A STAG2-PAXIP1/PAGR1 axis suppresses lung tumorigenesis [RNA-Seq]

The cohesin complex is a critical regulator of gene expression. STAG2 is the most frequently mutated cohesin subunit across several cancer types and is a key tumor suppressor in lung cancer. Here, we coupled somatic CRISPR-Cas9 genome editing and tumor barcoding with an autochthonous oncogenic KRAS-driven lung cancer model and show that STAG2 is uniquely tumor suppressive among all core and auxiliary cohesin components. The heterodimeric complex components PAXIP1 and PAGR1 have highly correlated effects with STAG2 in human lung cancer cell lines, are tumor suppressors in vivo, and are epistatic to STAG2 in oncogenic KRAS-driven lung tumorigenesis in vivo. Gene expression and chromatin accessibility similarities between STAG2- and PAXIP1-deficient neoplastic cells further relates STAG2-cohesin to PAXIP1/PAGR1. These findings reveal a STAG2-PAXIP1/PAGR1 tumor-suppressive axis and uncover novel PAXIP1-dependent and PAXIP1-independent STAG2-cohesin mediated mechanisms of lung tumor suppression. To characterize the molecular effects of STAG2-deficiency, we initiated tumors in KT and KT;Stag2flox mice and used FACS to isolate neoplastic cells (DAPIneg, lineageneg, Tomatopos cells) for molecular analyses To capture any changes in the molecular output of STAG2 deficiency during tumor development, we collected samples after 8 and 16 weeks of tumor growth. We initiated tumors using different viral titers such that mice would have similar overall tumor burden at time of analysis We performed RNA-seq on samples from each timepoint and of each genotype.