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Multiple myeloma, gammopathies

The WNT receptor ROR2 drives the interaction of multiple myeloma cells with the microenvironment through AKT activation

Leukemia volume 34, pages 257–270 (2020)Cite this article

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Abstract

Multiple myeloma is the second most frequent hematological cancer after lymphoma and remains an incurable disease. The pervasive support provided by the bone marrow microenvironment to myeloma cells is crucial for their survival. Here, an unbiased assessment of receptor tyrosine kinases overexpressed in myeloma identified ROR2, a receptor for the WNT noncanonical pathway, as highly expressed in myeloma cells. Its ligand, WNT5A is the most abundant growth factor in the bone marrow of myeloma patients. ROR2 mediates myeloma cells interactions with the surrounding bone marrow and its depletion resulted in detachment of myeloma cells from their niche in an in vivo model, triggering apoptosis and thus markedly delaying disease progression. Using in vitro and ex vivo 3D-culture systems, ROR2 was shown to exert a pivotal role in the adhesion of cancer cells to the microenvironment. Genomic studies revealed that the pathways mostly deregulated by ROR2 overexpression were PI3K/AKT and mTOR. Treatment of cells with specific PI3K inhibitors already used in the clinic reduced myeloma cell adhesion to the bone marrow. Together, our findings support the view that ROR2 and its downstream targets represent a novel therapeutic strategy for the large subgroup of MM patients whose cancer cells show ROR2 overexpression.

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Acknowledgements

The authors wish to thank all the members of Tonon’s lab for collaborative and helpful discussion and critical reading of the paper, and R. Molteni and R. Pardi for helpful suggestions. Funding for this research was provided by Fondazione Cariplo, Association for International Cancer Research (AICR no. 09-0713 to GT), Associazione Italiana per la Ricerca sul Cancro (AIRC Special Program Molecular Clinical Oncology, 5 per mille no. 9965 to GT), Multiple Myeloma Research Foundation (MMRF Research Fellow Award to MF), and Ministero della salute (GR-2011-02351686 to MF).

Author information

Author notes

  1. E. Antonini

    Present address: Molecular Haematology Laboratory, IRCCS San Raffaele Scientific Institute, Milan, Italy

  2. F. Storti

    Present address: Lab for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Schlieren, Switzerland

  3. V. Viganò

    Present address: Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy

  4. M. Gaviraghi

    Present address: Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy

Authors and Affiliations

  1. Functional Genomics of Cancer Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy

    M. Frenquelli, N. Caridi, E. Antonini, F. Storti, V. Viganò, M. Gaviraghi, M. Occhionorelli & G. Tonon

  2. Laboratory of Lymphoid Organ Development, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy

    S. Bianchessi

  3. Pathology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy

    L. Bongiovanni & M. Ponzoni

  4. Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy

    A. Spinelli

  5. Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy

    M. Marcatti

  6. Tumor Microenvironment, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy

    D. Belloni & E. Ferrero

  7. Cardiovascular Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA

    S. Karki

  8. Laboratory of Human Genetics of Neurological Disorders, CNS Inflammatory Unit, Institute of Experimental Neurology, IRCCS San Raffaele Scientific Institute, Milan, Italy

    P. Brambilla & F. Martinelli-Boneschi

  9. Milan Department of Biomedical Sciences for Health, University of Milan, Milan, Italy

    F. Martinelli-Boneschi

  10. Department of Neurology and Multiple Sclerosis (MS) Research Centre, IRCCS Policlinico San Donato, San Donato Milanese, MI, Italy

    F. Martinelli-Boneschi

  11. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    S. Colla

  12. Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    R. A. DePinho

  13. Center for Translational Genomics and Bioinformatics, IRCCS San Raffaele Scientific Institute, Milan, Italy

    G. Tonon

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  1. M. Frenquelli
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Contributions

MF designed the study, performed experiments, analyzed the data, and wrote the paper. NC, EA, FS, and VV performed experiments. SB and MO helped with in vivo experiments. MG provided technical help and helpful discussion. DB and EF performed 3D experiments. AS assisted with the in vivo imaging. LB and MP performed and analyzed histology samples. SC and RK prepared reagents. PB and FMB performed gene expression profiling. MM provided primary samples. RAD designed the study and critically reviewed the paper. GT designed the study, analyzed the data, and wrote the paper.

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Correspondence to M. Frenquelli or G. Tonon.

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The authors declare that they have no conflict of interest. Although not directly impacting this study, R.A.D. is a co-founder, advisor and director of Tvardi Therapeutics.

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Frenquelli, M., Caridi, N., Antonini, E. et al. The WNT receptor ROR2 drives the interaction of multiple myeloma cells with the microenvironment through AKT activation. Leukemia 34, 257–270 (2020). https://doi.org/10.1038/s41375-019-0486-9

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