title: Enhanced MET Translation and Signaling Sustains K-Ras-Driven Proliferation under Anchorage-Independent Growth Conditions.
abstract: Oncogenic K-Ras mutation occurs frequently in several types of cancers, including pancreatic and lung cancers. Tumors with K-Ras mutation are resistant to chemotherapeutic drugs as well as molecular targeting agents. Although numerous approaches are ongoing to find effective ways to treat these tumors, there are still no effective therapies for K-Ras mutant cancer patients. Here we report that K-Ras mutant cancers are more dependent on K-Ras in anchorage-independent culture conditions than in monolayer culture conditions. In seeking to determine mechanisms that contribute to the K-Ras dependency in anchorage-independent culture conditions, we discovered the involvement of Met in K-Ras-dependent, anchorage-independent cell growth. The Met signaling pathway is enhanced and plays an indispensable role in anchorage-independent growth even in cells in which Met is not amplified. Indeed, Met expression is elevated under anchorage-independent growth conditions and is regulated by K-Ras in a MAPK/ERK kinase (MEK)-dependent manner. Remarkably, in spite of a global downregulation of mRNA translation during anchorage-independent growth, we find that Met mRNA translation is specifically enhanced under these conditions. Importantly, ectopic expression of an active Met mutant rescues K-Ras ablation-derived growth suppression, indicating that K-Ras-mediated Met expression drives "K-Ras addiction" in anchorage-independent conditions. Our results indicate that enhanced Met expression and signaling is essential for anchorage-independent growth of K-Ras mutant cancer cells and suggests that pharmacological inhibitors of Met could be effective for K-Ras mutant tumor patients.
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California. Oncology Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Fujita-Sato
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Galeas
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
authors.forename: Morgan
authors.initials: M
authors.lastname: Truitt
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
authors.forename: Cameron
authors.initials: C
authors.lastname: Pitt
authors.affiliation: Department of Pathology, University of California San Francisco, San Francisco, California.
authors.forename: Anatoly
authors.initials: A
authors.lastname: Urisman
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
authors.forename: Sourav
authors.initials: S
authors.lastname: Bandyopadhyay
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
authors.forename: Davide
authors.initials: D
authors.lastname: Ruggero
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California. mccormic@cc.ucsf.edu.
authors.forename: Frank
authors.initials: F
authors.lastname: McCormick
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics*; D002478:Cells, Cultured; D011905:Genes, ras / Q000502:physiology*; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D014176:Protein Biosynthesis; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D046509:Tissue Culture Techniques
chemical_list: D019859:Proto-Oncogene Proteins c-met