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5. Wnt signaling in the pathogenesis of multiple myeloma

Author

van Andel, Harmen, Pals, Steven, Spaargaren, Marcel, Faculteit der Geneeskunde, Pals, Steven T., CCA - Cancer biology and immunology, and Graduate School

Abstract

Multiple myeloma (MM) is a clonal expansion of malignant plasma cells in the bone marrow (BM). Whereas numerous genetic and epigenetic abnormalities have been implicated in MM tumorigenesis, MM cells are highly dependent on a protective BM niche for growth and survival. The aim of the studies described in this thesis was to investigate the reciprocal interaction between multiple myeloma tumor cells and the bone marrow microenvironment. In particular, we focused on mechanisms that facilitate aberrant activation of the canonical Wnt signaling pathway in tumor cells. Oncogenic Wnt signaling typically results from mutations in core pathway components, which cause constitutive, ligand-independent signaling. Whereas most MMs display activation of the canonical Wnt pathway, these cell-intrinsic mutations are rare. Instead, aberrant Wnt signaling activation in MM cells was proposed to be driven by both autocrine Wnt ligands and paracrine Wnts produced in the MM niche. This thesis describes the identification of several genetic and epigenetic abnormalities in MM that sensitize tumor cells to Wnt ligands. Since Wnt signaling in MM cells is largely ligand dependent, it can be targeted by drugs/antibodies that act upstream in the pathway, interfering with Wnt secretion, sequestering Wnts, or blocking Wnt (co)receptors. In addition, the transcriptional effect of hypoxia in MM cells was studied, which identified ADM as an important regulator of angiogenesis in MM.

Published
2019

8. Syndecan-1 promotes Wnt/b-catenin signaling in multiple myeloma by presenting Wnts and R-spondins

Author

CMM Groep Maurice, Cancer, Regenerative Medicine and Stem Cells, CMM Sectie Molecular Cancer Research, Child Health, Hubrecht Institute with UMC, Ren, Zemin, Van Andel, Harmen, De Lau, Wim, Hartholt, Robin B., Maurice, Madelon M., Clevers, Hans, Kersten, Marie José, Spaargaren, Marcel, Pals, Steven T., CMM Groep Maurice, Cancer, Regenerative Medicine and Stem Cells, CMM Sectie Molecular Cancer Research, Child Health, Hubrecht Institute with UMC, Ren, Zemin, Van Andel, Harmen, De Lau, Wim, Hartholt, Robin B., Maurice, Madelon M., Clevers, Hans, Kersten, Marie José, Spaargaren, Marcel, and Pals, Steven T.

Published
2018

9. NLRX1 dampens oxidative stress and apoptosis in tissue injury via control of mitochondrial activity

Author

Stokman, Geurt, primary, Kors, Lotte, additional, Bakker, Pieter J., additional, Rampanelli, Elena, additional, Claessen, Nike, additional, Teske, Gwendoline J.D., additional, Butter, Loes, additional, van Andel, Harmen, additional, van den Bergh Weerman, Marius A., additional, Larsen, Per W.B., additional, Dessing, Mark C., additional, Zuurbier, Coert J., additional, Girardin, Stephen E., additional, Florquin, Sandrine, additional, and Leemans, Jaklien C., additional

Published
2017
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Author

Ren, Zemin, van Andel, Harmen, de Lau, Wim, Hartholt, Robin B, Maurice, Madelon M, Clevers, Hans, Kersten, Marie José, Spaargaren, Marcel, Pals, Steven T, Ren, Zemin, van Andel, Harmen, de Lau, Wim, Hartholt, Robin B, Maurice, Madelon M, Clevers, Hans, Kersten, Marie José, Spaargaren, Marcel, and Pals, Steven T

Published
2017

11. MET Signaling Mediates Intestinal Crypt-Villus Development, Regeneration, and Adenoma Formation and Is Promoted by Stem Cell CD44 Isoforms

