Article | Published:

Cellular and Molecular Biology

Suppression of TGFβ-mediated conversion of endothelial cells and fibroblasts into cancer associated (myo)fibroblasts via HDAC inhibition

British Journal of Cancervolume 118pages13591368 (2018) | Download Citation

Abstract

Background

Cancer-associated fibroblasts (CAFs) support tumour progression and invasion, and they secrete abundant extracellular matrix (ECM) that may shield tumour cells from immune checkpoint or kinase inhibitors. Targeting CAFs using drugs that revert their differentiation, or inhibit their tumour-supportive functions, has been considered as an anti-cancer strategy.

Methods

We have used human and murine cell culture models, atomic force microscopy (AFM), microarray analyses, CAF/tumour cell spheroid co-cultures and transgenic fibroblast reporter mice to study how targeting HDACs using small molecule inhibitors or siRNAs re-directs CAF differentiation and function in vitro and in vivo.

Results

From a small molecule screen, we identified Scriptaid, a selective inhibitor of HDACs 1/3/8, as a repressor of TGFβ-mediated CAF differentiation. Scriptaid inhibits ECM secretion, reduces cellular contraction and stiffness, and impairs collective cell invasion in CAF/tumour cell spheroid co-cultures. Scriptaid also reduces CAF abundance and delays tumour growth in vivo.

Conclusions

Scriptaid is a well-tolerated and effective HDACi that reverses many of the functional and phenotypic properties of CAFs. Impeding or reversing CAF activation/function by altering the cellular epigenetic regulatory machinery could control tumour growth and invasion, and be beneficial in combination with additional therapies that target cancer cells or immune cells directly.

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Note: This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License.

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Author information

Affiliations

  1. Department of Microbiology, Immunology, and Cancer Biology, The University of Virginia, Charlottesville, VA, 22908, USA

    • Dae Joong Kim
    •  & Andrew C. Dudley
  2. National Cancer Institute, Tumor Angiogenesis Unit, Center for Cancer Research, Frederick, MD, 21702, USA

    • James M. Dunleavey
  3. Children’s Cancer Institute, Kensington, NSW 2750, Australia

    • Lin Xiao
  4. Department of Surgery, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    • David W. Ollila
  5. Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    • Melissa A. Troester
  6. Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    • Carol A. Otey
  7. Department of Biomedical Engineering, The University of Virginia, Charlottesville, VA, 22908, USA

    • Wei Li
    •  & Thomas H. Barker
  8. Emily Couric Cancer Center, The University of Virginia, Charlottesville, VA, 22908, USA

    • Andrew C. Dudley

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Contributions

DJ.K designed and carried out the experiments and wrote the manuscript. J.M.D. assisted with microarray analysis, L.X. isolated tumour associated endothelial cells, D.W.O. provided human melanoma biopsies, M.A.T. provided human breast tissue CAFs, C.A.O. provided palladin antibodies and advice on the experimental design, W.L. carried out atomic force microscopy and analysis, T.H.B. provided the atomic force microscope, reagents, materials, and advice for the experimental design. A.C.D. designed the experiments and wrote the manuscript.

Competing interests

The authors declare no competing interests.

Ethics approval and consent

No human subjects were used. All animal experiments were performed in accordance with the University of North Carolina at Chapel Hill and the University of Virginia guidelines for animal handling and care.

Availability of materials

All materials and datasets will be made available by sending an email request to the corresponding author. Raw data from the array will also be deposited here (https://www.ncbi.nlm.nih.gov/geo/).

Corresponding author

Correspondence to Andrew C. Dudley.

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DOI

https://doi.org/10.1038/s41416-018-0072-3

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