title: Inactivation of Capicua drives cancer metastasis.
abstract: Metastasis is the leading cause of death in people with lung cancer, yet the molecular effectors underlying tumor dissemination remain poorly defined. Through the development of an in vivo spontaneous lung cancer metastasis model, we show that the developmentally regulated transcriptional repressor Capicua (CIC) suppresses invasion and metastasis. Inactivation of CIC relieves repression of its effector ETV4, driving ETV4-mediated upregulation of MMP24, which is necessary and sufficient for metastasis. Loss of CIC, or an increase in levels of its effectors ETV4 and MMP24, is a biomarker of tumor progression and worse outcomes in people with lung and/or gastric cancer. Our findings reveal CIC as a conserved metastasis suppressor, highlighting new anti-metastatic strategies that could potentially improve patient outcomes.
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California, USA.|Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Ross A
authors.initials: RA
authors.lastname: Okimoto
authors.affiliation: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Breitenbuecher
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Victor R
authors.initials: VR
authors.lastname: Olivas
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California, USA.|Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California, USA.|Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Gini
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Matan
authors.initials: M
authors.lastname: Hofree
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Asthana
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Gorjan
authors.initials: G
authors.lastname: Hrustanovic
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Flanagan
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California, USA.|Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Asmin
authors.initials: A
authors.lastname: Tulpule
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California, USA.|Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Collin M
authors.initials: CM
authors.lastname: Blakely
authors.affiliation: Clovis Oncology Inc., San Francisco, California, USA.
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Haringsma
authors.affiliation: Clovis Oncology Inc., San Francisco, California, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Simmons
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Gowen
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts, USA.
authors.forename: James
authors.initials: J
authors.lastname: Suh
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts, USA.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts, USA.
authors.forename: Siraj
authors.initials: S
authors.lastname: Ali
authors.affiliation: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schuler
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California, USA.|Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Trever G
authors.initials: TG
authors.lastname: Bivona
mesh_terms: D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D053504:Matrix Metalloproteinases, Membrane-Associated / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D017500:Adenovirus E1A Proteins; C498610:CIC protein, human; C498611:Cic protein, mouse; C079853:ETV4 protein, human; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins; C492243:MMP24 protein, human; D053504:Matrix Metalloproteinases, Membrane-Associated