Author

Joosten, Sander P J, Zeilstra, Jurrit, Van Andel, Harmen, Mijnals, R. Clinton, Zaunbrecher, Joost, Duivenvoorden, Annet A.M., van de Wetering, Marc, Clevers, Hans, Spaargaren, Marcel, Pals, Steven T., Joosten, Sander P J, Zeilstra, Jurrit, Van Andel, Harmen, Mijnals, R. Clinton, Zaunbrecher, Joost, Duivenvoorden, Annet A.M., van de Wetering, Marc, Clevers, Hans, Spaargaren, Marcel, and Pals, Steven T.

Published
2017

12. MET Signaling Mediates Intestinal Crypt-Villus Development, Regeneration, and Adenoma Formation and Is Promoted by Stem Cell CD44 Isoforms

Author

Hubrecht Institute with UMC, CMM Sectie Molecular Cancer Research, Cancer, Child Health, Regenerative Medicine and Stem Cells, Joosten, Sander P J, Zeilstra, Jurrit, Van Andel, Harmen, Mijnals, R. Clinton, Zaunbrecher, Joost, Duivenvoorden, Annet A.M., van de Wetering, Marc, Clevers, Hans, Spaargaren, Marcel, Pals, Steven T., Hubrecht Institute with UMC, CMM Sectie Molecular Cancer Research, Cancer, Child Health, Regenerative Medicine and Stem Cells, Joosten, Sander P J, Zeilstra, Jurrit, Van Andel, Harmen, Mijnals, R. Clinton, Zaunbrecher, Joost, Duivenvoorden, Annet A.M., van de Wetering, Marc, Clevers, Hans, Spaargaren, Marcel, and Pals, Steven T.

Published
2017

13. Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins

Author

Pathologie patiënten zorg, Hubrecht Institute with UMC, CMM Sectie Molecular Cancer Research, Cancer, Regenerative Medicine and Stem Cells, Child Health, Van Andel, Harmen, Ren, Zemin, Koopmans, Iris, Joosten, Sander P J, Kocemba, Kinga A., De Lau, Wim, Kersten, Marie José, De Bruin, Alexander M., Guikema, Jeroen E J, Clevers, Hans, Spaargaren, Marcel, Pals, Steven T., Pathologie patiënten zorg, Hubrecht Institute with UMC, CMM Sectie Molecular Cancer Research, Cancer, Regenerative Medicine and Stem Cells, Child Health, Van Andel, Harmen, Ren, Zemin, Koopmans, Iris, Joosten, Sander P J, Kocemba, Kinga A., De Lau, Wim, Kersten, Marie José, De Bruin, Alexander M., Guikema, Jeroen E J, Clevers, Hans, Spaargaren, Marcel, and Pals, Steven T.

Published
2017

14. Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins

Author

van Andel, Harmen, primary, Ren, Zemin, additional, Koopmans, Iris, additional, Joosten, Sander P. J., additional, Kocemba, Kinga A., additional, de Lau, Wim, additional, Kersten, Marie José, additional, de Bruin, Alexander M., additional, Guikema, Jeroen E. J., additional, Clevers, Hans, additional, Spaargaren, Marcel, additional, and Pals, Steven T., additional

Published
2016
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15. The DNA Damage Response Regulates RAG1/2 Expression in Pre–B Cells through ATM-FOXO1 Signaling

Author

Ochodnicka-Mackovicova, Katarina, primary, Bahjat, Mahnoush, additional, Maas, Chiel, additional, van der Veen, Amélie, additional, Bloedjes, Timon A., additional, de Bruin, Alexander M., additional, van Andel, Harmen, additional, Schrader, Carol E., additional, Hendriks, Rudi W., additional, Verhoeyen, Els, additional, Bende, Richard J., additional, van Noesel, Carel J. M., additional, and Guikema, Jeroen E. J., additional

Published
2016
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