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

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

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

28 Citaten (Scopus)


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/ß-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/ß-catenin signaling in MM cells. These results advocate targeting of the LGR4/R-spondin interaction as a therapeutic strategy in MM.

Originele taal-2Engels
Pagina's (van-tot)376-381
Aantal pagina's6
TijdschriftProceedings of the National Academy of Sciences of the United States of America
Nummer van het tijdschrift2
StatusGepubliceerd - 10 jan. 2017
Extern gepubliceerdJa


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