Through in vivo delivery of RCAS plasmids that carry guide RNAs (gRNAs) for a series of tumor suppressor genes (Trp53, Cdkn2a, and Pten), we show that we can efficiently generate high-grade tumors in mice that express both Cas9 and TVA in the Nestin or GFAP-positive cells. Here, TP53 is linked to neoplasm.