Posted December 29, 2020
Jun-Chieh J. Tsay, M.D., New York University School of Medicine, VA New York Harbor Healthcare System
Dr. Jun-Chieh J. Tsay
Nearly 25% of cancer deaths are attributed to lung cancer annually, more than breast, colon, and prostate cancer combined.1 Due to a lack of tools for early detection, lung cancer is often diagnosed as advanced disease, resulting in a 5-year survival rate of less than 20%.2 Current screening practice consists of CT scans followed by more invasive biopsy procedures to evaluate concerning findings. There is a critical need to develop precise, less-invasive methods to complement CT screening for early detection of lung cancer in order to improve patient outcomes.
With support from a fiscal year 2015 (FY15) Lung Cancer Research Program (LCRP) Career Development Award, Dr. Jun-Chieh Tsay at New York University School of Medicine is investigating biomarkers that can be detected in sputum-derived human bronchial epithelial cells (cells lining the airways). These biomarkers could then be included in a highly specific, non-invasive lung cancer diagnostic test that could aid in detecting lung cancer earlier than current approaches typically do. Dr. Tsay hypothesizes that lung epithelial cells located in the area adjacent to the tumor express a distinct oncogenic signature. U.S. Veterans have been identified as a critical population in this study due to their increased exposure to environmental hazards and carcinogens such as Agent Orange, radon, asbestos, uranium, beryllium, and fuel exhaust. Additionally, smoking rates in military personnel are 50% higher than in the civilian population, making Veterans a population at increased risk for lung cancer, and therefore an ideal group for biomarker studies.3
Dr. Tsay’s team performed RNA profiling of lung epithelial cells collected from lung cancer patients, and a subset of the data was included in a manuscript published in the American Journal of Respiratory Critical Care Medicine. Results included in this paper show that certain microbiota in the lower airway can cause genetic changes in lung epithelial cells that are linked to the development and progression of lung cancer. Specifically, the PI3K signaling pathway is activated when lung epithelial cells in culture were exposed to Veillonella — a bacterium commonly found in the oral microenvironment. Activation of the PI3K pathway is a known early event in lung carcinogenesis, indicating that Veillonella colonization of the lower respiratory tract may be an initiating event in lung cancer.
In a follow-up study recently published in Cancer Discovery, Dr. Tsay’s group found that patients with advanced lung cancer (stage IIIB – IV) often had lower airways enriched in bacteria more commonly found in the mouth, including Veillonella. Further, patients with oral microbiota in the lower airway were found to have poor prognosis compared to patients with more normal bacterial populations. Interestingly, early stage (I – IIIA) but not advanced stage (IIIB – IV) patients with oral microbiota in the lower airway demonstrated a worse survival than patients with normal microbiota. This finding suggests again that misplaced oral microbiota, termed dysbiosis, may be an initiating event in many lung cancers, and could serve as an important regional biomarker in early disease.
Dr. Tsay investigated the effect of dysbiosis in a preclinical model where typical lung cancer genetic lesions in Kras and p53 are present, and roughly 50% of mice develop lung tumors. The introduction of Veillonella in the lower airway of these animals led to decreased survival, weight loss, and increased tumor burden. Additionally, experimental dysbiosis in these mice led to changes in the immune microenvironment, which favored evasion of normal immunosurveillance. Indeed, when the mice were treated with an antibody that blocks IL-17 following induction of dysbiosis, the team found that tumor burden was reduced. These data suggest that dysbiosis plays a multidimensional role in lung cancer progression.
These studies highlight the importance of host-microbe interactions in lung cancer patients and confirm that new molecular markers found in lung epithelial cells, including P13K, could be used for early lung cancer detection from a non-invasive collection of patient sputum. Patient samples from the lower airway may also be analyzed for the presence of oral microbiota to serve as an alternate complementary biomarker. Further, Dr. Tsay’s work suggests that oral microbiota represent an important initiating event in lung cancer, and may provide for new lines of investigation and potential therapeutic targets. Importantly, work supported by this LCRP award address the critical need in the field for an accurate and non-invasive method of detecting lung cancer early in its progression in both high-risk Veteran populations and the general public.
Comparisons between microbiome and host transcriptomic signatures were conducted using samples where paired matched data was available (n=70). Network analysis based on conditional co-occurrence probability of microbiome and transcriptome data; Microbiome nodes (circles) are colored red for stage IIIB-IV lung cancer, green for stage I-IIIA lung cancer (based on a gradient) and sized by relative abundance. Edges connect microbiome nodes to pathway nodes and edge width is based on their conditional probability.
Tsay JJ, Wu BG, Badri MH, et al. 2018. Airway Microbiota Is Associated with Upregulation of the PI3K Pathway in Lung Cancer. Am J Respir Crit Care Med. 198(9):1188-1198.
Tsay JJ, Wu BG, Sulaiman I, et al. 2020. Lower Airway Dysbiosis Affects Lung Cancer Progression. Cancer Discov. Epub ahead of print.
Last updated Tuesday, December 29, 2020