The constitutive activity of the virally encoded chemokine receptor US28 accelerates glioblastoma growth

Raimond Heukers; Tian Shu Fan; Raymond H de Wit; Jeffrey R van Senten; Timo W M De Groof; Maarten P Bebelman; Tonny Lagerweij; Joao Vieira; Sabrina M de Munnik; Laura Smits-de Vries; Jody van Offenbeek; Afsar Rahbar; Diane van Hoorick; Cecilia Söderberg-Naucler; Thomas Würdinger; Rob Leurs; Marco Siderius; Henry F Vischer; Martine J Smit

doi:10.1038/s41388-018-0255-7

The constitutive activity of the virally encoded chemokine receptor US28 accelerates glioblastoma growth

Raimond Heukers, Tian Shu Fan, Raymond H de Wit, Jeffrey R van Senten, Timo W M De Groof, Maarten P Bebelman, Tonny Lagerweij, Joao Vieira, Sabrina M de Munnik, Laura Smits-de Vries, Jody van Offenbeek, Afsar Rahbar, Diane van Hoorick, Cecilia Söderberg-Naucler, Thomas Würdinger, Rob Leurs, Marco Siderius, Henry F Vischer, Martine J Smit

29 Citations (Scopus)

Abstract

Glioblastoma (GBM) is the most aggressive and an incurable type of brain cancer. Human cytomegalovirus (HCMV) DNA and encoded proteins, including the chemokine receptor US28, have been detected in GBM tumors. US28 displays constitutive activity and is able to bind several human chemokines, leading to the activation of various proliferative and inflammatory signaling pathways. Here we show that HCMV, through the expression of US28, significantly enhanced the growth of 3D spheroids of U251- and neurospheres of primary glioblastoma cells. Moreover, US28 expression accelerated the growth of glioblastoma cells in an orthotopic intracranial GBM-model in mice. We developed highly potent and selective US28-targeting nanobodies, which bind to the extracellular domain of US28 and detect US28 in GBM tissue. The nanobodies inhibited chemokine binding and reduced the constitutive US28-mediated signaling with nanomolar potencies and significantly impaired HCMV/US28-mediated tumor growth in vitro and in vivo. This study emphasizes the oncomodulatory role of HCMV-encoded US28 and provides a potential therapeutic approach for HCMV-positive tumors using the nanobody technology.

Original language	English
Journal	Oncogene
Volume	37
Issue number	30
Pages (from-to)	4110-4121
Number of pages	12
ISSN	0950-9232
DOIs	https://doi.org/10.1038/s41388-018-0255-7
Publication status	Published - 26 Jul 2018
Externally published	Yes

Keywords

Animals
Brain Neoplasms/genetics
COS Cells
Cell Line
Cell Proliferation/genetics
Cercopithecus aethiops
Cytomegalovirus/genetics
Female
Glioblastoma/genetics
HEK293 Cells
Humans
Mice
Mice, Nude
NIH 3T3 Cells
Receptors, Chemokine/genetics
Receptors, Virus/genetics
Signal Transduction/genetics
Viral Proteins/genetics

UN SDGs

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

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s41388-018-0255-7.pdfFinal published version, 2.14 MBLicence: CC BY

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Heukers, R., Fan, T. S., de Wit, R. H., van Senten, J. R., De Groof, T. W. M., Bebelman, M. P., Lagerweij, T., Vieira, J., de Munnik, S. M., Smits-de Vries, L., van Offenbeek, J., Rahbar, A., van Hoorick, D., Söderberg-Naucler, C., Würdinger, T., Leurs, R., Siderius, M., Vischer, H. F., & Smit, M. J. (2018). The constitutive activity of the virally encoded chemokine receptor US28 accelerates glioblastoma growth. Oncogene, 37(30), 4110-4121. https://doi.org/10.1038/s41388-018-0255-7

Heukers, R, Fan, TS, de Wit, RH, van Senten, JR, De Groof, TWM, Bebelman, MP, Lagerweij, T, Vieira, J, de Munnik, SM, Smits-de Vries, L, van Offenbeek, J, Rahbar, A, van Hoorick, D, Söderberg-Naucler, C, Würdinger, T, Leurs, R, Siderius, M, Vischer, HF & Smit, MJ 2018, 'The constitutive activity of the virally encoded chemokine receptor US28 accelerates glioblastoma growth', Oncogene, vol. 37, no. 30, pp. 4110-4121. https://doi.org/10.1038/s41388-018-0255-7

