Research
Lung Cancer & COPD
The research in the Moghaddam Laboratory is focused on 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. 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. This suggests a strong link between COPD-related airway inflammation (extrinsic inflammation) and lung cancer. In addition, it is known that mutant epithelial cells begin to edit the microenvironment as soon as they transform (intrinsic inflammation) but the exact mechanisms involved in this immuno-editing process from escaping the immunosurveillance to tumor progression still not well understood.
We have developed and interrogated various human-relevant mouse models that closely emulate the molecular pathobiology of human airway inflammation, COPD, and lung cancer. Using these models, we have previously shown that a network of immunomodulatory cytokines (namely IL-1β, IL-6 and IL-17/IL-22) released during inflammation (mainly regulated by the NF-κB/STAT3 crosstalk) promotes lung tumorigenesis by providing a pro-tumor lung microenvironment in a genetic mouse model of lung cancer with K-ras mutation. We have further demonstrated that targeting inflammatory pathways and modulating this cytokine network could be used as a preventive and therapeutic strategy for Kras mutant lung adenocarcinoma (KM-LUAD). We are currently dissecting the sex and cell-specific autocrine and paracrine mechanisms responsible for this phenomenon with genetic and pharmacologic approaches.
These projects will provide a better understanding of the role of specific inflammatory pathways in lung carcinogenesis, and subsequently allow preclinical testing of the efficacy of targeted anti-inflammatory agents in preventing lung cancer in high-risk population or patient with early metaplastic lesions. They 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.