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

Frenquelli, Michela; Caridi, Nicoletta; Antonini, Elena; Storti, Federica; Viganò, Valentina; Gaviraghi, Marco; Occhionorelli, Manuela; Bianchessi, Silvia; Bongiovanni, Lucia; Spinelli, Antonello E.; Marcatti, Magda; Belloni, Daniela; Ferrero, Elisabetta; Karki, Shakun; Brambilla, Paola; Boneschi, Filippo Martinelli; Colla, Simona; Ponzoni, Maurilio; DePinho, Ronald A.; Tonon, Giovanni

doi:10.1038/s41375-019-0486-9

Cited by 36 publications

(27 citation statements)

References 42 publications

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“…Almost all MM patients evolve from an asymptomatic pre-malignant stage termed monoclonal gammopathy of undetermined significance (MGUS). Despite that hotspot mutations of PIK3CA (E542K, E545K and H1047R) and AKT1 genes (E17K) are absent in MM [329], the R310C mutation of PIK3CA gene [330] is identified in some cases of MM, as well as ROR2 drives the interaction of MM cells with TME through AKT activation [331]. Furthermore, only the blockade of PIK3CA is sufficient to induce cell death in a sizeable subgroup of MM samples, and PIK3CA inhibitor BYL-719 in combination treatments with other compounds establishes anti-myeloma agents resulted in strongly enhanced MM cell death [332].…”

Section: Description Of the Pi3k/akt Pathway In The Hemato-immune Sysmentioning

confidence: 99%

Role of PI3K/AKT pathway in cancer: the framework of malignant behavior

et al. 2020

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Given that the PI3K/AKT pathway has manifested its compelling influence on multiple cellular process, we further review the roles of hyperactivation of PI3K/AKT pathway in various human cancers. We state the abnormalities of PI3K/AKT pathway in different cancers, which are closely related with tumorigenesis, proliferation, growth, apoptosis, invasion, metastasis, epithelial-mesenchymal transition, stem-like phenotype, immune microenvironment and drug resistance of cancer cells. In addition, we investigated the current clinical trials of inhibitors against PI3K/AKT pathway in cancers and found that the clinical efficacy of these inhibitors as monotherapy has so far been limited despite of the promising preclinical activity, which means combinations of targeted therapy may achieve better efficacies in cancers. In short, we hope to feature PI3K/ AKT pathway in cancers to the clinic and bring the new promising to patients for targeted therapies.

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Section: Description Of the Pi3k/akt Pathway In The Hemato-immune Sysmentioning

confidence: 99%

Role of PI3K/AKT pathway in cancer: the framework of malignant behavior

et al. 2020

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“…bFGF stimulation, among NIH/3T3 cells treated with control siRNA (si-Ctrl), only 31.1% of cells were at G1 phase and about half of cells were at G2/M phase (46.5%), while among the cells treated with si-Ror2, the proportions of cells at G1 phase were increased (si-Ror2#1, 41.8%; si-Ror2#2, 48.5%) and those at G2/M phase were decreased (si-Ror2#1, 36.3%; si-Ror2#2, 32.0%) ( Figure 3B). EdU-incorporation analysis revealed that entry into S phase was delayed in cells treated with si-Ror2 compared to those treated with si-Ctrl ( Figure 3C,D).…”

Section: F I G U R E 1 Expression Of Ror2 Is Upregulated By Serum-or mentioning

confidence: 99%

E2F1‐Ror2 signaling mediates coordinated transcriptional regulation to promote G1/S phase transition in bFGF‐stimulated NIH/3T3 fibroblasts

