title: In Vivo Genetic Screens of Patient-Derived Tumors Revealed Unexpected Frailty of the Transformed Phenotype.
abstract: The identification of genes maintaining cancer growth is critical to our understanding of tumorigenesis. We report the first in vivo genetic screen of patient-derived tumors, using metastatic melanomas and targeting 236 chromatin genes by expression of specific shRNA libraries. Our screens revealed unprecedented numerosity of genes indispensable for tumor growth (∼50% of tested genes) and unexpected functional heterogeneity among patients (<15% in common). Notably, these genes were not activated by somatic mutations in the same patients and are therefore distinguished from mutated cancer driver genes. We analyzed underlying molecular mechanisms of one of the identified genes, the Histone-lysine N-methyltransferase KMT2D, and showed that it promotes tumorigenesis by dysregulating a subset of transcriptional enhancers and target genes involved in cell migration. The assembly of enhancer genomic patterns by activated KMT2D was highly patient-specific, regardless of the identity of transcriptional targets, suggesting that KMT2D might be activated by distinct upstream signaling pathways.
  
  
  
  Drug targeting of biologically relevant cancer-associated mutations is considered a critical strategy to control cancer growth. Our functional in vivo genetic screens of patient-derived tumors showed unprecedented numerosity and interpatient heterogeneity of genes that are essential for tumor growth, but not mutated, suggesting that multiple, patient-specific signaling pathways are activated in tumors. Cancer Discov; 6(6); 650-63. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 561.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Bossi
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Cicalese
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy. Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy.
authors.forename: Gaetano I
authors.initials: GI
authors.lastname: Dellino
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Lucilla
authors.initials: L
authors.lastname: Luzi
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Riva
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Carolina
authors.initials: C
authors.lastname: D'Alesio
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Giuseppe R
authors.initials: GR
authors.lastname: Diaferia
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Carugo
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Cavallaro
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Rossana
authors.initials: R
authors.lastname: Piccioni
authors.affiliation: Division of Pathology, European Institute of Oncology, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Barberis
authors.affiliation: Division of Pathology, European Institute of Oncology, Milan, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Mazzarol
authors.affiliation: Division of Dermatoncology, European Institute of Oncology, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Testori
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Punzi
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Pallavicini
authors.affiliation: Division of Dermatoncology, European Institute of Oncology, Milan, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Tosti
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: Giacó
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Melloni
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Heffernan
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Gioacchino
authors.initials: G
authors.lastname: Natoli
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Giulio F
authors.initials: GF
authors.lastname: Draetta
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy. Department of Biosciences, University of Milan, Milan, Italy.
authors.forename: Saverio
authors.initials: S
authors.lastname: Minucci
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy. Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy.
authors.forename: PierGiuseppe
authors.initials: P
authors.lastname: Pelicci
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy. luisa.lanfrancone@ieo.eu.
authors.forename: Luisa
authors.initials: L
authors.lastname: Lanfrancone
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D047369:Chromatin Immunoprecipitation; D019295:Computational Biology / Q000379:methods; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D057890:Epigenomics / Q000379:methods; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D064593:Heterografts; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000378:metabolism; D009369:Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D010641:Phenotype; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D015203:Reproducibility of Results
chemical_list: D004268:DNA-Binding Proteins; C120898:KMT2D protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human