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Cooperating gene mutations are typically required to transform normal cells enabling growth in soft agar or in immunodeficient mice. For example, mutations in  Kras  and transformation-related protein 53 ( Trp53 ) are known to transform a variety of mesenchymal and epithelial cells  in vitro  and  in vivo . Identifying other genes that can cooperate with oncogenic  Kras  and substitute for  Trp53  mutation has the potential to lead to new insights into mechanisms of carcinogenesis. Here, we applied a genome-wide CRISPR/Cas9 knockout screen in  Kras  G12D  immortalized mouse embryonic fibroblasts (MEFs) to search for genes that when mutated cooperate with oncogenic  Kras  to induce transformation. We also tested if mutation of the identified candidate genes could cooperate with  Kras  G12D  to generate primary sarcomas in mice. In addition to identifying the well-known tumor suppressor cyclin dependent kinase inhibitor 2A ( Cdkn2a ), whose alternative reading frame product p19 activates  Trp53 , we also identified other putative tumor suppressors, such as F-box/WD repeat-containing protein 7 ( Fbxw7 ) and solute carrier family 9 member 3 ( Slc9a3 ). Remarkably, the TCGA database indicates that both  FBXW7  and  SLC9A3  are commonly co-mutated with  KRAS  in human cancers. However, we found that only mutation of  Trp53  or  Cdkn2a , but not  Fbxw7  or  Slc9a3  can cooperate with  Kras  G12D  to generate primary sarcomas in mice. These results show that mutations in oncogenic  Kras  and either  Fbxw7  or  Slc9a3  are sufficient for transformation  in vitro , but not for  in vivo  sarcomagenesis.

Genome-wide CRISPR Screen to Identify Genes that Suppress Transformation in the Presence of Endogenous KrasG12D