Our research team is interested in airway inflammation and its role in airway epithelial carcinogenesis. Tumor-promoting inflammation is a cancer hallmark, and it is considered an enabling characteristic due to its contributions to the acquisition of core hallmark capabilities. It is known that mutant epithelial cells begin to edit the tumor microenvironment as soon as they transform. Tumor cells produce various cytokines and chemokines that attract leukocytes. Leukocytes can amplify epithelial innate immune responses and have been shown to contribute to tumor promotion (intrinsic inflammation) but the exact mechanisms involved in this immuno-editing process from escaping the immunosurveillance to tumor progression still not well understood.
On the other hand, many environmental causes and risk factors for cancer are associated with chronic inflammation. According to epidemiological studies, up to 20% of cancers are linked to chronic infections and inflammation. Cigarette smoking is the principal cause of lung carcinogenesis. However, several studies have found that smokers with chronic obstructive pulmonary disease (COPD), an inflammatory disease of the lung, have an increased risk of lung cancer compared to smokers with comparable cigarette exposure but without COPD. Importantly, among smokers with COPD, even following smoke cessation, inflammation persists as does the increased risk of lung cancer. This suggests a strong link between COPD-related airway inflammation (extrinsic inflammation) and lung cancer independent of smoking.
We have previously shown that the numerous cytokines released during inflammation (intrinsic oncogene-driven or extrinsic COPD-related) promote lung tumorigenesis in a genetic mouse model of lung cancer. Of note, the risk and outcome of lung cancer are vastly distinct between men and women, especially for smokers. However, the reason for this sex disparity is poorly understood and extremely underappreciated. We recently made an astonishing sex specific discovery using a mouse model for K-ras-driven lung cancer. Therefore, we are currently dissecting the sex- and cell-type specific mechanistic roles of inflammatory signaling cues and the functional significance of targeting these inflammatory pathways in the pathogenesis of K-ras mutant lung cancer using genetic and pharmacologic approaches.
In addition, I am collaborating with teams and laboratories that have been at the forefront of these subjects to address novel questions with a state-of-the-art research collaborative and translate these findings to the clinic. Accordingly, Students and fellows working in my laboratory will have the opportunity to study lung biology, airway inflammation, molecular aspects of lung cancer, and tumor microenvironment while applying different techniques in these genetically engineered mice.
Our study will provide a better understanding of the role of specific inflammatory pathways in lung carcinogenesis, and subsequently allow preclinical testing of the efficacy of anti-inflammatory agents in preventing lung cancer in a high-risk population (smokers and COPD patients) or patient with early metaplastic lesions. This would also have a major impact on the treatment of patients with lung cancer by providing the basis for rationally directed immunotherapeutic modalities to improve the efficacy of currently available treatment regimens (e.g. chemotherapy, immune checkpoint blockade).