2020

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Ror2 signaling has been shown to regulate the cell cycle progression in normal and cancer cells. However, the molecular mechanism of the cell cycle progression upon activation of Ror2 signaling still remains unknown. Here, we found that the expression levels of Ror2 in G1‐arrested NIH/3T3 fibroblasts are low and are rapidly increased following the cell cycle progression induced by basic fibroblast growth factor (bFGF) stimulation. By expressing wild‐type or a dominant negative mutant of E2F1, we show that E2F1 mediates bFGF‐induced expression of Ror2, and that E2F1 binds to the promoter of the Ror2 gene to activate its expression. We also found that G1/S phase transition of bFGF‐stimulated NIH/3T3 cells is delayed by the suppressed expression of Ror2. RNA‐seq analysis revealed that the suppressed expression of Ror2 results in the decreased expression of various E2F target genes concomitantly with increased expression of Forkhead box O (FoxO) target genes, including p21Cip1, and p27Kip1. Moreover, the inhibitory effect of Ror2 knockdown on the cell cycle progression can be restored by suppressed expression of p21Cip1, p27Kip1,or FoxO3a. Collectively, these findings indicate that E2F1‐Ror2 signaling mediates the transcriptional activation and inhibition of E2F1‐driven and FoxO3a‐driven cell cycle‐regulated genes, respectively, thereby promoting G1/S phase transition of bFGF‐stimulated NIH/3T3 cells.

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“…ROR2 is involved in the WNT signaling pathway when associated with its ligand WNT5A and facilitates polarization of cells during embryonic development along with regulating migration and differentiation (9)(10)(11)(12). While largely downregulated after birth in mice (6) and humans (8,13), ROR2 is overexpressed in several cancers (7,9) including solid malignancies such as renal cell adenocarcinoma and subsets of breast cancer, and hematologic malignancies, such as multiple myeloma (14)(15)(16). Among solid malignancies without FDA-approved and marketed antibodybased cancer therapies, a notable indication is sarcoma where ROR2 overexpression was found in osteosarcoma, leiomyosarcoma, and gastrointestinal stromal tumor (GIST) (13,17).…”

Section: Introductionmentioning

confidence: 99%

Affinity maturation, humanization, and co-crystallization of a rabbit anti-human ROR2 monoclonal antibody for therapeutic applications

Goydel

Weber

Peng

et al. 2020

Journal of Biological Chemistry

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Antibodies are widely used as cancer therapeutics, but their current use is limited by the low number of antigens restricted to cancer cells. A receptor tyrosine kinase, receptor tyrosine kinase-like orphan receptor 2 (ROR2), is normally expressed only during embryogenesis and is tightly down-regulated in postnatal healthy tissues. However, it is up-regulated in a diverse set of hematologic and solid malignancies, thus ROR2 represents a candidate antigen for antibody-based cancer therapy. Here we describe the affinity maturation and humanization of a rabbit mAb that binds human and mouse ROR2 but not human ROR1 or other human cell-surface antigens. Co-crystallization of the parental rabbit mAb in complex with the human ROR2 kringle domain (hROR2-Kr) guided affinity maturation by heavy-chain complementarity-determining region 3 (HCDR3)-focused mutagenesis and selection. The affinity-matured rabbit mAb was then humanized by complementarity-determining region (CDR) grafting and framework fine tuning and again co-crystallized with hROR2-Kr. We show that the affinity-matured and humanized mAb retains strong affinity and specificity to ROR2 and, following conversion to a T cell–engaging bispecific antibody, has potent cytotoxicity toward ROR2-expressing cells. We anticipate that this humanized affinity-matured mAb will find application for antibody-based cancer therapy of ROR2-expressing neoplasms.

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

Cited by 36 publications

References 42 publications

Role of PI3K/AKT pathway in cancer: the framework of malignant behavior

Role of PI3K/AKT pathway in cancer: the framework of malignant behavior

E2F1‐Ror2 signaling mediates coordinated transcriptional regulation to promote G1/S phase transition in bFGF‐stimulated NIH/3T3 fibroblasts

Affinity maturation, humanization, and co-crystallization of a rabbit anti-human ROR2 monoclonal antibody for therapeutic applications

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