title: Trask loss enhances tumorigenic growth by liberating integrin signaling and growth factor receptor cross-talk in unanchored cells.
abstract: The cell surface glycoprotein Trask/CDCP1 is phosphorylated during anchorage loss in epithelial cells in which it inhibits integrin clustering, outside-in signaling, and cell adhesion. Its role in cancer has been difficult to understand, because of the lack of a discernible pattern in its various alterations in cancer cells. To address this issue, we generated mice lacking Trask function. Mammary tumors driven by the PyMT oncogene and skin tumors driven by the SmoM2 oncogene arose with accelerated kinetics in Trask-deficient mice, establishing a tumor suppressing function for this gene. Mechanistic investigations in mammary tumor cell lines derived from wild-type or Trask-deficient mice revealed a derepression of integrin signaling and an enhancement of integrin-growth factor receptor cross-talk, specifically in unanchored cell states. A similar restrictive link between anchorage and growth in untransformed epithelial cells was observed and disrupted by elimination of Trask. Together our results establish a tumor-suppressing function in Trask that restricts epithelial cell growth to the anchored state.
authors.affiliation: Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Danislav S
authors.initials: DS
authors.lastname: Spassov
authors.forename: Ching Hang
authors.initials: CH
authors.lastname: Wong
authors.forename: Sunny Y
authors.initials: SY
authors.lastname: Wong
authors.forename: Jeremy F
authors.initials: JF
authors.lastname: Reiter
authors.forename: Mark M
authors.initials: MM
authors.lastname: Moasser
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000502:physiology*; D015815:Cell Adhesion Molecules; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D016023:Integrins / Q000502:physiology*; D020935:MAP Kinase Signaling System; D008325:Mammary Neoplasms, Experimental / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017978:Receptors, Growth Factor / Q000502:physiology*; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D000951:Antigens, Neoplasm; C529673:CDCP1 protein, mouse; D015815:Cell Adhesion Molecules; D016023:Integrins; D008562:Membrane Glycoproteins; D017978:Receptors, Growth Factor; D013629:Tamoxifen; D051416:Focal Adhesion Protein-Tyrosine Kinases