Lung cancer is the most common cause of cancer-related death in Australia. Non-Small Cell Lung Cancer (NSCLC), which accounts for >80% of all lung cancers, has a five-year survival of approximately 14%. However, stage I/II NSCLC patients have an approximate 40 % five year survival rate, largely depending on the development of metastasis and therapy resistance. Our understanding and treatment of NSCLC contains several knowledge gaps and suffers from a lack of rapid, non-invasive prognostic markers.
Our previous work showed that hypoxia in the primary tumour is directly capable of promoting metastatic spread by secretion of factors into the blood circulation, causing systemic, pro-metastatic effects. Based on this knowledge, we postulated that hypoxia would modify the protein content of exosomes, thereby generating a protein signature capable of identifying patients at risk of developing metastasis. Using quantitative mass spectrometry to determine the content of exosomes secreted by hypoxic NSCLC cells, we found a number of proteins involved in metastatic progression of NSCLC to be at a higher abundance in hypoxic exosomes.
Receiver operating characteristic curves revealed that our exosome signature was a perfect classifier, demonstrating a sensitivity and specificity of 100%. Exosomes were then isolated from an independent, confirmation cohort. In complete agreement with our discovery cohort, our protein signature was capable of accurately identifying patients with early relapse and those with no relapse within 5 years of initial therapy. Currently, it is not possible to predict the occurrence of chemotherapy resistance or metastasis in NSCLC patients. This work has generated a novel, urgently needed predictive tool to identify NSCLC patients at risk of developing metastatic or chemoresistant disease, providing precise treatment decisions for early stage NSCLC patient management.