The miR-25-93-106b cluster regulates tumor metastasis and immune evasion via modulation of CXCL12 and PD-L1

Michele Cioffi; Sara M Trabulo; Mireia Vallespinos; Deepak Raj; Tony Bou Kheir; Meng-Lay Lin; Julfa Begum; Ann-Marie Baker; Ala Amgheib; Jaimy Saif; Manuel Perez; Joaquim Soriano; Manuel Desco; Maria Victoria Gomez-Gaviro; Lorena Cusso; Diego Megias; Alexandra Aicher; Christopher Heeschen

doi:10.18632/oncotarget.15450

The miR-25-93-106b cluster regulates tumor metastasis and immune evasion via modulation of CXCL12 and PD-L1

Michele Cioffi
, Sara M Trabulo
, Mireia Vallespinos
, Deepak Raj
, Tony Bou Kheir
, Meng-Lay Lin
, Julfa Begum
, Ann-Marie Baker
, Ala Amgheib
, Jaimy Saif
, Manuel Perez
, Joaquim Soriano
, Manuel Desco
, Maria Victoria Gomez-Gaviro
, Lorena Cusso
, Diego Megias
, Alexandra Aicher
, Christopher Heeschen

Stem Cells & Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London, UK.
Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, UK.
Confocal Microscopy Unit, Centro Nacional de Investigaciones Oncológicas, Spain.
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain.

Research output: Contribution to journal › Article › peer-review

80 Citations (Scopus)

62 Downloads (Pure)

Abstract

The stromal microenvironment controls response to injury and inflammation, and is also an important determinant of cancer cell behavior. However, our understanding of its modulation by miRNA (miR) and their respective targets is still sparse. Here, we identified the miR-25-93-106b cluster and two new target genes as critical drivers for metastasis and immune evasion of cancer cells. Using miR-25-93-106b knockout mice or antagomiRs, we demonstrated regulation of the production of the chemoattractant CXCL12 controlling bone marrow metastasis. Moreover, we identified the immune checkpoint PD-L1 (CD274) as a novel miR-93/106b target playing a central role in diminishing tumor immunity. Eventually, upregulation of miR-93 and miR-106b via miR-mimics or treatment with an epigenetic reader domain (BET) inhibitor resulted in diminished expression of CXCL12 and PD-L1. These data suggest a potential new therapeutic rationale for use of BET inhibitors for dual targeting of cancers with strong immunosuppressive and metastatic phenotypes.

Original language	English
Pages (from-to)	21609-21625
Number of pages	17
Journal	Oncotarget
Volume	8
Issue number	13
DOIs	https://doi.org/10.18632/oncotarget.15450
Publication status	Published - 17 Feb 2017

Bibliographical note

Licensed under a Creative Commons Attribution 3.0 License.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Animals
B7-H1 Antigen/metabolism
Chemokine CXCL12/metabolism
Flow Cytometry
Gene Expression Regulation, Neoplastic/genetics
Gene Knockout Techniques
Humans
Immunohistochemistry
In Situ Hybridization
Mice
MicroRNAs/genetics
Multigene Family/genetics
Neoplasm Invasiveness/genetics
Polymerase Chain Reaction
Tumor Escape/genetics

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10.18632/oncotarget.15450Licence: CC BY 3.0

The miR-25-93-106b cluster regulates tumor metastasisFinal published version, 13.8 MBLicence: CC BY 3.0

Cite this

Cioffi, M., Trabulo, S. M., Vallespinos, M., Raj, D., Kheir, T. B., Lin, M.-L., Begum, J., Baker, A.-M., Amgheib, A., Saif, J., Perez, M., Soriano, J., Desco, M., Gomez-Gaviro, M. V., Cusso, L., Megias, D., Aicher, A., & Heeschen, C. (2017). The miR-25-93-106b cluster regulates tumor metastasis and immune evasion via modulation of CXCL12 and PD-L1. Oncotarget, 8(13), 21609-21625. https://doi.org/10.18632/oncotarget.15450

@article{79564ffd19284b04a270879a703eb604,

title = "The miR-25-93-106b cluster regulates tumor metastasis and immune evasion via modulation of CXCL12 and PD-L1",

abstract = "The stromal microenvironment controls response to injury and inflammation, and is also an important determinant of cancer cell behavior. However, our understanding of its modulation by miRNA (miR) and their respective targets is still sparse. Here, we identified the miR-25-93-106b cluster and two new target genes as critical drivers for metastasis and immune evasion of cancer cells. Using miR-25-93-106b knockout mice or antagomiRs, we demonstrated regulation of the production of the chemoattractant CXCL12 controlling bone marrow metastasis. Moreover, we identified the immune checkpoint PD-L1 (CD274) as a novel miR-93/106b target playing a central role in diminishing tumor immunity. Eventually, upregulation of miR-93 and miR-106b via miR-mimics or treatment with an epigenetic reader domain (BET) inhibitor resulted in diminished expression of CXCL12 and PD-L1. These data suggest a potential new therapeutic rationale for use of BET inhibitors for dual targeting of cancers with strong immunosuppressive and metastatic phenotypes.",

