title: Targeting EphA3 inhibits cancer growth by disrupting the tumor stromal microenvironment.
abstract: Eph receptor tyrosine kinases are critical for cell-cell communication during normal and oncogenic tissue patterning and tumor growth. Somatic mutation profiles of several cancer genomes suggest EphA3 as a tumor suppressor, but its oncogenic expression pattern and role in tumorigenesis remain largely undefined. Here, we report unexpected EphA3 overexpression within the microenvironment of a range of human cancers and mouse tumor xenografts where its activation inhibits tumor growth. EphA3 is found on mouse bone marrow-derived cells with mesenchymal and myeloid phenotypes, and activation of EphA3(+)/CD90(+)/Sca1(+) mesenchymal/stromal cells with an EphA3 agonist leads to cell contraction, cell-cell segregation, and apoptosis. Treatment of mice with an agonistic α-EphA3 antibody inhibits tumor growth by severely disrupting the integrity and function of newly formed tumor stroma and microvasculature. Our data define EphA3 as a novel target for selective ablation of the tumor microenvironment and demonstrate the potential of EphA3 agonists for anticancer therapy.
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia. mary.vail@monash.edu Andrew.Scott@ludwig.edu.au Martin.Lackmann@monash.edu.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Vail
authors.affiliation: Ludwig Institute for Cancer Research, Melbourne, Victoria, Australia.
authors.forename: Carmel
authors.initials: C
authors.lastname: Murone
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia.
authors.forename: April
authors.initials: A
authors.lastname: Tan
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia.
authors.forename: Linda
authors.initials: L
authors.lastname: Hii
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia.
authors.forename: Degu
authors.initials: D
authors.lastname: Abebe
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Janes
authors.affiliation: Ludwig Institute for Cancer Research, Melbourne, Victoria, Australia.
authors.forename: Fook-Thean
authors.initials: FT
authors.lastname: Lee
authors.affiliation: KaloBios Pharmaceuticals, Inc., South San Francisco, California.
authors.forename: Mark
authors.initials: M
authors.lastname: Baer
authors.affiliation: KaloBios Pharmaceuticals, Inc., South San Francisco, California.
authors.forename: Varghese
authors.initials: V
authors.lastname: Palath
authors.affiliation: KaloBios Pharmaceuticals, Inc., South San Francisco, California.
authors.forename: Christopher
authors.initials: C
authors.lastname: Bebbington
authors.affiliation: KaloBios Pharmaceuticals, Inc., South San Francisco, California.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Yarranton
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia.
authors.forename: Carmen
authors.initials: C
authors.lastname: Llerena
authors.affiliation: Faculty of Information Technology, Monash University, Clayton, Victoria, Australia.
authors.forename: Slavisa
authors.initials: S
authors.lastname: Garic
authors.affiliation: Faculty of Information Technology, Monash University, Clayton, Victoria, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Abramson
authors.affiliation: Ludwig Institute for Cancer Research, Melbourne, Victoria, Australia.
authors.forename: Glenn
authors.initials: G
authors.lastname: Cartwright
authors.affiliation: Ludwig Institute for Cancer Research, Melbourne, Victoria, Australia. Faculty of Medicine, University of Melbourne, Victoria, Australia. mary.vail@monash.edu Andrew.Scott@ludwig.edu.au Martin.Lackmann@monash.edu.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Scott
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia. mary.vail@monash.edu Andrew.Scott@ludwig.edu.au Martin.Lackmann@monash.edu.
authors.forename: Martin
authors.initials: M
authors.lastname: Lackmann
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D020794:Receptor Protein-Tyrosine Kinases / Q000819:agonists* / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D036121:Receptor, EphA3 / Q000819:agonists* / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D017154:Stromal Cells / Q000187:drug effects / Q000473:pathology; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; C491718:EPHA3 protein, human; C491717:Epha3 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D036121:Receptor, EphA3