miR-200 deficiency promotes lung cancer metastasis by activating Notch signaling in cancer-associated fibroblasts

  1. Lin He1
  1. 1Division of Cellular and Developmental Biology, Molecular and Cell Biology Department, University of California at Berkeley, Berkeley, California 94705, USA;
  2. 2Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA;
  3. 3The Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
  4. 4Cambridge Institute of Therapeutic Immunology and Infectious Disease, Department of Medicine, University of Cambridge, Cambridge CB2 0AW, United Kingdom;
  5. 5Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil;
  6. 6Thermo Fisher Scientific, South San Francisco, California 94080, USA;
  7. 7Department of Statistics, University of California at Berkeley, Berkeley, California 94705, USA;
  8. 8Bioinformatics and Biostatistics, Department of Computational Biology, USR 3756, Centre National de la Recherche Scientifique, Institut Pasteur, Paris 01 45 68 80 00, France;
  9. 9Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;
  10. 10Department of Microbiology and Immunology, University of California at San Francisco Diabetes Center, W.M. Keck Center for Noncoding RNAs, University of California at San Francisco, San Francisco, California 94143, USA;
  11. 11Central Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China
  1. Corresponding authors: lhe{at}berkeley.edu, su_bo_s{at}hotmail.com

Abstract

Lung adenocarcinoma, the most prevalent lung cancer subtype, is characterized by its high propensity to metastasize. Despite the importance of metastasis in lung cancer mortality, its underlying cellular and molecular mechanisms remain largely elusive. Here, we identified miR-200 miRNAs as potent suppressors for lung adenocarcinoma metastasis. miR-200 expression is specifically repressed in mouse metastatic lung adenocarcinomas, and miR-200 decrease strongly correlates with poor patient survival. Consistently, deletion of mir-200c/141 in the KrasLSL-G12D/+; Trp53flox/flox lung adenocarcinoma mouse model significantly promoted metastasis, generating a desmoplastic tumor stroma highly reminiscent of metastatic human lung cancer. miR-200 deficiency in lung cancer cells promotes the proliferation and activation of adjacent cancer-associated fibroblasts (CAFs), which in turn elevates the metastatic potential of cancer cells. miR-200 regulates the functional interaction between cancer cells and CAFs, at least in part, by targeting Notch ligand Jagged1 and Jagged2 in cancer cells and inducing Notch activation in adjacent CAFs. Hence, the interaction between cancer cells and CAFs constitutes an essential mechanism to promote metastatic potential.

Keywords

Footnotes

  • Received March 9, 2021.
  • Accepted June 23, 2021.

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