Abstract A37: Tobacco smoke increases lung adenocarcinoma risk by downregulating TGF-beta and AhR-regulated focal adhesion proteins involved in injury resolution

Abstract

Abstract Background: The most prevalent type of lung cancer—lung adenocarcinoma—arises from the most distal reaches of the lung in the alveolar epithelium. The alveolar epithelium consists of two cell types: (i) thin type I alveolar epithelial cells (AT1) that facilitate gas exchange and constitute more than 90% of the alveolar surface, and (ii) cuboidal surfactant-producing type II (AT2) cells. Following injury, dynamic interactions between extracellular matrix components, integrins, focal adhesion proteins, and cytoskeletal components allow AT2 progenitor cells to migrate, spread, and transdifferentiate into AT1 cells to restore the denuded epithelial barrier. Methods: Utilizing primary human AT2 cells isolated from lung transplant remnants, our lab has established and extensively profiled an in vitro model of epithelial restitution, wherein AT2 cells differentiate over a period of six days into terminally differentiated AT1-like cells. Because cigarette smoking is the most recognized risk factor for lung adenocarcinoma (LUAD), and because the alveolar space is the primary target of tobacco smoke, we also compared the RNA-seq profiles of AT2>AT1 differentiation to those of A549 LUAD cells exposed to cigarette smoke condensate (CSC). Results: We find that CSC downregulates many factors that are upregulated in the AT2>AT1 restitution model, particularly integrins, extracellular matrix components, and novel focal adhesion proteins that are also downregulated in LUAD relative to adjacent normal tissue. We describe regulation of four such novel focal adhesion proteins, specifically by TGF-β and aryl hydrocarbon receptor (AhR)-mediated mechanisms. Conclusions: Our findings shed light on early mechanisms in the carcinogenic process, and support the notion that alveolar cells engaged in repeated cycles of injury and repair are critical actors in LUAD risk trajectories. Note: This abstract was not presented at the conference. Citation Format: Theresa Ryan Stueve, Chenchen Yang, Crystal N. Marconett, Chunli Yan, Beiyun Zhou, Zea Borok, Ite A. Laird-Offringa. Tobacco smoke increases lung adenocarcinoma risk by downregulating TGF-beta and AhR-regulated focal adhesion proteins involved in injury resolution [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr A37.