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Targeting breast cancer stem cells by a ROR2 specific antibody

ABSTRACT: ROR2 is a type I orphan-receptor tyrosine-kinase-like membrane protein. Its expression level is decreased after birth and barely detectable in adulthood. However, it is re-expressed by various cancer cells and is negatively correlated with patients' survival. The role of ROR2 in breast cancer is still unknown.This study demonstrated that ROR2 activates RhoA GTPase, and induces EMT in breast cancer. In addition, ROR2 is enriched in breast CSCs and required for maintaining the stemness features of CSCs. We developed a ROR2 specific antibody that inhibits breast cancer primary tumor growth and metastasis through targeting CSCs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE191159 | GEO | 2024/12/17

REPOSITORIES: GEO

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	GSE191159_DEseq.normCnt.xlsx	Xlsx
	GSE191159_DEseqAll_Treat_VS_Control.csv.gz	Csv

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Project description:Cellular heterogeneity in breast cancer encompasses many features, yet an understanding of the coexistence and regulation of various tumor cell subpopulations remains a significant challenge in cancer biology. In the current study, we approached tumor cell heterogeneity from the perspective of Wnt pathway biology to address how different modes of Wnt signaling shape the behaviors of diverse cell populations within a heterogeneous tumor landscape. Using a syngeneic TP53 null mouse model of breast cancer, we identified distinctions in the topology of canonical Wnt b-catenin dependent signaling activity and noncanonical b-catenin independent Ror2-mediated Wnt signaling across subtypes and within tumor cell subpopulations in vivo. We further discovered an antagonistic role for Ror2 in regulating canonical Wnt/b-catenin activity in vivo, where lentiviral shRNA depletion of Ror2 expression augmented canonical Wnt/b-catenin signaling activity across multiple basal-like models. Depletion of Ror2 expression yielded distinct phenotypic outcomes and divergent alterations in gene expression programs among different tumors, despite all sharing basal-like features. Notably, we uncovered cell state plasticity and adhesion dynamics regulated by Ror2, where Ras Homology Family Member A (RhoA) and Rho-Associated Coiled-Coil Kinase 1 (ROCK1) activity downstream of Dishevelled-2 (Dvl2) were implicated. Collectively, these studies illustrate the integration and collaboration of Wnt pathways in basal-like breast cancer, where Ror2 provides a spatiotemporal function to regulate the balance of Wnt signaling and cellular heterogeneity during tumor progression.

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