Aragon Institute of Nanoscience (INA), University of Zaragoza, Zaragoza, Spain.
12
Networking Research Centre on Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Madrid, Spain.
13
Department of Molecular, Cellular and Developmental Neurobiology, Instituto Cajal-CSIC, Madrid, Spain.
14
Roche-CHUS Joint Unit, University Clinical Hospital of Santiago (CHUS), Santiago de Compostela, Spain.
15
Translational Molecular Pathology Group, Vall d'Hebron Research Institute, Barcelona, Spain. sramon@vhebron.net.
16
CIBERONC (Centro de Investigación Biomédica en Red de Cáncer), Madrid, Spain. sramon@vhebron.net.
17
Hospital Vall d'Hebron, Anatomía Patológica, Barcelona, Spain. sramon@vhebron.net.

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.

KEYWORDS:

Breast; Cancer; Clone; Communication; Cooperation; Heterogeneity; MDA-MB-231; Metastasis; Tumor

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