Most cases of COPD and lung cancer are caused by cigarette smoking. Both diseases start in the airway epithelium, and COPD increases lung cancer risk 4.5-fold. Using airway epithelium genome-wide transcriptome analysis, we and others have concluded that smoking causes a field of molecular changes throughout the airway epithelium manifested by abnormal expression of genes/pathways relevant to COPD and lung cancer. In a paradigm shift from the strategy of assessing the entire differentiated airway epithelium to understand the disordered airway epithelial biology of COPD and lung cancer, this proposal focuses on airway basal cells (BC), the stem/progenitor cells from which the differentiated airway epithelium is derived. Our preliminary observations show that the BC transcriptome of smokers is markedly different from that of nonsmokers, it is a primitive, less differentiated transcriptome including human embryonic stem cell genes progressively up-regulated in COPD and lung cancer, it predicts lung cancer aggressiveness and survival, and is associated with a molecular phenotype of p53 inactivation. Therefore we hypothesize that smoking-dependent reprogramming of the BC transcriptome represents a common molecular pathogenetic mechanism of smoking-associated COPD and lung cancer, thus both """"""""BC disorders,"""""""" and that the BC transcriptome progressively adopts a cancer-like phenotype in smokers, in smokers with COPD and in the non-malignant airway epithelium of smokers with COPD with lung cancer. If correct, the consequence is a progressive inability of such reprogrammed BC to differentiate to a normal ciliated mucociliary epithelium. These studies should lead to identification of molecular pathways commonly altered in COPD and lung cancer vulnerable to therapeutic intervention to prevent or reverse the disordered BC transcriptome associated with these diseases.
Aim 1 - using genome-wide gene expression profiling, assess the hypothesis that compared to healthy nonsmokers, the airway BC transcriptome of smokers, smokers with COPD and non-malignant epithelium of COPD smokers with lung cancer is progressively disordered and reprogrammed toward a common COPD and cancer-associated molecular phenotype.
Aim 2 - examine the hypothesis that BC of smokers, smokers with COPD and non-malignant epithelium of COPD smokers with lung cancer progressively exhibit a defective capacity to differentiate into normal airway epithelium when placed on air-liquid interface culture but will generate progressively increasing numbers of colonies in clonogenic assays.
Aim 3 - assess the hypothesis that by genetic/pharmacologic modulation of the abnormally expressed genes/pathways in the BC of smokers, COPD smokers and COPD smokers with lung cancer, will reverse their defective differentiation and self-renewal functions.
COPD and lung cancer are the most common smoking-related diseases, which are also pathogenetically linked since COPD conveys a 4.5-fold increased risk for lung cancer. In this study, the common molecular and cellular origins of COPD and lung cancer will be investigated by studying air- way epithelium basal cells, the stem/progenitor cells that renew the airway epithelium. We hypothesize that transcriptional reprogramming of the airway basal cells, which arises prior to histological or clinical disease manifestation, is the central biologic link between COPD and lung cancer.
|Staudt, Michelle R; Salit, Jacqueline; Kaner, Robert J et al. (2018) Altered lung biology of healthy never smokers following acute inhalation of E-cigarettes. Respir Res 19:78|
|Zuo, Wu-Lin; Shenoy, Sushila A; Li, Sheng et al. (2018) Ontogeny and Biology of Human Small Airway Epithelial Club Cells. Am J Respir Crit Care Med 198:1375-1388|
|O'Beirne, Sarah L; Shenoy, Sushila A; Salit, Jacqueline et al. (2018) Ambient Pollution-related Reprogramming of the Human Small Airway Epithelial Transcriptome. Am J Respir Crit Care Med 198:1413-1422|
|Zhang, Haijun; Yang, Jing; Walters, Matthew S et al. (2018) Mandatory role of HMGA1 in human airway epithelial normal differentiation and post-injury regeneration. Oncotarget 9:14324-14337|
|Gomi, Kazunori; Tang, Yongjiang; Arbelaez, Vanessa et al. (2017) Endothelial Cell Mediated Promotion of Ciliated Cell Differentiation of Human Airway Basal Cells via Insulin and Insulin-Like Growth Factor 1 Receptor Mediated Signaling. Stem Cell Rev 13:309-317|
|Chung, Nancy P Y; Ou, Xuemei; Khan, K M Faisal et al. (2017) HIV Reprograms Human Airway Basal Stem/Progenitor Cells to Acquire a Tissue-Destructive Phenotype. Cell Rep 19:1091-1100|
|Yang, Jing; Zuo, Wu-Lin; Fukui, Tomoya et al. (2017) Smoking-Dependent Distal-to-Proximal Repatterning of the Adult Human Small Airway Epithelium. Am J Respir Crit Care Med 196:340-352|
|Strulovici-Barel, Yael; Staudt, Michelle R; Krause, Anja et al. (2016) Persistence of circulating endothelial microparticles in COPD despite smoking cessation. Thorax 71:1137-1144|
|Zhou, Haixia; Brekman, Angelika; Zuo, Wu-Lin et al. (2016) POU2AF1 Functions in the Human Airway Epithelium To Regulate Expression of Host Defense Genes. J Immunol 196:3159-67|
|Strulovici-Barel, Yael; Shaykhiev, Renat; Salit, Jacqueline et al. (2016) Pulmonary Abnormalities in Young, Light-Use Waterpipe (Hookah) Smokers. Am J Respir Crit Care Med 194:587-95|
Showing the most recent 10 out of 34 publications