Journal
SCIENCE
Volume 351, Issue 6277, Pages 1042-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aad3680
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Funding
- C. J. Martin Overseas Biomedical Fellowship from the National Health and Medical Research Council of Australia [NHMRC APP1071853]
- National Research Foundation, Singapore [NRF-NRFF2015-04]
- National Medical Research Council, Singapore [NMRC/TCR/007-NCC/2013]
- Ludwig Center for Molecular Oncology at MIT
- Breast Cancer Research Foundation
- Samuel Waxman Cancer Research Foundation
- NIH [R01-CA078461]
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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.
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