ChloroquineV1, Pmc, Curation, bibRecord, 000036

The role of clonal communication and heterogeneity in breast cancer

Identifieur interne : 000036 ( Pmc/Curation ); précédent : 000035; suivant : 000037

The role of clonal communication and heterogeneity in breast cancer

Auteurs : Ana Martín-Pardillos [Espagne] ; Ángeles Valls Chiva [Espagne] ; Gemma Bande Vargas [Espagne] ; Pablo Hurtado Blanco [Espagne] ; Roberto Pi Eiro Cid [Espagne] ; Pedro J. Guijarro [Espagne] ; Stefan Hümmer [Espagne] ; Eva Bejar Serrano [Espagne] ; Aitor Rodriguez-Casanova [Espagne] ; Ángel Diaz-Lagares [Espagne] ; Josep Castellvi [Espagne] ; Samuel Miravet-Verde [Espagne] ; Luis Serrano [Espagne] ; María Lluch-Senar [Espagne] ; Víctor Sebastian [Espagne] ; Ana Bribian [Espagne] ; Laura L Pez-Mascaraque [Espagne] ; Rafael L Pez-L Pez [Espagne] ; Santiago Ram N Y Cajal [Espagne]

Source :

BMC Cancer [ 1471-2407 ] ; 2019.

RBID : PMC:6612119

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.

Electronic supplementary material

The online version of this article (10.1186/s12885-019-5883-y) contains supplementary material, which is available to authorized users.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612119

