title: Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability.
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.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Diwakar R
authors.initials: DR
authors.lastname: Pattabiraman
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Bierie
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Katharina Isabelle
authors.initials: KI
authors.lastname: Kober
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Prathapan
authors.initials: P
authors.lastname: Thiru
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Jordan A
authors.initials: JA
authors.lastname: Krall
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Zill
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Reinhardt
authors.affiliation: 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.
authors.forename: Wai Leong
authors.initials: WL
authors.lastname: Tam
authors.affiliation: 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.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Weinberg
mesh_terms: D000249:Adenosine Monophosphate / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D002772:Cholera Toxin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D044127:Epigenesis, Genetic; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D056466:Histone Demethylases / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D042361:Mammary Glands, Human / Q000378:metabolism / Q000473:pathology; D008648:Mesoderm / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D015290:Second Messenger Systems; D023041:Xenograft Model Antitumor Assays
chemical_list: D018398:Homeodomain Proteins; C117905:PHF2 protein, human; D005576:Colforsin; D000249:Adenosine Monophosphate; D002772:Cholera Toxin; D056466:Histone Demethylases; D017868:Cyclic AMP-Dependent Protein Kinases