An In Vivo Functional Genomics Screen Identifies New Regulators of Tumorigenesis in Non-Small Cell Lung Cancer

dc.contributor.advisorShay, Jerry W.en
dc.contributor.committeeMemberMinna, John D.en
dc.contributor.committeeMemberRoth, Michael G.en
dc.contributor.committeeMemberWhite, Michael A.en
dc.creatorHight, Suzie K.en
dc.creator.orcid0000-0001-6624-8373
dc.date.accessioned2018-01-04T21:12:08Z
dc.date.available2018-01-04T21:12:08Z
dc.date.created2015-12
dc.date.issued2015-11-24
dc.date.submittedDecember 2015
dc.date.updated2018-01-04T21:06:22Z
dc.description.abstractCancer cells are characterized by the aberrant regulation of signaling pathways that govern responses to growth stimuli, resulting in dysregulated cellular proliferation. The accumulated genomic alterations that cause this malignant growth phenotype can also result in acquired vulnerabilities in the tumor. Loss-of-function screening using pooled short hairpin RNAs (shRNAs) is a powerful method for identifying new therapeutic targets in cancer. We have tested the use of parallel in vitro and in vivo screens using a mini-library of shRNAs to identify previously unknown acquired vulnerabilities in lung cancer. Using a mini-library of 1062 lentiviral shRNAs targeting nuclear hormone receptors and their coregulators (120 genes total), we screened the lung adenocarcinoma cell line NCI-H1819 for dependency on these genes during in vitro and in vivo growth. We identified six genes required for survival in vitro (BRCA1, CCND1, MED1, PHB, HNRNPU, and PELP1), and three genes that were required for tumor survival in vivo, but not in vitro: FOXA1, HDAC1, and NCOR2. None of these genes were mutated by full exome sequencing of H1819, however FOXA1 was found to be co-amplified with NKX2-1 on chromosome 14q. Here we report that NSCLC cell lines and tumor samples have significantly higher FOXA1 expression compared to normal lung epithelial cells and tissues, and that 14q-amplified NSCLC cell lines are preferentially dependent on FOXA1 for clonogenicity and in vivo growth. Integrative transcriptomic and cistromic analyses identified a subset of direct FOXA1 targets as positive regulators of key growth signaling pathways, and negative regulators of several growth inhibitory mechanisms. This regulatory function appears to be partially independent of NKX2-1, and combing de novo motif discovery with expression analyses has identified several other putative FOXA1 coregulators. Our findings provide new insight into the functional consequences of 14q amplification in lung adenocarcinomas and suggest exploration of new transcriptional networks for potential therapeutic vulnerabilities.en
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc1017760180
dc.identifier.urihttps://hdl.handle.net/2152.5/4462
dc.language.isoenen
dc.subjectCarcinoma, Non-Small-Cell Lungen
dc.subjectGene Expression Regulation, Neoplasticen
dc.subjectLung Neoplasmsen
dc.subjectReceptors, Cytoplasmic and Nuclearen
dc.titleAn In Vivo Functional Genomics Screen Identifies New Regulators of Tumorigenesis in Non-Small Cell Lung Canceren
dc.typeThesisen
dc.type.materialtexten
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineCancer Biologyen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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