DOI: 10.1186/s12885-019-5883-y
PubMed: 31277602
PubMed Central: 6612119

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<author><name sortKey="Castellvi, Josep" sort="Castellvi, Josep" uniqKey="Castellvi J" first="Josep" last="Castellvi">Josep Castellvi</name>
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<author><name sortKey="Sebastian, Victor" sort="Sebastian, Victor" uniqKey="Sebastian V" first="Víctor" last="Sebastian">Víctor Sebastian</name>
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Zaragoza, Spain</nlm:aff>
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<author><name sortKey="Bribian, Ana" sort="Bribian, Ana" uniqKey="Bribian A" first="Ana" last="Bribian">Ana Bribian</name>
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Madrid, Spain</nlm:aff>
<country xml:lang="fr">Espagne</country>
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<author><name sortKey="L Pez L Pez, Rafael" sort="L Pez L Pez, Rafael" uniqKey="L Pez L Pez R" first="Rafael" last="L Pez-L Pez">Rafael L Pez-L Pez</name>
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Santiago de Compostela, Spain</nlm:aff>
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<author><name sortKey="Martin Pardillos, Ana" sort="Martin Pardillos, Ana" uniqKey="Martin Pardillos A" first="Ana" last="Martín-Pardillos">Ana Martín-Pardillos</name>
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Barcelona, Spain</nlm:aff>
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<country xml:lang="fr">Espagne</country>
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<author><name sortKey="Valls Chiva, Angeles" sort="Valls Chiva, Angeles" uniqKey="Valls Chiva A" first="Ángeles" last="Valls Chiva">Ángeles Valls Chiva</name>
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Barcelona, Spain</nlm:aff>
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<author><name sortKey="Bande Vargas, Gemma" sort="Bande Vargas, Gemma" uniqKey="Bande Vargas G" first="Gemma" last="Bande Vargas">Gemma Bande Vargas</name>
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Barcelona, Spain</nlm:aff>
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<author><name sortKey="Hurtado Blanco, Pablo" sort="Hurtado Blanco, Pablo" uniqKey="Hurtado Blanco P" first="Pablo" last="Hurtado Blanco">Pablo Hurtado Blanco</name>
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<institution-id institution-id-type="GRID">grid.411048.8</institution-id>
<institution>Cancer Modelling Lab, Roche-CHUS Joint Unit,</institution>
</institution-wrap>
Santiago de Compostela, Spain</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Santiago de Compostela</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Pi Eiro Cid, Roberto" sort="Pi Eiro Cid, Roberto" uniqKey="Pi Eiro Cid R" first="Roberto" last="Pi Eiro Cid">Roberto Pi Eiro Cid</name>
<affiliation wicri:level="1"><nlm:aff id="Aff2">CIBERONC (Centro de Investigación Biomédica en Red de Cáncer), Madrid, Spain</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>CIBERONC (Centro de Investigación Biomédica en Red de Cáncer), Madrid</wicri:regionArea>
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<institution>Cancer Modelling Lab, Roche-CHUS Joint Unit,</institution>
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Santiago de Compostela, Spain</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Santiago de Compostela</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Guijarro, Pedro J" sort="Guijarro, Pedro J" uniqKey="Guijarro P" first="Pedro J." last="Guijarro">Pedro J. Guijarro</name>
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<institution>Vall d’Hebron Research Institute,</institution>
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Barcelona, Spain</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Barcelona</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Hummer, Stefan" sort="Hummer, Stefan" uniqKey="Hummer S" first="Stefan" last="Hümmer">Stefan Hümmer</name>
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<institution-id institution-id-type="GRID">grid.430994.3</institution-id>
<institution>Translational Molecular Pathology Group,</institution>
<institution>Vall d’Hebron Research Institute,</institution>
</institution-wrap>
Barcelona, Spain</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Barcelona</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="Aff2">CIBERONC (Centro de Investigación Biomédica en Red de Cáncer), Madrid, Spain</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>CIBERONC (Centro de Investigación Biomédica en Red de Cáncer), Madrid</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Bejar Serrano, Eva" sort="Bejar Serrano, Eva" uniqKey="Bejar Serrano E" first="Eva" last="Bejar Serrano">Eva Bejar Serrano</name>
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<institution-id institution-id-type="GRID">grid.430994.3</institution-id>
<institution>Translational Molecular Pathology Group,</institution>
<institution>Vall d’Hebron Research Institute,</institution>
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Barcelona, Spain</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Barcelona</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="Aff2">CIBERONC (Centro de Investigación Biomédica en Red de Cáncer), Madrid, Spain</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>CIBERONC (Centro de Investigación Biomédica en Red de Cáncer), Madrid</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Rodriguez Casanova, Aitor" sort="Rodriguez Casanova, Aitor" uniqKey="Rodriguez Casanova A" first="Aitor" last="Rodriguez-Casanova">Aitor Rodriguez-Casanova</name>
