Figure S5. Summary of the in vivo... | Rockefeller University Press

Figure S5.

$Summary of the in vivo genetic experiments as they related to the essential role of cohesin in general and the specific tumor suppressive function of STAG2-cohesin and PAXIP1/PAGR1, as well as a summary of the most parsimonious model of STAG2-cohesin and PAXIP1/PAGR1 mediated tumor suppression and mutations in PAXIP1 and PAGR1 and downregulation of PAXIP1 mRNA expression in a subset of AMLs. (a) Interpretations of results from Figs. 1, 2, and 3 describing the distinct phenotypes controlled by STAG2- and STAG1-cohesin, homozygous and heterozygous inactivation of cohesin components, and the role of PAXIP1 on lung tumorigenesis in vivo. The lung tumor suppressive effect of Stag2 is well established in oncogenic KRAS-driven lung tumors (Cai et al., 2021; Blair et al., 2023), confirmed in the current study, and extended to lung cancer driven by other oncogenes (Blair et al., 2023). The compensation of STAG1 and STAG2 in the essential functions of cohesin, in general, is well established in cell lines (Arruda et al., 2020; van der Lelij et al., 2017; Canudas and Smith, 2009) and confirmed in lung cancer by our in vivo studies, including the genetic epistasis between Stag1 and Stag2. While homozygous inactivation of each core and auxiliary cohesin component greatly reduced lung tumorigenesis, heterozygous inactivation of Smc3 using a floxed allele increases tumorigenesis. This likely explains the mutations in cohesin components in human cancer and extends the importance of dysregulation of this complex to a much larger fraction of lung adenocarcinomas. Finally, while Paxip1 or Pagr1 inactivation increased lung tumorigenesis, inactivation of either gene did not reduce tumorigenesis of Stag2-deficient tumors, as would have been expected if Paxip1/Pagr1 were also involved in the essential cohesin function. (b) Multiple models could have explained how STAG2-cohesin and the PAXIP1/PAGR1 complex cooperate to suppress lung tumorigenesis. However, our genetic epistasis data (Fig. 3) and molecular analyses (Figs. 4 and 5) are most consistent with Model 3 in which the major role of PAXIP1/PAGR1 is to work with STAG2-cohesin to regulate a subset of genes that are controlled by STAG2-cohesin. (c) Oncoprint of AMLs from TCGA accessed through cBioPortal. 190 samples with mutation and copy number data. Mutation type is indicated. (d) mRNA expression of PAXIP1 in AMLs from TCGA accessed through cBioPortal. 165 samples with mutation, copy number, and gene expression data. Sample were split based on putative copy number of PAXIP1. Each dot is a sample. Note low expression in a subset of sample with likely unaltered DNA copy number (diploid samples). (e) Oncoprint of AMLs from DCFI-Oncopanel-3 samples from GENIE accessed through cBioPortal. 80 samples with mutation data. SMC1A and PAGR1 were not profiled. Mutation type is indicated.$

Summary of the in vivo genetic experiments as they related to the essential role of cohesin in general and the specific tumor suppressive function of STAG2-cohesin and PAXIP1/PAGR1, as well as a summary of the most parsimonious model of STAG2-cohesin and PAXIP1/PAGR1 mediated tumor suppression and mutations in PAXIP1 and PAGR1 and downregulation of PAXIP1 mRNA expression in a subset of AML s. (a) Interpretations of results from Figs. 1, 2, and 3 describing the distinct phenotypes controlled by STAG2- and STAG1-cohesin, homozygous and heterozygous inactivation of cohesin components, and the role of PAXIP1 on lung tumorigenesis in vivo. The lung tumor suppressive effect of Stag2 is well established in oncogenic KRAS-driven lung tumors (Cai et al., 2021; Blair et al., 2023), confirmed in the current study, and extended to lung cancer driven by other oncogenes (Blair et al., 2023). The compensation of STAG1 and STAG2 in the essential functions of cohesin, in general, is well established in cell lines (Arruda et al., 2020; van der Lelij et al., 2017; Canudas and Smith, 2009) and confirmed in lung cancer by our in vivo studies, including the genetic epistasis between Stag1 and Stag2. While homozygous inactivation of each core and auxiliary cohesin component greatly reduced lung tumorigenesis, heterozygous inactivation of Smc3 using a floxed allele increases tumorigenesis. This likely explains the mutations in cohesin components in human cancer and extends the importance of dysregulation of this complex to a much larger fraction of lung adenocarcinomas. Finally, while Paxip1 or Pagr1 inactivation increased lung tumorigenesis, inactivation of either gene did not reduce tumorigenesis of Stag2-deficient tumors, as would have been expected if Paxip1/Pagr1 were also involved in the essential cohesin function. (b) Multiple models could have explained how STAG2-cohesin and the PAXIP1/PAGR1 complex cooperate to suppress lung tumorigenesis. However, our genetic epistasis data (Fig. 3) and molecular analyses (Figs. 4 and 5) are most consistent with Model 3 in which the major role of PAXIP1/PAGR1 is to work with STAG2-cohesin to regulate a subset of genes that are controlled by STAG2-cohesin. (c) Oncoprint of AMLs from TCGA accessed through cBioPortal. 190 samples with mutation and copy number data. Mutation type is indicated. (d) mRNA expression of PAXIP1 in AMLs from TCGA accessed through cBioPortal. 165 samples with mutation, copy number, and gene expression data. Sample were split based on putative copy number of PAXIP1. Each dot is a sample. Note low expression in a subset of sample with likely unaltered DNA copy number (diploid samples). (e) Oncoprint of AMLs from DCFI-Oncopanel-3 samples from GENIE accessed through cBioPortal. 80 samples with mutation data. SMC1A and PAGR1 were not profiled. Mutation type is indicated.

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