Adaptive metabolic reprogramming of metastatic non-small cell lung cancer cells upon glucose deprivation

Ph.D. ; Lung cancer was globally the most commonly diagnosed cancer, and is the leading cause of death in cancer worldwide in 2018. The estimated mortality rate of lung cancer patients (18.4%) was found to be higher than that of other leading cancer sites illustrating that lung cancer is a dire disease. Diagnosed lung cancers are frequently at an advanced stage in cancer where metastasis is formed in multiple areas with only 16% of diagnosis are still found at an early localized stage. Nearly 50% of patients with lung cancer have metastasized to the brain already, where nutrient levels in the secondary tumour microenvironment is different to that of the primary microenvironment of the lung. One of the mechanisms for this metastasis may involve strong selective pressure from nutrient deprivation in the tumour microenvironment. However, the underlying adaptive molecular events involved are not fully delineated. This thesis studies the adaptive molecular events of which these brain metastases adapt, survive and propagate to harsher microenvironments at either primary, invading or metastatic sites. These sites exert selective pressures on tumour cells through reduction of nutrients, specifically glucose. ; Our laboratory had identified a rare brain metastasis cell line of lung cancer origin: A1115, that exhibited a high glycolytic phenotype and strong reliance on Warburg effect for survival. Characterization of the metabolic phenotype of A1115 along with 4 other lung adenocarcinoma cell lines revealed A1115 to have the highest dependence on glycolysis and the lowest utilization of mitochondrial oxidative phosphorylation (OXPHOS) for metabolism. Furthermore, comparison between A1115 and A549, a lung cancer cell line that has a similar mutational landscape revealed glucose deprivation induced a more detrimental response to the survival and propagation of A1115 than A549. A1115 also showed upregulation of activated levels of nutrient sensor enzyme AMP-activated protein kinase (AMPK) upon glucose deprivation. On the ...