journal contribution
posted on 2023-03-31, 01:09 authored by David M. Walter, Olivia S. Venancio, Elizabeth L. Buza, John W. Tobias, Charuhas Deshpande, A. Andrea Gudiel, Caroline Kim-Kiselak, Michelle Cicchini, Travis J. Yates, David M. Feldser Figure legends for supplementary figures.
Funding
AACR-Bayer HealthCare Basic Cancer Research Fellowship
NIH
American Lung Association
Center of Excellence in Environmental Toxicology training
University of Pennsylvania's Undergraduate Research Mentorship program
American Cancer Society, North Texas Pay If Group Postdoctoral Fellowship
Penn Abramson Cancer Center core grant
History
ARTICLE ABSTRACT
Chromatin-modifying genes are frequently mutated in human lung adenocarcinoma, but the functional impact of these mutations on disease initiation and progression is not well understood. Using a CRISPR-based approach, we systematically inactivated three of the most commonly mutated chromatin regulatory genes in two KrasG12D-driven mouse models of lung adenocarcinoma to characterize the impact of their loss. Targeted inactivation of SWI/SNF nucleosome–remodeling complex members Smarca4 (Brg1) or Arid1a had complex effects on lung adenocarcinoma initiation and progression. Loss of either Brg1 or Arid1a were selected against in early-stage tumors, but Brg1 loss continued to limit disease progression over time, whereas loss of Arid1a eventually promoted development of higher grade lesions. In contrast to these stage-specific effects, loss of the histone methyltransferase Setd2 had robust tumor-promoting consequences. Despite disparate impacts of Setd2 and Arid1a loss on tumor development, each resulted in a gene expression profile with significant overlap. Setd2 inactivation and subsequent loss of H3K36me3 led to the swift expansion and accelerated progression of both early- and late-stage tumors. However, Setd2 loss per se was insufficient to overcome a p53-regulated barrier to malignant progression, nor establish the prometastatic cellular states that stochastically evolve during lung adenocarcinoma progression. Our study uncovers differential and context-dependent effects of SWI/SNF complex member loss, identifies Setd2 as a potent tumor suppressor in lung adenocarcinoma, and establishes model systems to facilitate further study of chromatin deregulation in lung cancer. Cancer Res; 77(7); 1719–29. ©2017 AACR.
