The liver kinase B1 supports mammary epithelial morphogenesis by inhibiting critical factors that mediate epithelial‐mesenchymal transition

  • Kalliopi Tzavlaki
    Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Biomedical Center Uppsala University Uppsala Sweden
  • Yae Ohata
    Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Biomedical Center Uppsala University Uppsala Sweden
  • Anita Morén
    Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Biomedical Center Uppsala University Uppsala Sweden
  • Yukihide Watanabe
    Department of Experimental Pathology and Transborder Medical Research Center, Faculty of Medicine University of Tsukuba Tsukuba Ibaraki Japan
  • Jens Eriksson
    Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Biomedical Center Uppsala University Uppsala Sweden
  • Maiko Tsuchiya
    Department of Oral Pathology, Graduate School of Medical and Dental Sciences Tokyo Medical and Dental University Tokyo Japan
  • Yuki Kubo
    Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences Tokyo Medical and Dental University Tokyo Japan
  • Kouhei Yamamoto
    Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences Tokyo Medical and Dental University Tokyo Japan
  • Mikael E. Sellin
    Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Biomedical Center Uppsala University Uppsala Sweden
  • Mitsuyasu Kato
    Department of Experimental Pathology and Transborder Medical Research Center, Faculty of Medicine University of Tsukuba Tsukuba Ibaraki Japan
  • Laia Caja
    Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Biomedical Center Uppsala University Uppsala Sweden
  • Carl‐Henrik Heldin
    Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Biomedical Center Uppsala University Uppsala Sweden
  • Aristidis Moustakas
    Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Biomedical Center Uppsala University Uppsala Sweden

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<jats:title>Abstract</jats:title><jats:p>The liver kinase B1 (LKB1) controls cellular metabolism and cell polarity across species. We previously established a mechanism for negative regulation of transforming growth factor β (TGFβ) signaling by LKB1. The impact of this mechanism in the context of epithelial polarity and morphogenesis remains unknown. After demonstrating that human mammary tissue expresses robust LKB1 protein levels, whereas invasive breast cancer exhibits significantly reduced LKB1 levels, we focused on mammary morphogenesis studies in three dimensional (3D) acinar organoids. CRISPR/Cas9‐introduced loss‐of‐function mutations of <jats:italic>STK11</jats:italic> (<jats:italic>LKB1</jats:italic>) led to profound defects in the formation of 3D organoids, resulting in amorphous outgrowth and loss of rotation of young organoids embedded in matrigel. This defect was associated with an enhanced signaling by TGFβ, including TGFβ auto‐induction and induction of transcription factors that mediate epithelial‐mesenchymal transition (EMT). Protein marker analysis confirmed a more efficient EMT response to TGFβ signaling in <jats:italic>LKB1</jats:italic> knockout cells. Accordingly, chemical inhibition of the TGFβ type I receptor kinase largely restored the morphogenetic defect of <jats:italic>LKB1</jats:italic> knockout cells. Similarly, chemical inhibition of the bone morphogenetic protein pathway or the TANK‐binding kinase 1, or genetic silencing of the EMT factor SNAI1, partially restored the <jats:italic>LKB1</jats:italic> knockout defect. Thus, LKB1 sustains mammary epithelial morphogenesis by limiting pathways that promote EMT. The observed downregulation of LKB1 expression in breast cancer is therefore predicted to associate with enhanced EMT induced by SNAI1 and TGFβ family members.</jats:p>

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