Abstract 821: Dissecting the role of Stag2 in lung adenocarcinoma

Abstract

Abstract Lung cancer is the most common cause of cancer-related deaths worldwide. Cancers are driven by genomic alterations that activate tumor-promoting oncogenes and inactivate tumor suppressor genes. While some of the most common driver genes have been extensively characterized, many tumor suppressor genes are less well studied. A better understanding of the mechanisms by which different tumor suppressor genes constrain tumorigenesis has the potential to uncover unappreciated biological processes that influence carcinogenesis. Recently, we performed an in vivo screen within a genetically engineered mouse model of oncogenic KRAS-driven lung cancer and found that STAG2 inactivation dramatically increases tumor growth. While STAG2 is mutated in ~4% of human lung adenocarcinomas, 20% of lung adenocarcinomas are low or negative for STAG2 protein. STAG2 is a subunit of one of the two major cohesin complexes, which are present in all cell types and have been implicated in many different cellular processes. STAG2 has not previously been recognized as a critical tumor suppressor in lung cancer and the mechanism through which its inactivation drives lung tumor growth is unknown. Immunohistochemistry, low-pass whole genome sequencing, and analysis of canonical target genes suggest that STAG2 inactivation is not associated with mechanisms previously implicated in other cancer types including chromosomal instability, increased DNA damage, or the activation of MEK/ERK or cGAS/STING signaling. Interesting, we have found that Stag2 is the only cohesin subunit that functions as a tumor suppressor in lung cancer in vivo. Chromatin accessibility profiling and gene expression analyses on Stag2-proficient and -deficient mouse lung adenocarcinoma cells have unveiled potential mediators and effects of STAG2 function. Ongoing genomic analyses of human and mouse lung cancers will demystify the relationship between major cohesin complexes, uncover the impact of STAG2 inactivation on cohesin binding genome wide, and investigate the role of Stag2 inactivation on the tumor microenvironment. We anticipate that our study will uncover the mechanisms of STAG2-mediated tumor suppression in lung cancer and provide novel insights into lung tumorigenesis. Citation Format: Emily L. Ashkin, Hongchen Cai, Yuning J. Tang, Chuan Li, Su Kit Chew, King Hung, Julia Belk, Saswati Karmakar, Jess Hebert, Maryam Yousefi, Charles Swanton, Dmitri A. Petrov, Monte Winslow. Dissecting the role of Stag2 in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 821.