title: The RON receptor tyrosine kinase promotes metastasis by triggering MBD4-dependent DNA methylation reprogramming.
abstract: Metastasis is the major cause of death in cancer patients, yet the genetic and epigenetic programs that drive metastasis are poorly understood. Here, we report an epigenetic reprogramming pathway that is required for breast cancer metastasis. Concerted differential DNA methylation is initiated by the activation of the RON receptor tyrosine kinase by its ligand, macrophage stimulating protein (MSP). Through PI3K signaling, RON/MSP promotes expression of the G:T mismatch-specific thymine glycosylase MBD4. RON/MSP and MBD4-dependent aberrant DNA methylation results in the misregulation of a specific set of genes. Knockdown of MBD4 reverses methylation at these specific loci and blocks metastasis. We also show that the MBD4 glycosylase catalytic residue is required for RON/MSP-driven metastasis. Analysis of human breast cancers revealed that this epigenetic program is significantly associated with poor clinical outcome. Furthermore, inhibition of Ron kinase activity with a pharmacological agent blocks metastasis of patient-derived breast tumor grafts in vivo.
authors.affiliation: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112, USA.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Cunha
authors.affiliation: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112, USA.
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Lin
authors.affiliation: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Goossen
authors.affiliation: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112, USA.
authors.forename: Christa I
authors.initials: CI
authors.lastname: DeVette
authors.affiliation: OSI/Astellas, Bioscience Park Drive, Farmingdale, NY 11735, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Albertella
authors.affiliation: OSI/Astellas, Bioscience Park Drive, Farmingdale, NY 11735, USA.
authors.forename: Stuart
authors.initials: S
authors.lastname: Thomson
authors.affiliation: OSI/Astellas, Bioscience Park Drive, Farmingdale, NY 11735, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Mulvihill
authors.affiliation: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112, USA. Electronic address: alana.welm@hci.utah.edu.
authors.forename: Alana L
authors.initials: AL
authors.lastname: Welm
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics; D019175:DNA Methylation; D004706:Endodeoxyribonucleases / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D011518:Proto-Oncogene Proteins; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor; D019869:Phosphatidylinositol 3-Kinases; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; D004706:Endodeoxyribonucleases; C118712:MBD4 protein, human