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Molecular characterization of the CXCR4 / CXCR7 axis in germ cell tumors and its targetability using nanobody-drug-conjugates

Being stimulated by the chemokine CXCL12, the CXCR4 / CXCR7 cascade is involved in tumor proliferation, migration, and metastasis. The interaction between CXCL12, secreted by cells from the microenvironment, and its receptors is complex and has been ascribed to promote chemotherapy resistance. Howev...

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Autores principales: Wakileh, Gamal A., Bierholz, Philipp, Kotthoff, Mara, Skowron, Margaretha A., Bremmer, Felix, Stephan, Alexa, Anbuhl, Stephanie M., Heukers, Raimond, Smit, Martine J., Ströbel, Philipp, Nettersheim, Daniel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10668499/
https://www.ncbi.nlm.nih.gov/pubmed/37996954
http://dx.doi.org/10.1186/s40164-023-00460-9
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author Wakileh, Gamal A.
Bierholz, Philipp
Kotthoff, Mara
Skowron, Margaretha A.
Bremmer, Felix
Stephan, Alexa
Anbuhl, Stephanie M.
Heukers, Raimond
Smit, Martine J.
Ströbel, Philipp
Nettersheim, Daniel
author_facet Wakileh, Gamal A.
Bierholz, Philipp
Kotthoff, Mara
Skowron, Margaretha A.
Bremmer, Felix
Stephan, Alexa
Anbuhl, Stephanie M.
Heukers, Raimond
Smit, Martine J.
Ströbel, Philipp
Nettersheim, Daniel
author_sort Wakileh, Gamal A.
collection PubMed
description Being stimulated by the chemokine CXCL12, the CXCR4 / CXCR7 cascade is involved in tumor proliferation, migration, and metastasis. The interaction between CXCL12, secreted by cells from the microenvironment, and its receptors is complex and has been ascribed to promote chemotherapy resistance. However, the role of this signaling axis and its targetability in germ cell tumors (GCT) is not fully understood. Thus, this study investigated the therapeutic efficacy of a nanobody-drug-conjugate targeting CXCR4 (CXCR4-NDC) and functionally characterized this signaling pathway in GCT using small molecule inhibitors and nanobodies. As shown by diminished cell viability, enhanced apoptosis induction, and detection of mitotic catastrophes, we confirmed the cytotoxic efficacy of the CXCR4-NDC in CXCR4(+)-GCT cells (i.e. seminoma and yolk-sac tumor), while non-malignant CXCR4(−)-fibroblasts, remained largely unaffected. Stimulation of CXCR4(+) / CXCR7(+)-GCT cells with CXCL12 resulted in an enhanced proliferative and migratory capacity, while this effect could be reverted using CXCR4 inhibitors or a CXCR7-nanobody. Molecularly, the CXCR4 / CXCR7-signaling cascade could be activated independently of MAPK (ERK1 / 2)-phosphorylation. Although, in CXCR4(−) / CXCR7(−)-embryonal carcinoma cells, CXCR7-expression was re-induced upon inhibition of ERK1 / 2-signaling. This study identified a nanobody-drug-conjugate targeting CXCR4 as a putative therapeutic option for GCT, i.e. seminoma and yolk-sac tumors. Furthermore, this study shed light on the functional role of the CXCR4 / CXCR7 / CXCL12-signaling cascade in GCT, demonstrating an important influence on proliferation and migration. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40164-023-00460-9.
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spelling pubmed-106684992023-11-23 Molecular characterization of the CXCR4 / CXCR7 axis in germ cell tumors and its targetability using nanobody-drug-conjugates Wakileh, Gamal A. Bierholz, Philipp Kotthoff, Mara Skowron, Margaretha A. Bremmer, Felix Stephan, Alexa Anbuhl, Stephanie M. Heukers, Raimond Smit, Martine J. Ströbel, Philipp Nettersheim, Daniel Exp Hematol Oncol Correspondence Being stimulated by the chemokine CXCL12, the CXCR4 / CXCR7 cascade is involved in tumor proliferation, migration, and metastasis. The interaction between CXCL12, secreted by cells from the microenvironment, and its receptors is complex and has been ascribed to promote chemotherapy resistance. However, the role of this signaling axis and its targetability in germ cell tumors (GCT) is not fully understood. Thus, this study investigated the therapeutic efficacy of a nanobody-drug-conjugate targeting CXCR4 (CXCR4-NDC) and functionally characterized this signaling pathway in GCT using small molecule inhibitors and nanobodies. As shown by diminished cell viability, enhanced apoptosis induction, and detection of mitotic catastrophes, we confirmed the cytotoxic efficacy of the CXCR4-NDC in CXCR4(+)-GCT cells (i.e. seminoma and yolk-sac tumor), while non-malignant CXCR4(−)-fibroblasts, remained largely unaffected. Stimulation of CXCR4(+) / CXCR7(+)-GCT cells with CXCL12 resulted in an enhanced proliferative and migratory capacity, while this effect could be reverted using CXCR4 inhibitors or a CXCR7-nanobody. Molecularly, the CXCR4 / CXCR7-signaling cascade could be activated independently of MAPK (ERK1 / 2)-phosphorylation. Although, in CXCR4(−) / CXCR7(−)-embryonal carcinoma cells, CXCR7-expression was re-induced upon inhibition of ERK1 / 2-signaling. This study identified a nanobody-drug-conjugate targeting CXCR4 as a putative therapeutic option for GCT, i.e. seminoma and yolk-sac tumors. Furthermore, this study shed light on the functional role of the CXCR4 / CXCR7 / CXCL12-signaling cascade in GCT, demonstrating an important influence on proliferation and migration. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40164-023-00460-9. BioMed Central 2023-11-23 /pmc/articles/PMC10668499/ /pubmed/37996954 http://dx.doi.org/10.1186/s40164-023-00460-9 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Correspondence
Wakileh, Gamal A.
Bierholz, Philipp
Kotthoff, Mara
Skowron, Margaretha A.
Bremmer, Felix
Stephan, Alexa
Anbuhl, Stephanie M.
Heukers, Raimond
Smit, Martine J.
Ströbel, Philipp
Nettersheim, Daniel
Molecular characterization of the CXCR4 / CXCR7 axis in germ cell tumors and its targetability using nanobody-drug-conjugates
title Molecular characterization of the CXCR4 / CXCR7 axis in germ cell tumors and its targetability using nanobody-drug-conjugates
title_full Molecular characterization of the CXCR4 / CXCR7 axis in germ cell tumors and its targetability using nanobody-drug-conjugates
title_fullStr Molecular characterization of the CXCR4 / CXCR7 axis in germ cell tumors and its targetability using nanobody-drug-conjugates
title_full_unstemmed Molecular characterization of the CXCR4 / CXCR7 axis in germ cell tumors and its targetability using nanobody-drug-conjugates
title_short Molecular characterization of the CXCR4 / CXCR7 axis in germ cell tumors and its targetability using nanobody-drug-conjugates
title_sort molecular characterization of the cxcr4 / cxcr7 axis in germ cell tumors and its targetability using nanobody-drug-conjugates
topic Correspondence
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10668499/
https://www.ncbi.nlm.nih.gov/pubmed/37996954
http://dx.doi.org/10.1186/s40164-023-00460-9
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