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

Significance Multiple myeloma (MM) cells are highly dependent on signals provided by the bone marrow (BM) niche for growth and survival. Most MMs 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 BM niche. In this study we uncover a pivotal role for the leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4)/R-spondin axis in facilitating activation of Wnt signaling in MM. LGR4 is expressed by most MMs, but not by healthy plasma cells, and is regulated by STAT3 signaling. LGR4 expression allows MMs to respond to (pre)osteoblast–derived R-spondins, resulting in stabilization of Wnt receptors and greatly enhanced sensitivity to auto- and paracrine Wnt ligands. These results advocate targeting of proximal Wnt signaling in MM.