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

Research output: Contribution to JournalArticleAcademicpeer-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.

LanguageEnglish
Pages1-12
Number of pages12
JournalOncogene
Volume2018
DOIs
Publication statusPublished - 30 Apr 2018

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Chemokine Receptors
Glioblastoma
Cytomegalovirus
Single-Domain Antibodies
Growth
Chemokines
Neoplasms
Brain Neoplasms
Technology
DNA
Proteins

Cite this

Heukers, Raimond ; Fan, Tian Shu ; de Wit, Raymond H. ; van Senten, Jeffrey R. ; de Groof, Timo W.M. ; Bebelman, Maarten P. ; Lagerweij, Tonny ; Vieira, Joao ; de Munnik, Sabrina M. ; Smits-de Vries, Laura ; van Offenbeek, Jody ; Rahbar, Afsar ; van Hoorick, Diane ; Söderberg-Naucler, Cecilia ; Würdinger, Thomas ; Leurs, Rob ; Siderius, Marco ; Vischer, Henry F. ; Smit, Martine J. / The constitutive activity of the virally encoded chemokine receptor US28 accelerates glioblastoma growth. In: Oncogene. 2018 ; Vol. 2018. pp. 1-12.
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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 = "4",
day = "30",
doi = "10.1038/s41388-018-0255-7",
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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, pp. 1-12. https://doi.org/10.1038/s41388-018-0255-7

The constitutive activity of the virally encoded chemokine receptor US28 accelerates glioblastoma growth. / Heukers, Raimond; Fan, Tian Shu; de Wit, Raymond H.; van Senten, Jeffrey R.; de Groof, Timo W.M.; Bebelman, Maarten P.; Lagerweij, Tonny; Vieira, Joao; de Munnik, Sabrina M.; Smits-de Vries, Laura; van Offenbeek, Jody; Rahbar, Afsar; van Hoorick, Diane; Söderberg-Naucler, Cecilia; Würdinger, Thomas; Leurs, Rob; Siderius, Marco; Vischer, Henry F.; Smit, Martine J.

In: Oncogene, Vol. 2018, 30.04.2018, p. 1-12.

Research output: Contribution to JournalArticleAcademicpeer-review

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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.

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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.

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