Oncogene-Induced Signaling Heterogeneity in Lung Cancer
| dc.contributor.advisor | Garcia, Christine K. | en |
| dc.contributor.committeeMember | White, Michael A. | en |
| dc.contributor.committeeMember | Cobb, Melanie H. | en |
| dc.contributor.committeeMember | Altschuler, Steven J. | en |
| dc.contributor.committeeMember | Wu, Lani | en |
| dc.contributor.committeeMember | Minna, John D. | en |
| dc.creator | Deb, Dhruba | en |
| dc.creator.orcid | 0000-0001-9861-0699 | |
| dc.date.accessioned | 2017-09-05T14:52:21Z | |
| dc.date.available | 2017-09-05T14:52:21Z | |
| dc.date.created | 2015-08 | |
| dc.date.issued | 2015-07-22 | |
| dc.date.submitted | August 2015 | |
| dc.date.updated | 2017-09-05T14:44:43Z | |
| dc.description.abstract | Lung cancer causes the maximum number of cancer related deaths worldwide. In recent years, the cancer genome atlas (TCGA) initiative has identified 138 frequently occurring driver oncogenes and tumor suppressor genes in lung cancer. Currently, only 15 of these genes can be targeted therapeutically. Study of downstream signaling alterations of these oncogenes and tumor suppressor genes may identify novel therapeutic targets. Although studies on genetic heterogeneity in subclonal populations within one tumor using deep sequencing and multiple sectioning have gained popularity recently, the signaling heterogeneity within tumor cells with identical genetic changes remain poorly understood. Hence, I focus on TP53, KRas and C-Myc as they are among the most frequently occurring oncogenic alterations in lung adenocarcinoma. The downstream signaling changes of these genes may be different from one cell to another. Here, I develop high throughput approaches to study alterations of 6 major signaling readouts - phospho-Erk1/2, phospho-Stat3, Smad2/3, β-catenin, P65, and Foxo1 and quantitatively analyze thousands of cells with defined set of genetic changes. I ask - Can I utilize oncogene-induced signaling alterations in single cells to identify novel targetable vulnerabilities? Using single-cell image analysis I show that the genetically transformed HBECs with all 3 oncogenic changes (TP53, KRas and C-Myc) show significant signaling heterogeneity. They exhibit downregulated Smad2/3 signaling in single cells. Next, using a dominant negative construct, I confirm that this phenotype is partially reversible by the removal of C-Myc oncogenic stress. I further observe that the transformed HBECs exhibit upregulated Stat3 signaling in single cells. In addition, the Stat3 inhibitor Stattic causes more cell death in transformed HBECs. Interestingly, our single-cell image analysis suggests that Stat3 upregulation and Smad2/3 downregulation are mutually exclusive. Hence, Stattic will not be able to target the Smad2/3 downregulated cells. To target Smad2/3 downregulated cells, I identify Bcl6, a downstream target of Smad2/3, and I show that Bcl6 is a novel targetable vulnerability in transformed HBECs. I observe that C-Myc and Bcl6 gene expressions are strongly correlated in cell populations as well as in single-cell level. I further show that Bcl6 can be a targetable vulnerability in a subset of c-Myc addicted non-small cell lung cancers. I conclude that single-cell analysis of driver oncogenes and their downstream signaling can identify novel targetable vulnerabilities. | en |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.oclc | 1002856813 | |
| dc.identifier.uri | https://hdl.handle.net/2152.5/4213 | |
| dc.language.iso | en | en |
| dc.subject | Carcinoma, Squamous Cell | en |
| dc.subject | Lung Neoplasms | en |
| dc.subject | Proto-Oncogene Proteins c-myc | en |
| dc.subject | Smad2 Protein | en |
| dc.subject | Transforming Growth Factor beta | en |
| dc.title | Oncogene-Induced Signaling Heterogeneity in Lung Cancer | en |
| dc.type | Thesis | en |
| dc.type.material | text | en |
| thesis.degree.department | Graduate School of Biomedical Sciences | en |
| thesis.degree.discipline | Cancer Biology | en |
| thesis.degree.grantor | UT Southwestern Medical Center | en |
| thesis.degree.level | Doctoral | en |
| thesis.degree.name | Doctor of Philosophy | en |