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title = "The constitutive activity of the virally encoded chemokine receptor US28 accelerates glioblastoma growth",

abstract = "Glioblastoma (GBM) is the most aggressive and an incurable type of brain cancer. Human cytomegalovirus (HCMV) DNA and encoded proteins, including the chemokine receptor US28, have been detected in GBM tumors. US28 displays constitutive activity and is able to bind several human chemokines, leading to the activation of various proliferative and inflammatory signaling pathways. Here we show that HCMV, through the expression of US28, significantly enhanced the growth of 3D spheroids of U251- and neurospheres of primary glioblastoma cells. Moreover, US28 expression accelerated the growth of glioblastoma cells in an orthotopic intracranial GBM-model in mice. We developed highly potent and selective US28-targeting nanobodies, which bind to the extracellular domain of US28 and detect US28 in GBM tissue. The nanobodies inhibited chemokine binding and reduced the constitutive US28-mediated signaling with nanomolar potencies and significantly impaired HCMV/US28-mediated tumor growth in vitro and in vivo. This study emphasizes the oncomodulatory role of HCMV-encoded US28 and provides a potential therapeutic approach for HCMV-positive tumors using the nanobody technology.",

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T1 - The constitutive activity of the virally encoded chemokine receptor US28 accelerates glioblastoma growth

AU - Heukers, Raimond

AU - Fan, Tian Shu

AU - de Wit, Raymond H

AU - van Senten, Jeffrey R

AU - De Groof, Timo W M

AU - Bebelman, Maarten P

AU - Lagerweij, Tonny

AU - Vieira, Joao

AU - de Munnik, Sabrina M

AU - Smits-de Vries, Laura

AU - van Offenbeek, Jody

AU - Rahbar, Afsar

AU - van Hoorick, Diane

AU - Söderberg-Naucler, Cecilia

AU - Würdinger, Thomas

AU - Leurs, Rob

AU - Siderius, Marco

AU - Vischer, Henry F

AU - Smit, Martine J

PY - 2018/7/26

Y1 - 2018/7/26

N2 - Glioblastoma (GBM) is the most aggressive and an incurable type of brain cancer. Human cytomegalovirus (HCMV) DNA and encoded proteins, including the chemokine receptor US28, have been detected in GBM tumors. US28 displays constitutive activity and is able to bind several human chemokines, leading to the activation of various proliferative and inflammatory signaling pathways. Here we show that HCMV, through the expression of US28, significantly enhanced the growth of 3D spheroids of U251- and neurospheres of primary glioblastoma cells. Moreover, US28 expression accelerated the growth of glioblastoma cells in an orthotopic intracranial GBM-model in mice. We developed highly potent and selective US28-targeting nanobodies, which bind to the extracellular domain of US28 and detect US28 in GBM tissue. The nanobodies inhibited chemokine binding and reduced the constitutive US28-mediated signaling with nanomolar potencies and significantly impaired HCMV/US28-mediated tumor growth in vitro and in vivo. This study emphasizes the oncomodulatory role of HCMV-encoded US28 and provides a potential therapeutic approach for HCMV-positive tumors using the nanobody technology.

AB - Glioblastoma (GBM) is the most aggressive and an incurable type of brain cancer. Human cytomegalovirus (HCMV) DNA and encoded proteins, including the chemokine receptor US28, have been detected in GBM tumors. US28 displays constitutive activity and is able to bind several human chemokines, leading to the activation of various proliferative and inflammatory signaling pathways. Here we show that HCMV, through the expression of US28, significantly enhanced the growth of 3D spheroids of U251- and neurospheres of primary glioblastoma cells. Moreover, US28 expression accelerated the growth of glioblastoma cells in an orthotopic intracranial GBM-model in mice. We developed highly potent and selective US28-targeting nanobodies, which bind to the extracellular domain of US28 and detect US28 in GBM tissue. The nanobodies inhibited chemokine binding and reduced the constitutive US28-mediated signaling with nanomolar potencies and significantly impaired HCMV/US28-mediated tumor growth in vitro and in vivo. This study emphasizes the oncomodulatory role of HCMV-encoded US28 and provides a potential therapeutic approach for HCMV-positive tumors using the nanobody technology.

KW - Animals

KW - Brain Neoplasms/genetics

KW - COS Cells

KW - Cell Line

KW - Cell Proliferation/genetics

KW - Cercopithecus aethiops

KW - Cytomegalovirus/genetics

KW - Female

KW - Glioblastoma/genetics

KW - HEK293 Cells

KW - Humans

KW - Mice

KW - Mice, Nude

KW - NIH 3T3 Cells

KW - Receptors, Chemokine/genetics

KW - Receptors, Virus/genetics

KW - Signal Transduction/genetics

KW - Viral Proteins/genetics

U2 - 10.1038/s41388-018-0255-7

DO - 10.1038/s41388-018-0255-7

M3 - Journal article

C2 - 29706656

SN - 0950-9232

VL - 37

SP - 4110

EP - 4121

JO - Oncogene

JF - Oncogene

IS - 30

ER -

The constitutive activity of the virally encoded chemokine receptor US28 accelerates glioblastoma growth

Abstract

Keywords

UN SDGs

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