Smoking-related lung repair and early stage lung cancer
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Lung cancer is the most deadly cancer worldwide, accounting for more deaths than prostate cancer, breast cancer and colon cancer combined. It is indisputable that cigarette smoking is highly correlated with the risk of developing lung cancer. The low survival rate suggests that better detection methods and therapies are desperately needed. We believe that to truly understand the biology of this disease, we need to identify and examine the tumor-initiating cells in lung cancer. Tumor-initiating cells are a population of cells capable of indefinite self-renewal and have the ability to develop into all the heterogeneous cell types of a tumor. This tumor-initiating cell could be a rare stem cell, a progenitor cell, or a differentiated cell that has developed the ability to self-renew. Our understanding of stem/progenitor cells in the proximal airway epithelium is limited, but some populations have been identified with self-renewing and differentiation properties. Keratin 14 (K14)-expressing cells are a unique subpopulation of airway epithelial cells that are present in the submucosal glands in the steady state. K14+ cells are a reparative cell population and the loss of K14 expression is associated with the return to normal, fully repaired airway epithelium. K14+ cells are also present in premalignant lesions and in varying numbers of patients with non-small cell lung cancer (NSCLC). The persistence of K14+ cells could therefore be associated with dysregulated repair that could lead to indefinite self-renewal and tumor initiation. The first hypothesis to be tested is whether the presence of K14+ cells in NSCLC tumors correlates with patient prognosis. Since tumor-initiating cells are thought to be the source of recurrence and/or micrometastasis, it is therefore important to determine if there is an association between K14 expression and prognosis in smoking-related NSCLC tumors. The second hypothesis to be tested is whether gene expression and epigenetic profiling of cell populations from K14- normal basal cells, K14+ premalignant lesions, and K14+/- cells in NSCLCs will determine the stepwise changes in this putative tumor-initiating cell population and lead to an increased understanding of the mechanisms of NSCLC carcinogenesis. Addressing these knowledge gaps will benefit us in understanding the progression of NSCLCs, and the potential role of aberrant repair in tumor initiation. In Specific Aim 1, we will analyze a human lung cancer tissue microarray with immunostaining of K14. Our preliminary data showed that the presence of K14+ cells in NSCLC was predictive of poor prognosis especially in the smoker population, where K14+ tumor correlated with metastasis. In Specific Aim 2, we will perform laser capture microdissection on fresh frozen human lung cancer tissues to isolate specific cell populations with distinct K14 expression pattern throughout stages of tumor progression. RNA will be extracted from these cells for mRNA and microRNA expression profiling. In Specific Aim 3, we will further investigate the mechanism of NSCLC progression in K14+ cells by delineating the DNA methylation status of this cell population in each stage of carcinogenesis. These studies have the potential to carry a significant clinical impact. Firstly, K14 expression in NSCLC could be used to help determine risk of recurrence/metastases even in low stage tumors, particularly in smokers. Secondly, defining genetic and epigenetic stepwise changes in a cell population as it progresses to NSCLC has the potential to lead to the discovery of new biomarkers for early detection and novel therapeutic targets that could be used for designing a more patient-oriented personalized treatment regime.