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<institution-id institution-id-type="GRID">grid.411048.8</institution-id>
<institution>Cancer Epigenomics, Translational Medical Oncology (Oncomet), Health Research Institute of Santiago (IDIS),</institution>
<institution>University Clinical Hospital of Santiago (CHUS),</institution>
</institution-wrap>
Santiago de Compostela, Spain</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Santiago de Compostela</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Diaz Lagares, Angel" sort="Diaz Lagares, Angel" uniqKey="Diaz Lagares A" first="Ángel" last="Diaz-Lagares">Ángel Diaz-Lagares</name>
<affiliation wicri:level="1"><nlm:aff id="Aff2">CIBERONC (Centro de Investigación Biomédica en Red de Cáncer), Madrid, Spain</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>CIBERONC (Centro de Investigación Biomédica en Red de Cáncer), Madrid</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 8816 6945</institution-id>
<institution-id institution-id-type="GRID">grid.411048.8</institution-id>
<institution>Cancer Epigenomics, Translational Medical Oncology (Oncomet), Health Research Institute of Santiago (IDIS),</institution>
<institution>University Clinical Hospital of Santiago (CHUS),</institution>
</institution-wrap>
Santiago de Compostela, Spain</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Santiago de Compostela</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Castellvi, Josep" sort="Castellvi, Josep" uniqKey="Castellvi J" first="Josep" last="Castellvi">Josep Castellvi</name>
<affiliation wicri:level="1"><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0675 8654</institution-id>
<institution-id institution-id-type="GRID">grid.411083.f</institution-id>
<institution>Hospital Vall d’Hebron, Anatomía Patológica,</institution>
</institution-wrap>
Barcelona, Spain</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Barcelona</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Miravet Verde, Samuel" sort="Miravet Verde, Samuel" uniqKey="Miravet Verde S" first="Samuel" last="Miravet-Verde">Samuel Miravet-Verde</name>
<affiliation wicri:level="1"><nlm:aff id="Aff6">EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), The Institute of Science and Technology, Barcelona, Spain</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), The Institute of Science and Technology, Barcelona</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Serrano, Luis" sort="Serrano, Luis" uniqKey="Serrano L" first="Luis" last="Serrano">Luis Serrano</name>
<affiliation wicri:level="1"><nlm:aff id="Aff6">EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), The Institute of Science and Technology, Barcelona, Spain</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), The Institute of Science and Technology, Barcelona</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="Aff7"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2172 2676</institution-id>
<institution-id institution-id-type="GRID">grid.5612.0</institution-id>
<institution>Universitat Pompeu Fabra (UPF),</institution>
</institution-wrap>
Barcelona, Spain</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Barcelona</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="Aff8"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9601 989X</institution-id>
<institution-id institution-id-type="GRID">grid.425902.8</institution-id>
<institution>Institució Catalana de Recerca i Estudis Avançats (ICREA),</institution>
</institution-wrap>
Barcelona, Spain</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Barcelona</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Lluch Senar, Maria" sort="Lluch Senar, Maria" uniqKey="Lluch Senar M" first="María" last="Lluch-Senar">María Lluch-Senar</name>
<affiliation wicri:level="1"><nlm:aff id="Aff6">EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), The Institute of Science and Technology, Barcelona, Spain</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), The Institute of Science and Technology, Barcelona</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Sebastian, Victor" sort="Sebastian, Victor" uniqKey="Sebastian V" first="Víctor" last="Sebastian">Víctor Sebastian</name>
<affiliation wicri:level="1"><nlm:aff id="Aff9"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2152 8769</institution-id>
<institution-id institution-id-type="GRID">grid.11205.37</institution-id>
<institution>Department of Chemical Engineering,</institution>
<institution>Aragon Institute of Nanoscience (INA), University of Zaragoza,</institution>
</institution-wrap>
Zaragoza, Spain</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Zaragoza</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="Aff10">Networking Research Centre on Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Madrid, Spain</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Networking Research Centre on Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Madrid</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Bribian, Ana" sort="Bribian, Ana" uniqKey="Bribian A" first="Ana" last="Bribian">Ana Bribian</name>
<affiliation wicri:level="1"><nlm:aff id="Aff11"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2177 5516</institution-id>
<institution-id institution-id-type="GRID">grid.419043.b</institution-id>
<institution>Department of Molecular, Cellular and Developmental Neurobiology,</institution>
<institution>Instituto Cajal-CSIC,</institution>
</institution-wrap>
