Project description:Using an in vitro model for malignant transformation of human bronchial epithelial cells (HBECs) we have found epithelial-to-mesenchymal transition (EMT) and expression of the EMT-transcription factor ZEB1 are early and critical events. Specifically, we found preexisting oncogenic mutations in TP53 and KRAS were required for HBECs to engage EMT machinery in response to microenvironmental (serum/TGFβ) or specific oncogenetic (MYC) EMT-inducing factors, which induce EMT through distinct TGFβ-dependent and vitamin D receptor (VDR)-dependent pathways, respectively, with both requiring ZEB1. Functional studies demonstrated ZEB1 causally promotes the malignant progression of HBECs and tumorigenicity of NSCLC and small cell lung cancer (SCLC) lines. Mechanistically ZEB1 directly represses ESRP1 leading to increased mesenchymal splicing of CD44, which drives a switch to CD44hi status and defines a highly transformed subpopulation. This was supported by finding ZEB1 is expressed in early-stage primary non-small cell lung cancers (NSCLC), as early as stage IB tumors, and its expression correlates with TNM stage. We conclude that: ZEB1-induced EMT and associated ESRP1 and CD44 molecular changes are important biomarkers for lung cancer pathogenesis; TGFβ and VDR are EMT chemoprevention targets; and as such, ZEB1 represents an important therapeutic target in NSCLC and SCLC.
Project description:Idiopathic Pulmonary Fibrosis (IPF) is characterized by progressive, often fatal loss of lung function due to overactive collagen production and tissue scarring. IPF patients have a sevenfold-increased risk of developing lung cancer. The COVID-19 pandemic has increased the number of patients with lung diseases, and infection can worsen prognoses for those with chronic lung diseases and disease-associated cancer. Understanding the molecular pathogenesis of IPFassociated lung cancer is imperative for identifying diagnostic biomarkers and targeted therapies that will facilitate prevention of IPF and progression to lung cancer. To understand how IPF-associated fibroblast activation, matrix remodeling, epithelial-mesenchymal transition, and immune modulation influences lung cancer predisposition, we developed a mouse model to recapitulate the molecular pathogenesis of pulmonary fibrosis-associated lung cancer using the bleomycin and Lewis Lung Carcinoma models. We demonstrate that development of pulmonary fibrosis-associated lung cancer is likely linked to increased abundance of tumor-associated macrophages and a unique gene signature that supports an immune-suppressive microenvironment through secreted factors. Not surprisingly, pre-existing fibrosis provides a pre-metastatic niche and results in augmented tumor growth, and tumors associated with bleomycin-induced fibrosis are characterized by a dramatic loss of cytokeratin expression, indicative of epithelial-to-mesenchymal transition. Implications: This characterization of tumors associated with lung diseases provides new therapeutic targets that may aid in the development of treatment paradigms for lung cancer patients with pre-existing pulmonary diseases.
Project description:Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is the leading cause of death in patients with systemic sclerosis (SSc) with unclear pathogenesis and limited treatment options. Evidence strongly supports an important role for profibrotic, SPP1-expressing macrophages in SSc-ILD. We sought to define the transcriptome and chromatin structural changes of SPP1 SSc-ILD macrophages, so as to better understand their role in promoting fibrosis and to identify transcription factors associated with open chromatin driving their altered phenotype.