Vangl-dependent Wnt/planar cell polarity signaling mediates collective breast carcinoma motility and distant metastasis

Breast Cancer Research

Research

Kacey VanderVorst¹  Kermit L. Carraway¹  Hyun Lee¹  Julie A. Learn¹  Maria Hernandez¹  Courtney A. Dreyer¹  Anastasia L. Berg¹  George R. R. Bell²  Sean R. Collins²  Jason Hatakeyama³ 

[1] Department of Biochemistry and Molecular Medicine and University of California Davis Comprehensive Cancer Center, University of California Davis School of Medicine, Sacramento, CA, USA;Department of Microbiology and Molecular Genetics, University of California Davis, Davis, CA, USA;Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA;

关键词: Collective cell migration;    Planar cell polarity;    Non-canonical Wnt;    Metastasis;   

DOI  :  10.1186/s13058-023-01651-2

 received in 2022-12-18, accepted in 2023-04-23,  发布年份 2023

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© The Author(s) 2023

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