ArticleProceedings of the National Academy of Sciences of the United States of America2017
Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 51 citations in OpenAlex.
- Myeloid Cell-Specific Deletion of LGR4 Suppresses Atherosclerotic Lesion Formation.Arteriosclerosis, thrombosis, and vascular biology · 2026Article
- CD70/CD27 signaling promotes the pathogenesis of multiple myeloma and represents a promising therapeutic target.Leukemia · 2026Article
- Regulatory mechanisms of LGR4 on cancer and cancer stem cell properties.Discover oncology · 2026Review
- Targeting Wnt/β-catenin signaling enhances the efficacy of anti-CD38 immunotherapy in multiple myeloma.Neoplasia (New York, N.Y.) · 2025Article
- Distinct structural mechanisms of LGR4 modulation by Norrin and RSPOs in Wnt/β-catenin signaling.Nature communications · 2025Article
- Genetic, epigenetic, and molecular determinants of multiple myeloma and precursor plasma cell disorders: a pathophysiological overview.Medical oncology (Northwood, London, England) · 2025Review
- LGR4 promotes proliferation and homing via activation of the NF‑κB signaling pathway in multiple myeloma.International journal of oncology · 2025Article
- Structural insights into the LGR4-RSPO2-ZNRF3 complexes regulating WNT/β-catenin signaling.Nature communications · 2025Article
- The role of LGR4 in bone metabolism and tumor bone metastasis.Frontiers in endocrinology · 2025Review
- Polymorphisms in transcription factor binding sites and enhancer regions and pancreatic ductal adenocarcinoma risk.Human genomics · 2024Article
- LncRNA-CCAT5-mediated crosstalk between Wnt/β-Catenin and STAT3 signaling suggests novel therapeutic approaches for metastatic gastric cancer with high Wnt activity.Cancer communications (London, England) · 2024Article
- LGR4: A New Receptor Member in Endocrine and Metabolic Diseases.Endocrine reviews · 2023Review
- Molecular and immunological mechanisms of clonal evolution in multiple myeloma.Frontiers in immunology · 2023Review
- LGR4, a G Protein-Coupled Receptor With a Systemic Role: From Development to Metabolic Regulation.Frontiers in endocrinology · 2022Review
- The clinical significance of spondin 2 eccentric expression in peripheral blood mononuclear cells in bronchial asthma.Journal of clinical laboratory analysis · 2021Article
- Review
- Emerging Roles for LGR4 in Organ Development, Energy Metabolism and Carcinogenesis.Frontiers in genetics · 2021Review
- The role of Wnt/β-catenin signaling pathway in the pathogenesis and treatment of multiple myeloma (review).American journal of translational research · 2021Review
- AKT signaling restrains tumor suppressive functions of FOXO transcription factors and GSK3 kinase in multiple myeloma.Blood advances · 2020Article
- Review
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.