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Luu, Jennifer K.

University of British Columbia

Lung cancer and its most common subtype, lung adenocarcinoma (LUAD), is the leading cause of global cancer mortality. Mortality is partially attributed to late stage diagnosis, where curative options are limited and less effective for patient survival. Current screening guidelines are prone to false positive results, and there are no lung cancer-specific biomarkers to aid detection. This is especially relevant for never smokers, a lung cancer patient demographic often characterized by the EGFR oncogenic mutation. Never smokers lack concrete screening guidelines; this makes biomarker discovery and validation crucial for earlier detection. The collective set of secreted proteins derived from a cell, known as the secretome, has been explored as a potential source of cancer biomarkers. However, LUAD secretome studies have been limited to late stage or metastatic tumors; investigation of secretome changes during malignant transformation may thus be more suitable for biomarker discovery. This thesis investigated changes in the secretome in an EGFR-driven model of LUAD malignant transformation. In this study, I generated a stepwise model of EGFR-driven malignant transformation by generating stable lung epithelial cell lines and selecting EGFR mutant NSCLC cell lines. I also developed and optimized a mass spectrometry protocol to profile the secretome of my model. With this pipeline, I identified differentially expressed proteins in advanced LUAD. I then validated these findings by performing differential gene expression (DGE) analysis on an EGFR mutant LUAD patient cohort. Finally, validated secreted proteins were assessed for effects on overall patient survival resulting in 4 EGFR-specific and 1 non-specific biomarker candidates. This work provides insight into potential secretome changes during LUAD malignant transformation, biomarker candidates for further validation, and illustrates the potential of the secretome in EGFR mutant LUAD detection.

Text

2022-08-11

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/82320

Pathology and Laboratory Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/