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Description
Malignant Pleural Mesothelioma is a type of lung cancer usually discovered at an advanced stage at which point there is no cure. Six primary MPM cell lines were used to conduct in vitro research to make conclusions about specific gene mutations associated with Mesothelioma. DNA exome sequencing, a time efficient and inexpensive technique, was used for identifying specific DNA mutations. Computational analysis of exome sequencing data was used to make conclusions about copy number variation among common MPM genes. Results show a CDKN2A gene heterozygous deletion in Meso24 cell line. This data is validated by a previous CRISPR-Cas9 outgrowth screen for Meso24 where the knocked-out gene caused increased Meso24 growth.
ContributorsKrdi, Ghena (Author) / Plaisier, Christopher (Thesis director) / Wilson, Melissa (Committee member) / School of Life Sciences (Contributor) / Hugh Downs School of Human Communication (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05
Description
Diffuse pleural mesothelioma (DPM) is a devastating lung cancer most commonly diagnosed at an advanced stage with a poor prognosis for patients. Therapies available to patients after diagnosis currently include surgical resection, radiotherapy, immunotherapy, and chemotherapy. However, these therapies only prolong life for about a year and a half on average. DPM patients desperately need effective therapies in the form of drugs, drug combinations, and miRNA-based therapies, that could lengthen overall survival and provide a better quality of life. I hypothesized that focusing on DPM tumor biology would streamline the process for discovering new therapies that will have a lasting impact for patients. I have applied systems biology methods to mine multiomic data from patient DPM tumors to discover new therapeutic options. I began by developing a somatic mutation integration pipeline, which created a comprehensive somatic mutational profile of DPM tumors from patient genomic and transcriptomic data. The somatic mutational profile was used in the generation of dpmSYGNAL, a disease-relevant gene regulatory network (GRN) trained on patient tumor multiomic data. I integrated this GRN with functional genomics screens performed on two low-passage primary DPM tumor cell lines and identified gene vulnerabilities that could be targeted by FDA-approved inhibitors and drug combinations. I also developed a pipeline to integrate miRNA target genes from biotinylated pulldowns with RNA-seq data from a study re-expressing the miRNA hsa-miR-497-5p in DPM cell lines. I determined that the re-expression of hsa-miR-497-5p had early pro-apoptotic effects and inhibited the cell cycle at later time points. The identification of inhibitors, combinations of inhibitors, and a therapeutic miRNA demonstrates that DPM biology can be used as a guide to discover new therapeutics for DPM.
ContributorsWilferd, Sierra Fe (Author) / Plaisier, Christopher L (Thesis advisor) / Anderson, Karen (Committee member) / Wilson, Melissa (Committee member) / Hoang, Chuong D (Committee member) / Arizona State University (Publisher)
Created2024