Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability
Year: 2016
Type: article
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.
Source: Science
Language: English
Topic: Cancer Cells and Metastasis
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: American Cancer Society, Breast Cancer Research Foundation, Samuel Waxman Cancer Research Foundation, Virginia and D.K. Ludwig Fund for Cancer Research, Broad Institute, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Verastem Oncology, National Research Foundation, National Research Foundation Singapore, National Institutes of Health, Ludwig Center at Harvard, Medical Research Council, National Health and Medical Research Council, National Medical Research Council, National Cancer Institute
Awards: Exploiting the epithelial-to-mesenchymal transition for the differentiation of cancer stem cells, G3771020494, Exploiting the epithelial-to-mesenchymal transition for the differentiation of cancer stem cells, G6534215251, G7160909116, Mechanisms of Breast Development and Carcinogenesis, Targeting the epithelial-to-mesenchymal transition in basal-like breast cancers, Induced Differentiation to Deplete CSCs from Breast Cancer
OpenAlex ID: W2289283229