title: Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins.
abstract: The unrestrained growth of tumor cells is generally attributed to mutations in essential growth control genes, but tumor cells are also affected by, or even addicted to, signals from the microenvironment. As therapeutic targets, these extrinsic signals may be equally significant as mutated oncogenes. In multiple myeloma (MM), a plasma cell malignancy, most tumors display hallmarks of active Wnt signaling but lack activating Wnt-pathway mutations, suggesting activation by autocrine Wnt ligands and/or paracrine Wnts emanating from the bone marrow (BM) niche. Here, we report a pivotal role for the R-spondin/leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) axis in driving aberrant Wnt/β-catenin signaling in MM. We show that LGR4 is expressed by MM plasma cells, but not by normal plasma cells or B cells. This aberrant LGR4 expression is driven by IL-6/STAT3 signaling and allows MM cells to hijack R-spondins produced by (pre)osteoblasts in the BM niche, resulting in Wnt (co)receptor stabilization and a dramatically increased sensitivity to auto- and paracrine Wnts. Our study identifies aberrant R-spondin/LGR4 signaling with consequent deregulation of Wnt (co)receptor turnover as a driver of oncogenic Wnt/β-catenin signaling in MM cells. These results advocate targeting of the LGR4/R-spondin interaction as a therapeutic strategy in MM.
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.|Lymphoma and Myeloma Center Amsterdam (LYMMCARE), 1105AZ Amsterdam, The Netherlands.
authors.forename: Harmen
authors.initials: H
authors.lastname: van Andel
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.|Lymphoma and Myeloma Center Amsterdam (LYMMCARE), 1105AZ Amsterdam, The Netherlands.
authors.forename: Zemin
authors.initials: Z
authors.lastname: Ren
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.|Lymphoma and Myeloma Center Amsterdam (LYMMCARE), 1105AZ Amsterdam, The Netherlands.
authors.forename: Iris
authors.initials: I
authors.lastname: Koopmans
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.|Lymphoma and Myeloma Center Amsterdam (LYMMCARE), 1105AZ Amsterdam, The Netherlands.
authors.forename: Sander P J
authors.initials: SP
authors.lastname: Joosten
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.|Lymphoma and Myeloma Center Amsterdam (LYMMCARE), 1105AZ Amsterdam, The Netherlands.|Department of Medical Biochemistry, Jagiellonian University Medical College, 31008 Krakow, Poland.
authors.forename: Kinga A
authors.initials: KA
authors.lastname: Kocemba
authors.affiliation: Hubrecht Institute, 3584CT Utrecht, The Netherlands.
authors.forename: Wim
authors.initials: W
authors.lastname: de Lau
authors.affiliation: Lymphoma and Myeloma Center Amsterdam (LYMMCARE), 1105AZ Amsterdam, The Netherlands.|Department of Hematology, Academic Medical Center, University of Amsterdam, 1105AZ Amsterdam, The Netherlands.
authors.forename: Marie José
authors.initials: MJ
authors.lastname: Kersten
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.|Lymphoma and Myeloma Center Amsterdam (LYMMCARE), 1105AZ Amsterdam, The Netherlands.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: de Bruin
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.|Lymphoma and Myeloma Center Amsterdam (LYMMCARE), 1105AZ Amsterdam, The Netherlands.
authors.forename: Jeroen E J
authors.initials: JE
authors.lastname: Guikema
authors.affiliation: Hubrecht Institute, 3584CT Utrecht, The Netherlands; h.clevers@hubrecht.eu s.t.pals@amc.uva.nl.
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.|Lymphoma and Myeloma Center Amsterdam (LYMMCARE), 1105AZ Amsterdam, The Netherlands.
authors.forename: Marcel
authors.initials: M
authors.lastname: Spaargaren
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; h.clevers@hubrecht.eu s.t.pals@amc.uva.nl.|Lymphoma and Myeloma Center Amsterdam (LYMMCARE), 1105AZ Amsterdam, The Netherlands.
authors.forename: Steven T
authors.initials: ST
authors.lastname: Pals
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008024:Ligands; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D009101:Multiple Myeloma / Q000378:metabolism*; D010006:Osteoblasts / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D008024:Ligands; D008562:Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; D050796:STAT3 Transcription Factor; D051153:Wnt Proteins; D051176:beta Catenin
keywords: LGR4; R-spondins; Wnt signaling; multiple myeloma; osteoblast