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

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 tumou...

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Bibliographic Details
Published in:British journal of cancer 2018-05, Vol.118 (10), p.1359-1368
Main Authors: Kim, Dae Joong, Dunleavey, James M., Xiao, Lin, Ollila, David W., Troester, Melissa A., Otey, Carol A., Li, Wei, Barker, Thomas H., Dudley, Andrew C.
Format: Article
Language:English
Subjects:
631/67/232
631/67/327
Animal models
Atomic force microscopy
Biomedical and Life Sciences
Biomedicine
Cancer
Cancer Research
Cell culture
Contraction
Culture
Drug delivery
Drug Resistance
Endothelial cells
Epidemiology
Epigenetics
Extracellular matrix
Fibroblasts
Histone deacetylase
Immune checkpoint
Immunosuppressive agents
Inhibitors
Microscopy
Molecular chains
Molecular Medicine
Oncology
Reversing
Secretion
siRNA
Transgenic mice
Tumors
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Summary: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.
ISSN:0007-0920
1532-1827
DOI:10.1038/s41416-018-0072-3