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Science. 2016 Mar 4;351(6277):aad3680. doi: 10.1126/science.aad3680.

Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability.

Author information

1
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
2
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Genome Institute of Singapore, 60 Biopolis Street, Singapore. Cancer Science Institute of Singapore, 14 Medical Drive, Singapore.
3
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Ludwig Center for Molecular Oncology at MIT, Cambridge, MA 02142, USA. weinberg@wi.mit.edu.

Abstract

The epithelial-to-mesenchymal transition enables carcinoma cells to acquire malignancy-associated traits and the properties of tumor-initiating cells (TICs). TICs have emerged in recent years as important targets for cancer therapy, owing to their ability to drive clinical relapse and enable metastasis. Here, we propose a strategy to eliminate mesenchymal TICs by inducing their conversion to more epithelial counterparts that have lost tumor-initiating ability. We report that increases in intracellular levels of the second messenger, adenosine 3',5'-monophosphate, and the subsequent activation of protein kinase A (PKA) induce a mesenchymal-to-epithelial transition (MET) in mesenchymal human mammary epithelial cells. PKA activation triggers epigenetic reprogramming of TICs by the histone demethylase PHF2, which promotes their differentiation and loss of tumor-initiating ability. This study provides proof-of-principle for inducing an MET as differentiation therapy for TICs and uncovers a role for PKA in enforcing and maintaining the epithelial state.

PMID:
26941323
PMCID:
PMC5131720
DOI:
10.1126/science.aad3680
[Indexed for MEDLINE]
Free PMC Article

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