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^*

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

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
Pages (from-to)	1-12
Number of pages	12
Journal	Oncogene
Volume	2018
Issue number	30
DOIs	https://doi.org/10.1038/s41388-018-0255-7
Publication status	Published - 30 Apr 2018

Funding

Funding: This work was supported by the Netherlands Organization for Scientific Research (NWO: Vici grant 016.140.657) and the Dutch Technology Foundation (STW, 11462).

Funders	Funder number
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	016.140.657
Stichting voor de Technische Wetenschappen	11462

UN SDGs

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

Access to Document

10.1038/s41388-018-0255-7

Persistent URL (handle)

Persistent link

Cite this

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, 2018(30), 1-12. https://doi.org/10.1038/s41388-018-0255-7

@article{06aa900b6a9b4ae59ccd0ffcf629de94,

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.",

author = "Raimond Heukers and Fan, {Tian Shu} and {de Wit}, {Raymond H.} and {van Senten}, {Jeffrey R.} and {de Groof}, {Timo W.M.} and Bebelman, {Maarten P.} and Tonny Lagerweij and Joao Vieira and {de Munnik}, {Sabrina M.} and {Smits-de Vries}, Laura and {van Offenbeek}, Jody and Afsar Rahbar and {van Hoorick}, Diane and Cecilia S{\"o}derberg-Naucler and Thomas W{\"u}rdinger and Rob Leurs and Marco Siderius and Vischer, {Henry F.} and Smit, {Martine J.}",

year = "2018",

month = apr,

day = "30",

doi = "10.1038/s41388-018-0255-7",

language = "English",

volume = "2018",

pages = "1--12",

journal = "Oncogene",

issn = "0950-9232",

publisher = "Springer Nature",

number = "30",

}

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. 2018, no. 30, pp. 1-12. https://doi.org/10.1038/s41388-018-0255-7

TY - JOUR

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 - 2018/4/30

Y1 - 2018/4/30

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.

UR - http://www.scopus.com/inward/record.url?scp=85046092802&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85046092802&partnerID=8YFLogxK

U2 - 10.1038/s41388-018-0255-7

DO - 10.1038/s41388-018-0255-7

M3 - Article

AN - SCOPUS:85046092802

SN - 0950-9232

VL - 2018

SP - 1

EP - 12

JO - Oncogene

JF - Oncogene

IS - 30

ER -

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

Abstract

Funding

UN SDGs

Access to Document

Persistent URL (handle)

Other files and links

Fingerprint

Cite this