Ror2-mediated alternative Wnt signaling regulates cell fate and adhesion during mammary tumor progression

Year: 2017

Type: article

Abstract: Cellular heterogeneity is a common feature in breast cancer, 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 β-catenin-dependent signaling activity and non-canonical β-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/β-catenin activity in vivo, where lentiviral shRNA depletion of Ror2 expression augmented canonical Wnt/β-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, which influenced Ras Homology Family Member A (RhoA) and Rho-Associated Coiled-Coil Kinase 1 (ROCK1) activity downstream of Dishevelled-2 (Dvl2). 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.

Source: Oncogene

DOI: 10.1038/onc.2017.206

Authors: K Roarty, A D Pfefferle, C J Creighton, C M Perou, J M Rosen

Institutions: Baylor College of Medicine, University of North Carolina at Chapel Hill, UNC Lineberger Comprehensive Cancer Center, Dan L Duncan Comprehensive Cancer Center

Language: English

Topic: Wnt/β-catenin signaling in development and cancer

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $5,990

Funders: U.S. Department of Defense, Dan L. Duncan Cancer Center, Baylor College of Medicine, John S. Dunn Gulf Coast Consortium for Chemical Genomics, National Institutes of Health, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources, Eunice Kennedy Shriver National Institute of Child Health and Human Development

OpenAlex ID: W2675697980