Seyed Javad Moghaddam
Professor
The University of Texas MD Anderson Cancer Center
Department of Pulmonary Medicine
Overall, the research in my laboratory focuses on the interplay between inflammation and lung cancer. Lung cancer, particularly lung adenocarcinoma (LUAD) is the second most common type of cancer, and the leading cause of cancer related mortality worldwide. The most successful, straightforward preventive strategy to reduce the incidence of lung cancer is by sustained prevention of tobacco consumption. However, not all individuals respond to behavioral intervention. Furthermore, because of the persistent risk among former smokers, and patients with chronic obstructive pulmonary disease (COPD), as well as increased diagnosis of early-stage lung cancer with the recommended screening method (low-dose CT scan), preventive strategies targeting pathways that stop the progression from premalignant and early-stage lung cancer to advanced stages would be a valuable resource for halting this deadly disease. To this end, we study the role of tumor-promoting inflammation, intrinsic (e.g., oncogene-driven) and/or extrinsic (e.g., combustible cigarette smoke, electronic cigarette vapors, or pathogen-induced) in the pathogenesis of lung cancer. My laboratory has developed and interrogated various human-relevant mouse models that closely emulate the molecular pathobiology of human airway inflammation such as those in COPD and K-ras mutant LUAD (KM-LUAD) aiming to discover targets for preventive and therapeutic purposes. My group was the first to report a causal role for COPD-type airway inflammation in the promotion of lung cancer via activation of toll-like receptors (TLRs). We have also shown that a network of immunomodulatory cytokines (namely IL-1B, IL-6, and IL-17/IL-22) released during inflammation (mainly regulated by the NF-kB/STAT3 crosstalk) promotes lung tumorigenesis by providing a pro-tumor lung microenvironment dominated by immunosuppressive myeloid cells such as neutrophils, alternatively activated macrophages, and myeloid derived suppressor cells. We have further shown that modulating this cytokine network could be used as a preventive and therapeutic strategy for lung cancer by reprogramming the protumor immunosuppressive tumor microenvironment toward an antitumor phenotype. These findings and our success in preclinically targeting this cytokine network and signaling pathways lay the foundation for the design of personalized and targeted interventions to protract the premalignant lesions and their progression. 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 are currently dissecting the mechanisms of tumor promotion by these cytokines and signaling pathways in a sex and cell type specific manner using genetic and pharmacologic (preclinical/translational) approaches in mouse models and clinical samples. Another area of the research in my laboratory explores the the interplay between host microbiome, dysregulated mucin production, and immunomodulatory responses in the pathogenesis lung cancer. We were the first group showing that Muc5ac, the main airway secretory mucin, deletion leads to a significant reduction in K-ras driven lung tumorigenesis, and its expression is a significant predictor of poor disease-free survival in patients with KM-LUAD. We are specifically exploring the interaction between mucins and myeloid cells, as well as their potential effects on lung microbiome in the context of lung inflammation that is induced by exposure to combustible cigarette smoke, electronic cigarette vapors, pathogens, and other insults to the airway epithelium. Students working in my laboratory will have the opportunity to study lung biology, airway inflammation, molecular and immunological aspects of lung cancer, and tumor microenvironment. Techniques include transgenic modeling, small animal surgery and tissue harvesting, histopathology, microscopic analysis, immunohistochemistry (IHC/IF), DNA/RNA and protein based techniques, microbiome analysis, as well as immune cell sorting and profiling.
Education & Training
MD, Shaheed Beheshti University of Medical Sciences, 1996