Madrid, Spain</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Madrid</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="L Pez Mascaraque, Laura" sort="L Pez Mascaraque, Laura" uniqKey="L Pez Mascaraque L" first="Laura" last="L Pez-Mascaraque">Laura L Pez-Mascaraque</name>
<affiliation wicri:level="1"><nlm:aff id="Aff11"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2177 5516</institution-id>
<institution-id institution-id-type="GRID">grid.419043.b</institution-id>
<institution>Department of Molecular, Cellular and Developmental Neurobiology,</institution>
<institution>Instituto Cajal-CSIC,</institution>
</institution-wrap>
Madrid, Spain</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Madrid</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="L Pez L Pez, Rafael" sort="L Pez L Pez, Rafael" uniqKey="L Pez L Pez R" first="Rafael" last="L Pez-L Pez">Rafael L Pez-L Pez</name>
<affiliation wicri:level="1"><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 8816 6945</institution-id>
<institution-id institution-id-type="GRID">grid.411048.8</institution-id>
<institution>Cancer Epigenomics, Translational Medical Oncology (Oncomet), Health Research Institute of Santiago (IDIS),</institution>
<institution>University Clinical Hospital of Santiago (CHUS),</institution>
</institution-wrap>
Santiago de Compostela, Spain</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Santiago de Compostela</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="Aff12"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 8816 6945</institution-id>
<institution-id institution-id-type="GRID">grid.411048.8</institution-id>
<institution>Roche-CHUS Joint Unit,</institution>
<institution>University Clinical Hospital of Santiago (CHUS),</institution>
</institution-wrap>
Santiago de Compostela, Spain</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Santiago de Compostela</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Ram N Y Cajal, Santiago" sort="Ram N Y Cajal, Santiago" uniqKey="Ram N Y Cajal S" first="Santiago" last="Ram N Y Cajal">Santiago Ram N Y Cajal</name>
<affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1763 0287</institution-id>
<institution-id institution-id-type="GRID">grid.430994.3</institution-id>
<institution>Translational Molecular Pathology Group,</institution>
<institution>Vall d’Hebron Research Institute,</institution>
</institution-wrap>
Barcelona, Spain</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Barcelona</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="Aff2">CIBERONC (Centro de Investigación Biomédica en Red de Cáncer), Madrid, Spain</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>CIBERONC (Centro de Investigación Biomédica en Red de Cáncer), Madrid</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0675 8654</institution-id>
<institution-id institution-id-type="GRID">grid.411083.f</institution-id>
<institution>Hospital Vall d’Hebron, Anatomía Patológica,</institution>
</institution-wrap>
Barcelona, Spain</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Barcelona</wicri:regionArea>
</affiliation>
</author>
</analytic>
<series><title level="j">BMC Cancer</title>
<idno type="eISSN">1471-2407</idno>
<imprint><date when="2019">2019</date>
</imprint>
</series>
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<front><div type="abstract" xml:lang="en"><sec><title>Background</title>
<p id="Par1">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.</p>
</sec>
<sec><title>Methods</title>
<p id="Par2">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.</p>
</sec>
<sec><title>Results</title>
<p id="Par3">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<italic>,</italic>
 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.</p>
</sec>
<sec><title>Conclusions</title>
<p id="Par4">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.</p>
</sec>
<sec><title>Electronic supplementary material</title>
<p>The online version of this article (10.1186/s12885-019-5883-y) contains supplementary material, which is available to authorized users.</p>
</sec>
</div>
</front>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
  <front><journal-meta><journal-id journal-id-type="nlm-ta">BMC Cancer</journal-id>
<journal-id journal-id-type="iso-abbrev">BMC Cancer</journal-id>
<journal-title-group><journal-title>BMC Cancer</journal-title>
</journal-title-group>
<issn pub-type="epub">1471-2407</issn>
<publisher><publisher-name>BioMed Central</publisher-name>
<publisher-loc>London</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">31277602</article-id>
<article-id pub-id-type="pmc">6612119</article-id>
<article-id pub-id-type="publisher-id">5883</article-id>
<article-id pub-id-type="doi">10.1186/s12885-019-5883-y</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>The role of clonal communication and heterogeneity in breast cancer</article-title>
</title-group>
<contrib-group><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0003-1717-8465</contrib-id>
<name><surname>Martín-Pardillos</surname>
<given-names>Ana</given-names>
</name>
<address><phone>+34 93 2746824</phone>
<email>ana.martin@vhir.org</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
<xref ref-type="aff" rid="Aff2">2</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="yes"><name><surname>Valls Chiva</surname>
<given-names>Ángeles</given-names>
</name>
<address><email>angeles_11-3@hotmail.com</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="yes"><name><surname>Bande Vargas</surname>
<given-names>Gemma</given-names>
</name>
<address><email>gemma.bande94@gmail.com</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hurtado Blanco</surname>
<given-names>Pablo</given-names>
</name>
