ArticleBreast cancer research : BCR2023
Vangl-dependent Wnt/planar cell polarity signaling mediates collective breast carcinoma motility and distant metastasis.
Article in Breast cancer research : BCR, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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22 citing papers in PubMed, 26 citations in OpenAlex.
- Phosphorylated HPV‑16 E7 disrupts planar cell polarity in cervical cancer cells through vangl1 dysregulation.PLoS pathogens · 2026Article
- Role of epithelial-mesenchymal transition (EMT) in malignancies: current status and future prospects.Signal transduction and targeted therapy · 2026Review
- Hypoxia-induced mechanism of TNBC promoting tumour cell proliferation through exosomal miRNA.Mammalian genome : official journal of the International Mammalian Genome Society · 2026Article
- CRB2 Facilitates Epithelial Ovarian Cancer Progression by Inducing Polarity Changes via Activation of the Wnt/PCP Signalling Pathway.Journal of cellular and molecular medicine · 2026Article
- VANGL1 links angiogenesis-stemness programs and tumor microenvironment remodeling: a pan-cancer, multi-omics study with translational validation.Frontiers in oncology · 2026Article
- Emerging Approaches in Breast Cancer: From Molecular Mechanisms to Diagnosis and Therapeutic Strategies.Oncology research · 2026Review
- The Role of Actin-Binding Proteins in Breast Cancer Progression.Breast cancer (Dove Medical Press) · 2026Review
- Distinct transcriptional regulation of the Wnt and TGFβ signaling families associated with wound healing and fibrotic outcomes to lens injury.Experimental eye research · 2025Article
- Coupling mathematical modeling with a novel human intestinal stem cell system to understand feedback regulation during planar cell polarity.bioRxiv : the preprint server for biology · 2025Article
- Primary cilia and cancer: a tale of many faces.Oncogene · 2025Review
- Recent advances in understanding the role of Wnt5a in prostate cancer and bone metastasis.Discover oncology · 2025Review
- VANGL2 downregulates HINT1 to inhibit the ATM-p53 pathway and promote cisplatin resistance in small cell lung cancer.Cell death discovery · 2025Article
- Breaking barriers in cancer diagnosis: unveiling the 4Ms of biosensors.RSC advances · 2025Review
- Targeting Wnt-driven metabolic adaptations in cancer: integrating glycolysis, glutaminolysis, IDO1-mediated immune evasion, and therapeutic delivery strategies.Frontiers in cell and developmental biology · 2025Review
- Organoids in breast cancer translational research: intersection of technologies.Translational breast cancer research : a journal focusing on translational research in breast cancer · 2025Review
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- Wnt Signaling in Hepatocellular Carcinoma: Biological Mechanisms and Therapeutic Opportunities.Cells · 2024Review
- Interplay between Wnt signaling molecules and exosomal miRNAs in breast cancer (Review).Oncology reports · 2024Review
- Stearoylation cycle regulates the cell surface distribution of the PCP protein Vangl2.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundIn light of the growing appreciation for the role of collective cell motility in metastasis, a deeper understanding of the underlying signaling pathways will be critical to translating these observations to the treatment of advanced cancers. Here, we examine the contribution of Wnt/planar cell polarity (Wnt/PCP), one of the non-canonical Wnt signaling pathways and defined by the involvement of the tetraspanin-like proteins Vangl1 and Vangl2, to breast tumor cell motility, collective cell invasiveness and mammary tumor metastasis.
methodsVangl1 and Vangl2 knockdown and overexpression and Wnt5a stimulation were employed to manipulate Wnt/PCP signaling in a battery of breast cancer cell lines representing all breast cancer subtypes, and in tumor organoids from MMTV-PyMT mice. Cell migration was assessed by scratch and organoid invasion assays, Vangl protein subcellular localization was assessed by confocal fluorescence microscopy, and RhoA activation was assessed in real time by fluorescence imaging with an advanced FRET biosensor. The impact of Wnt/PCP suppression on mammary tumor growth and metastasis was assessed by determining the effect of conditional Vangl2 knockout on the MMTV-NDL mouse mammary tumor model.
resultsWe observed that Vangl2 knockdown suppresses the motility of all breast cancer cell lines examined, and overexpression drives the invasiveness of collectively migrating MMTV-PyMT organoids. Vangl2-dependent RhoA activity is localized in real time to a subpopulation of motile leader cells displaying a hyper-protrusive leading edge, Vangl protein is localized to leader cell protrusions within leader cells, and actin cytoskeletal regulator RhoA is preferentially activated in the leader cells of a migrating collective. Mammary gland-specific knockout of Vangl2 results in a striking decrease in lung metastases in MMTV-NDL mice, but does not impact primary tumor growth characteristics.
conclusionsWe conclude that Vangl-dependent Wnt/PCP signaling promotes breast cancer collective cell migration independent of breast tumor subtype and facilitates distant metastasis in a genetically engineered mouse model of breast cancer. Our observations are consistent with a model whereby Vangl proteins localized at the leading edge of leader cells in a migrating collective act through RhoA to mediate the cytoskeletal rearrangements required for pro-migratory protrusion formation.
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