title: Widespread FRA1-dependent control of mesenchymal transdifferentiation programs in colorectal cancer cells.
abstract: Tumor invasion and metastasis involves complex remodeling of gene expression programs governing epithelial homeostasis. Mutational activation of the RAS-ERK is a frequent occurrence in many cancers and has been shown to drive overexpression of the AP-1 family transcription factor FRA1, a potent regulator of migration and invasion in a variety of tumor cell types. However, the nature of FRA1 transcriptional targets and the molecular pathways through which they promote tumor progression remain poorly understood. We found that FRA1 was strongly expressed in tumor cells at the invasive front of human colorectal cancers (CRCs), and that its depletion suppressed mesenchymal-like features in CRC cells in vitro. Genome-wide analysis of FRA1 chromatin occupancy and transcriptional regulation identified epithelial-mesenchymal transition (EMT)-related genes as a major class of direct FRA1 targets in CRC cells. Expression of the pro-mesenchymal subset of these genes predicted adverse outcomes in CRC patients, and involved FRA-1-dependent regulation and cooperation with TGFβ signaling pathway. Our findings reveal an unexpectedly widespread and direct role for FRA1 in control of epithelial-mesenchymal plasticity in CRC cells, and suggest that FRA1 plays an important role in mediating cross talk between oncogenic RAS-ERK and TGFβ signaling networks during tumor progression.
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Department of Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, Victoria, Australia.
authors.forename: Jeannine
authors.initials: J
authors.lastname: Diesch
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria, Australia; Department of Pathology, University of Melbourne, Victoria, Australia.
authors.forename: Elaine
authors.initials: E
authors.lastname: Sanij
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Department of Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, Victoria, Australia.
authors.forename: Omer
authors.initials: O
authors.lastname: Gilan
authors.affiliation: Walter and Eliza Institute of Medical Research, Victoria, Australia.
authors.forename: Christopher
authors.initials: C
authors.lastname: Love
authors.affiliation: Ludwig Institute for Cancer Research, Victoria, Australia.
authors.forename: Hoanh
authors.initials: H
authors.lastname: Tran
authors.affiliation: Walter and Eliza Institute of Medical Research, Victoria, Australia.
authors.forename: Nicholas I
authors.initials: NI
authors.lastname: Fleming
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Jason
authors.initials: J
authors.lastname: Ellul
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Department of Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, Victoria, Australia.
authors.forename: Marcia
authors.initials: M
authors.lastname: Amalia
authors.affiliation: Faculty of Medicine, Bar-Ilan University, Tel-Aviv, Israel.
authors.forename: Izhak
authors.initials: I
authors.lastname: Haviv
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Department of Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria, Australia.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Pearson
authors.affiliation: School of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, United Kingdom.
authors.forename: Eugene
authors.initials: E
authors.lastname: Tulchinsky
authors.affiliation: Ludwig Institute for Cancer Research, Victoria, Australia.
authors.forename: John M
authors.initials: JM
authors.lastname: Mariadason
authors.affiliation: Walter and Eliza Institute of Medical Research, Victoria, Australia.
authors.forename: Oliver M
authors.initials: OM
authors.lastname: Sieber
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Department of Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria, Australia; Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia; School of Biomedical Sciences, University of Queensland, Queensland, Australia.
authors.forename: Ross D
authors.initials: RD
authors.lastname: Hannan
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria, Australia; Department of Pathology, University of Melbourne, Victoria, Australia.
authors.forename: Amardeep S
authors.initials: AS
authors.lastname: Dhillon
mesh_terms: D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D000099169:Fos-Related Antigen 1
chemical_list: D016760:Proto-Oncogene Proteins c-fos; D016212:Transforming Growth Factor beta; D000099169:Fos-Related Antigen 1