<address><email>felurh@gmail.com</email>
</address>
<xref ref-type="aff" rid="Aff3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Piñeiro Cid</surname>
<given-names>Roberto</given-names>
</name>
<address><email>Roberto.Pineiro.Cid@sergas.es</email>
</address>
<xref ref-type="aff" rid="Aff2">2</xref>
<xref ref-type="aff" rid="Aff3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Guijarro</surname>
<given-names>Pedro J.</given-names>
</name>
<address><email>pedro.guijarro@vhir.org</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hümmer</surname>
<given-names>Stefan</given-names>
</name>
<address><email>stefan.hummer@vhir.org</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
<xref ref-type="aff" rid="Aff2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bejar Serrano</surname>
<given-names>Eva</given-names>
</name>
<address><email>eva.bejar@vhir.org</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
<xref ref-type="aff" rid="Aff2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Rodriguez-Casanova</surname>
<given-names>Aitor</given-names>
</name>
<address><email>aitorrodriguez@me.com</email>
</address>
<xref ref-type="aff" rid="Aff4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Diaz-Lagares</surname>
<given-names>Ángel</given-names>
</name>
<address><email>adiazla@gmail.com</email>
</address>
<xref ref-type="aff" rid="Aff2">2</xref>
<xref ref-type="aff" rid="Aff4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Castellvi</surname>
<given-names>Josep</given-names>
</name>
<address><email>joscastellvi@vhebron.net</email>
</address>
<xref ref-type="aff" rid="Aff5">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Miravet-Verde</surname>
<given-names>Samuel</given-names>
</name>
<address><email>samuel.miravet@crg.eu</email>
</address>
<xref ref-type="aff" rid="Aff6">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Serrano</surname>
<given-names>Luis</given-names>
</name>
<address><email>luis.serrano@crg.eu</email>
</address>
<xref ref-type="aff" rid="Aff6">6</xref>
<xref ref-type="aff" rid="Aff7">7</xref>
<xref ref-type="aff" rid="Aff8">8</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lluch-Senar</surname>
<given-names>María</given-names>
</name>
<address><email>maria.lluch@crg.eu</email>
</address>
<xref ref-type="aff" rid="Aff6">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sebastian</surname>
<given-names>Víctor</given-names>
</name>
<address><email>victorse@unizar.es</email>
</address>
<xref ref-type="aff" rid="Aff9">9</xref>
<xref ref-type="aff" rid="Aff10">10</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bribian</surname>
<given-names>Ana</given-names>
</name>
<address><email>abribian@cajal.csic.es</email>
</address>
<xref ref-type="aff" rid="Aff11">11</xref>
</contrib>
<contrib contrib-type="author"><name><surname>López-Mascaraque</surname>
<given-names>Laura</given-names>
</name>
<address><email>mascaraque@cajal.csic.es</email>
</address>
<xref ref-type="aff" rid="Aff11">11</xref>
</contrib>
<contrib contrib-type="author"><name><surname>López-López</surname>
<given-names>Rafael</given-names>
</name>
<address><email>rafa.lopez.lopez@gmail.com</email>
</address>
<xref ref-type="aff" rid="Aff4">4</xref>
<xref ref-type="aff" rid="Aff12">12</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Ramón y Cajal</surname>
<given-names>Santiago</given-names>
</name>
<address><phone>+34 93 2746824</phone>
<email>sramon@vhebron.net</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
<xref ref-type="aff" rid="Aff2">2</xref>
<xref ref-type="aff" rid="Aff5">5</xref>
</contrib>
<aff id="Aff1"><label>1</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1763 0287</institution-id>
<institution-id institution-id-type="GRID">grid.430994.3</institution-id>
<institution>Translational Molecular Pathology Group,</institution>
<institution>Vall d’Hebron Research Institute,</institution>
</institution-wrap>
Barcelona, Spain</aff>
<aff id="Aff2"><label>2</label>
CIBERONC (Centro de Investigación Biomédica en Red de Cáncer), Madrid, Spain</aff>
<aff id="Aff3"><label>3</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0000 8816 6945</institution-id>
<institution-id institution-id-type="GRID">grid.411048.8</institution-id>
<institution>Cancer Modelling Lab, Roche-CHUS Joint Unit,</institution>
</institution-wrap>
Santiago de Compostela, Spain</aff>
<aff id="Aff4"><label>4</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0000 8816 6945</institution-id>
<institution-id institution-id-type="GRID">grid.411048.8</institution-id>
<institution>Cancer Epigenomics, Translational Medical Oncology (Oncomet), Health Research Institute of Santiago (IDIS),</institution>
<institution>University Clinical Hospital of Santiago (CHUS),</institution>
</institution-wrap>
Santiago de Compostela, Spain</aff>
<aff id="Aff5"><label>5</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0675 8654</institution-id>
<institution-id institution-id-type="GRID">grid.411083.f</institution-id>
<institution>Hospital Vall d’Hebron, Anatomía Patológica,</institution>
</institution-wrap>
Barcelona, Spain</aff>
<aff id="Aff6"><label>6</label>
EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), The Institute of Science and Technology, Barcelona, Spain</aff>
<aff id="Aff7"><label>7</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2172 2676</institution-id>
<institution-id institution-id-type="GRID">grid.5612.0</institution-id>
<institution>Universitat Pompeu Fabra (UPF),</institution>
</institution-wrap>
Barcelona, Spain</aff>
<aff id="Aff8"><label>8</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9601 989X</institution-id>