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author = "Michele Cioffi and Trabulo, \{Sara M\} and Mireia Vallespinos and Deepak Raj and Kheir, \{Tony Bou\} and Meng-Lay Lin and Julfa Begum and Ann-Marie Baker and Ala Amgheib and Jaimy Saif and Manuel Perez and Joaquim Soriano and Manuel Desco and Gomez-Gaviro, \{Maria Victoria\} and Lorena Cusso and Diego Megias and Alexandra Aicher and Christopher Heeschen",

note = "Licensed under a Creative Commons Attribution 3.0 License. ",

year = "2017",

month = feb,

day = "17",

doi = "10.18632/oncotarget.15450",

language = "English",

volume = "8",

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Cioffi, M, Trabulo, SM, Vallespinos, M, Raj, D, Kheir, TB, Lin, M-L, Begum, J, Baker, A-M, Amgheib, A, Saif, J, Perez, M, Soriano, J, Desco, M, Gomez-Gaviro, MV, Cusso, L, Megias, D, Aicher, A & Heeschen, C 2017, 'The miR-25-93-106b cluster regulates tumor metastasis and immune evasion via modulation of CXCL12 and PD-L1', Oncotarget, vol. 8, no. 13, pp. 21609-21625. https://doi.org/10.18632/oncotarget.15450

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T1 - The miR-25-93-106b cluster regulates tumor metastasis and immune evasion via modulation of CXCL12 and PD-L1

AU - Cioffi, Michele

AU - Trabulo, Sara M

AU - Vallespinos, Mireia

AU - Raj, Deepak

AU - Kheir, Tony Bou

AU - Lin, Meng-Lay

AU - Begum, Julfa

AU - Baker, Ann-Marie

AU - Amgheib, Ala

AU - Saif, Jaimy

AU - Perez, Manuel

AU - Soriano, Joaquim

AU - Desco, Manuel

AU - Gomez-Gaviro, Maria Victoria

AU - Cusso, Lorena

AU - Megias, Diego

AU - Aicher, Alexandra

AU - Heeschen, Christopher

N1 - Licensed under a Creative Commons Attribution 3.0 License.

PY - 2017/2/17

Y1 - 2017/2/17

N2 - The stromal microenvironment controls response to injury and inflammation, and is also an important determinant of cancer cell behavior. However, our understanding of its modulation by miRNA (miR) and their respective targets is still sparse. Here, we identified the miR-25-93-106b cluster and two new target genes as critical drivers for metastasis and immune evasion of cancer cells. Using miR-25-93-106b knockout mice or antagomiRs, we demonstrated regulation of the production of the chemoattractant CXCL12 controlling bone marrow metastasis. Moreover, we identified the immune checkpoint PD-L1 (CD274) as a novel miR-93/106b target playing a central role in diminishing tumor immunity. Eventually, upregulation of miR-93 and miR-106b via miR-mimics or treatment with an epigenetic reader domain (BET) inhibitor resulted in diminished expression of CXCL12 and PD-L1. These data suggest a potential new therapeutic rationale for use of BET inhibitors for dual targeting of cancers with strong immunosuppressive and metastatic phenotypes.

AB - The stromal microenvironment controls response to injury and inflammation, and is also an important determinant of cancer cell behavior. However, our understanding of its modulation by miRNA (miR) and their respective targets is still sparse. Here, we identified the miR-25-93-106b cluster and two new target genes as critical drivers for metastasis and immune evasion of cancer cells. Using miR-25-93-106b knockout mice or antagomiRs, we demonstrated regulation of the production of the chemoattractant CXCL12 controlling bone marrow metastasis. Moreover, we identified the immune checkpoint PD-L1 (CD274) as a novel miR-93/106b target playing a central role in diminishing tumor immunity. Eventually, upregulation of miR-93 and miR-106b via miR-mimics or treatment with an epigenetic reader domain (BET) inhibitor resulted in diminished expression of CXCL12 and PD-L1. These data suggest a potential new therapeutic rationale for use of BET inhibitors for dual targeting of cancers with strong immunosuppressive and metastatic phenotypes.

KW - Animals

KW - B7-H1 Antigen/metabolism

KW - Chemokine CXCL12/metabolism

KW - Flow Cytometry

KW - Gene Expression Regulation, Neoplastic/genetics

KW - Gene Knockout Techniques

KW - Humans

KW - Immunohistochemistry

KW - In Situ Hybridization

KW - Mice

KW - MicroRNAs/genetics

KW - Multigene Family/genetics

KW - Neoplasm Invasiveness/genetics

KW - Polymerase Chain Reaction

KW - Tumor Escape/genetics

UR - http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=15450&path[]=49361

U2 - 10.18632/oncotarget.15450

DO - 10.18632/oncotarget.15450

M3 - Article

C2 - 28423491

VL - 8

SP - 21609

EP - 21625

JO - Oncotarget

JF - Oncotarget

IS - 13

ER -

The miR-25-93-106b cluster regulates tumor metastasis and immune evasion via modulation of CXCL12 and PD-L1

Abstract

Bibliographical note

UN SDGs

Keywords

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