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4. 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

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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

6. 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

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

Author

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., 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

8. 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

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

Author

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., 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

10. 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

Abstract

BACKGROUND & AIMS: Resistance of metastatic human colorectal cancer cells to drugs that block epidermal growth factor (EGF) receptor signaling could be caused by aberrant activity of other receptor tyrosine kinases, activating overlapping signaling pathways. One of these receptor tyrosine kinases could be MET, the receptor for hepatocyte growth factor (HGF). We investigated how MET signaling, and its interaction with CD44 (a putative MET coreceptor regulated by Wnt signaling and highly expressed by intestinal stem cells [ISCs] and adenomas) affects intestinal homeostasis, regeneration, and adenoma formation in mini-gut organoids and mice.METHODS: We established organoid cultures from ISCs stimulated with HGF or EGF and assessed intestinal differentiation by immunohistochemistry. Mice with total epithelial disruption of MET (AhCre/Metfl/fl/LacZ) or ISC-specific disruption of MET (Lgr5Creert2/Metfl/fl/LacZ) and control mice (AhCre/Met+/+/LacZ, Lgr5Creert2/Met+/+/LacZ) were exposed to 10 Gy total body irradiation; intestinal tissues were collected, and homeostasis and regeneration were assessed by immunohistochemistry. We investigated adenoma organoid expansion stimulated by HGF or EGF using adenomas derived from Lgr5Creert2/Metfl/fl/Apcfl/fl and Lgr5Creert2/Met+/+/Apcfl/fl mice. The same mice were evaluated for adenoma prevalence and size. We also quantified adenomas in AhCre/Metfl/fl/Apcfl/+ mice compared with AhCre/Met+/+/Apcfl/+ control mice. We studied expansion of organoids generated from crypts and adenomas, stimulated by HGF or EGF, that were derived from mice expressing different CD44 splice variants (Cd44+/+, Cd44-/-, Cd44s/s, or Cd44v4-10/v4-10 mice).RESULTS: Crypts incubated with EGF or HGF expanded into self-organizing mini-guts with similar levels of efficacy and contained all differentiated cell lineages. MET-deficient mice did not have defects in intestinal homeostasis. Total body irradiation reduced numbers of proliferating crypts

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

Author

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., 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

13. 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

14. 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

15. 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

Abstract

BACKGROUND & AIMS: Resistance of metastatic human colorectal cancer cells to drugs that block epidermal growth factor (EGF) receptor signaling could be caused by aberrant activity of other receptor tyrosine kinases, activating overlapping signaling pathways. One of these receptor tyrosine kinases could be MET, the receptor for hepatocyte growth factor (HGF). We investigated how MET signaling, and its interaction with CD44 (a putative MET coreceptor regulated by Wnt signaling and highly expressed by intestinal stem cells [ISCs] and adenomas) affects intestinal homeostasis, regeneration, and adenoma formation in mini-gut organoids and mice.METHODS: We established organoid cultures from ISCs stimulated with HGF or EGF and assessed intestinal differentiation by immunohistochemistry. Mice with total epithelial disruption of MET (AhCre/Metfl/fl/LacZ) or ISC-specific disruption of MET (Lgr5Creert2/Metfl/fl/LacZ) and control mice (AhCre/Met+/+/LacZ, Lgr5Creert2/Met+/+/LacZ) were exposed to 10 Gy total body irradiation; intestinal tissues were collected, and homeostasis and regeneration were assessed by immunohistochemistry. We investigated adenoma organoid expansion stimulated by HGF or EGF using adenomas derived from Lgr5Creert2/Metfl/fl/Apcfl/fl and Lgr5Creert2/Met+/+/Apcfl/fl mice. The same mice were evaluated for adenoma prevalence and size. We also quantified adenomas in AhCre/Metfl/fl/Apcfl/+ mice compared with AhCre/Met+/+/Apcfl/+ control mice. We studied expansion of organoids generated from crypts and adenomas, stimulated by HGF or EGF, that were derived from mice expressing different CD44 splice variants (Cd44+/+, Cd44-/-, Cd44s/s, or Cd44v4-10/v4-10 mice).RESULTS: Crypts incubated with EGF or HGF expanded into self-organizing mini-guts with similar levels of efficacy and contained all differentiated cell lineages. MET-deficient mice did not have defects in intestinal homeostasis. Total body irradiation reduced numbers of proliferating crypts

Published
2017

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