<institution-id institution-id-type="GRID">grid.425902.8</institution-id>
<institution>Institució Catalana de Recerca i Estudis Avançats (ICREA),</institution>
</institution-wrap>
Barcelona, Spain</aff>
<aff id="Aff9"><label>9</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2152 8769</institution-id>
<institution-id institution-id-type="GRID">grid.11205.37</institution-id>
<institution>Department of Chemical Engineering,</institution>
<institution>Aragon Institute of Nanoscience (INA), University of Zaragoza,</institution>
</institution-wrap>
Zaragoza, Spain</aff>
<aff id="Aff10"><label>10</label>
Networking Research Centre on Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Madrid, Spain</aff>
<aff id="Aff11"><label>11</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2177 5516</institution-id>
<institution-id institution-id-type="GRID">grid.419043.b</institution-id>
<institution>Department of Molecular, Cellular and Developmental Neurobiology,</institution>
<institution>Instituto Cajal-CSIC,</institution>
</institution-wrap>
Madrid, Spain</aff>
<aff id="Aff12"><label>12</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0000 8816 6945</institution-id>
<institution-id institution-id-type="GRID">grid.411048.8</institution-id>
<institution>Roche-CHUS Joint Unit,</institution>
<institution>University Clinical Hospital of Santiago (CHUS),</institution>
</institution-wrap>
Santiago de Compostela, Spain</aff>
</contrib-group>
<pub-date pub-type="epub"><day>5</day>
<month>7</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>5</day>
<month>7</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="collection"><year>2019</year>
</pub-date>
<volume>19</volume>
<elocation-id>666</elocation-id>
<history><date date-type="received"><day>28</day>
<month>5</month>
<year>2019</year>
</date>
<date date-type="accepted"><day>26</day>
<month>6</month>
<year>2019</year>
</date>
</history>
<permissions><copyright-statement>© The Author(s). 2019</copyright-statement>
<license license-type="OpenAccess"><license-p><bold>Open Access</bold>
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
), 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 (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/publicdomain/zero/1.0/">http://creativecommons.org/publicdomain/zero/1.0/</ext-link>
) applies to the data made available in this article, unless otherwise stated.</license-p>
</license>
</permissions>
<abstract id="Abs1"><sec><title>Background</title>
<p id="Par1">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.</p>
</sec>
<sec><title>Methods</title>
<p id="Par2">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.</p>
</sec>
<sec><title>Results</title>
<p id="Par3">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<italic>,</italic>
 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.</p>
</sec>
<sec><title>Conclusions</title>
<p id="Par4">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.</p>
</sec>
<sec><title>Electronic supplementary material</title>
<p>The online version of this article (10.1186/s12885-019-5883-y) contains supplementary material, which is available to authorized users.</p>
</sec>
</abstract>
<kwd-group xml:lang="en"><title>Keywords</title>
<kwd>Tumor</kwd>
<kwd>Breast</kwd>
<kwd>Cancer</kwd>
<kwd>Metastasis</kwd>
<kwd>Heterogeneity</kwd>
<kwd>Clone</kwd>
<kwd>Communication</kwd>
<kwd>Cooperation</kwd>
<kwd>MDA-MB-231</kwd>
</kwd-group>
<funding-group><award-group><funding-source><institution>Fondo de Investigaciones Sanitarias </institution>
</funding-source>
<award-id>PI17/02247 and PI14/01320</award-id>
<principal-award-recipient><name><surname>Ramón y Cajal</surname>
<given-names>Santiago</given-names>
</name>
</principal-award-recipient>
</award-group>
</funding-group>
<funding-group><award-group><funding-source><institution>Centro de Investigación Biomédica en Red de Cáncer</institution>
</funding-source>
<award-id>CIBERONC; CB16/12/00363</award-id>
<principal-award-recipient><name><surname>Ramón y Cajal</surname>
<given-names>Santiago</given-names>
</name>
</principal-award-recipient>
</award-group>
</funding-group>
<funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">http://dx.doi.org/10.13039/501100002809</institution-id>
<institution>Generalitat de Catalunya</institution>
</institution-wrap>
</funding-source>
<award-id>AGAUR; 2017 SGR 1799 and 2014 SGR 1131</award-id>
<principal-award-recipient><name><surname>Ramón y Cajal</surname>
<given-names>Santiago</given-names>
</name>
</principal-award-recipient>
</award-group>
</funding-group>
<funding-group><award-group><funding-source><institution>FP7 People: Marie-Curie Actions (COFUND)</institution>
</funding-source>
<award-id>267128</award-id>
<principal-award-recipient><name><surname>Martín-Pardillos</surname>
<given-names>Ana</given-names>
</name>
</principal-award-recipient>
</award-group>
</funding-group>
<funding-group><award-group><funding-source><institution>ISCIII</institution>
</funding-source>
<award-id>JR17/00016</award-id>
<principal-award-recipient><name><surname>Diaz-Lagares</surname>
<given-names>Ángel</given-names>
</name>
</principal-award-recipient>
</award-group>
</funding-group>
<custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name>
<meta-value>© The Author(s) 2019</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
</front>
</pmc>
</record>

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The role of clonal communication and heterogeneity in breast cancer

The role of clonal communication and heterogeneity in breast cancer

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