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Morphological screening of mesenchymal mammary tumor organoids to identify drugs that reverse epithelial-mesenchymal transition

Author

Listed:
  • Na Zhao

    (Baylor College of Medicine)

  • Reid T. Powell

    (Center for Translational Cancer Research, Texas A&M Health Science Center, Institute of Biosciences and Technology)

  • Xueying Yuan

    (Baylor College of Medicine)

  • Goeun Bae

    (Center for Translational Cancer Research, Texas A&M Health Science Center, Institute of Biosciences and Technology)

  • Kevin P. Roarty

    (Baylor College of Medicine)

  • Fabio Stossi

    (Baylor College of Medicine
    Integrated Microscopy Core, Baylor College of Medicine)

  • Martina Strempfl

    (Graz University of Technology, NAWI Graz)

  • Michael J. Toneff

    (Department of Biology, Widener University)

  • Hannah L. Johnson

    (Integrated Microscopy Core, Baylor College of Medicine)

  • Sendurai A. Mani

    (University of Texas MD Anderson Cancer Center)

  • Philip Jones

    (Institute of Applied Cancer Science (IACS), University of Texas MD Anderson Cancer Center)

  • Clifford C. Stephan

    (Center for Translational Cancer Research, Texas A&M Health Science Center, Institute of Biosciences and Technology)

  • Jeffrey M. Rosen

    (Baylor College of Medicine)

Abstract

The epithelial-mesenchymal transition (EMT) has been implicated in conferring stem cell properties and therapeutic resistance to cancer cells. Therefore, identification of drugs that can reprogram EMT may provide new therapeutic strategies. Here, we report that cells derived from claudin-low mammary tumors, a mesenchymal subtype of triple-negative breast cancer, exhibit a distinctive organoid structure with extended “spikes” in 3D matrices. Upon a miR-200 induced mesenchymal-epithelial transition (MET), the organoids switch to a smoother round morphology. Based on these observations, we developed a morphological screening method with accompanying analytical pipelines that leverage deep neural networks and nearest neighborhood classification to screen for EMT-reversing drugs. Through screening of a targeted epigenetic drug library, we identified multiple class I HDAC inhibitors and Bromodomain inhibitors that reverse EMT. These data support the use of morphological screening of mesenchymal mammary tumor organoids as a platform to identify drugs that reverse EMT.

Suggested Citation

  • Na Zhao & Reid T. Powell & Xueying Yuan & Goeun Bae & Kevin P. Roarty & Fabio Stossi & Martina Strempfl & Michael J. Toneff & Hannah L. Johnson & Sendurai A. Mani & Philip Jones & Clifford C. Stephan , 2021. "Morphological screening of mesenchymal mammary tumor organoids to identify drugs that reverse epithelial-mesenchymal transition," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24545-3
    DOI: 10.1038/s41467-021-24545-3
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