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

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

Publication date: May 31, 2019

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.

Frenquelli, M., Caridi, N., Antonini, E., Storti, F., , Vigan`o, Gaviraghi, M., Occhionorelli, M., Bianchessi, S., Bongiovanni, L., Spinelli, A., Marcatti, M., Belloni, D., Ferrero, E., Karki, S., Brambilla, P., Martinelli-Boneschi, F., Colla, S., Ponzoni, M., DePinho, R.A., and Tonon, G. The WNT receptor ROR2 drives the interaction of multiple myeloma cells with the microenvironment through AKT activation. 18177. 2019 Leukemia.

Concepts Keywords
3D Culture systems
Adhesion Incurable disease
AKT Multiple myeloma
Apoptosis Frequent hematological lymphoma
Bone Marrow Tyrosine kinase receptors
Deregulated Multiple myeloma
Growth Factor RTT
Hematological ROR2
Leukemia Apoptosis
Ligand
Lymphoma
Microenvironment
MTOR
Multiple Myeloma
Myeloma
PI3K
Receptor
Subgroup
Tyrosine
Vivo

Semantics

Type Source Name
gene UNIPROT LARGE1
gene UNIPROT MTOR
gene UNIPROT PIK3CG
gene UNIPROT PIK3CB
gene UNIPROT PIK3CD
gene UNIPROT PIK3CA
disease MESH disease progression
pathway BSID Apoptosis
disease MESH growth
gene UNIPROT WNT5A
drug DRUGBANK L-Tyrosine
disease DOID myeloma
disease DOID lymphoma
disease MESH lymphoma
disease DOID cancer
disease MESH cancer
gene UNIPROT AKT1
disease DOID multiple myeloma
disease MESH multiple myeloma
gene UNIPROT RORA
gene UNIPROT ROR2

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