Cancer is a leading cause of morbidity and mortality worldwide. Developing molecularly targeted therapies to improve patient outcomes will require comprehensive understanding of the genetic events that give rise to cancer. Large-scale efforts to catalog the genetic aberrations in human tumors are currently underway. Transposon-based insertional mutagenesis screens provide a complementary, comparative genomics approach for cancer gene discovery. Sleeping Beauty (SB) transposon mutagenesis has been used to identify genes that contribute to intestinal tumor formation. Two of the identified genes, Rspo2 and Wac, were the subjects of this thesis research. R-spondin 2 (RSPO2) belongs to the R-spondin family of secreted Wnt agonists. Activation of RSPO2 and 3 has been identified in human colorectal and liver cancer, although the functional significance of these lesions has not been proven, and genetic screens in mice suggested that Rspo2 and Rspo3 are oncogenic in the mammary gland as well. Here we present an analysis of RSPO2 and 3 in human colon, breast, and liver cancer. We found that expression of RSPO2 and 3 was increased in subsets of all three tumor types, and correlated with activation of Wnt signaling in these tumors compared to normal tissues. We further investigated the functional significance of increased RSPO2 in breast and liver cancer models. We showed that RSPO2 can activate Wnt signaling in non-transformed breast epithelial cells and RSPO2 overexpression is required for Wnt signaling and proliferation in an RSPO2-high breast cancer cell line. We developed an in vivo model of RSPO2 activation in the mouse liver using hydrodynamic tranfection with transposon-based DNA vectors followed by Fah selection. We found that increased expression of RSPO2 in the liver activated Wnt signaling and promoted hepatomegaly. RSPO2 overexpression cooperated with Trp53 inactivation to initiate tumor formation. Hepatocellular carcinomas that formed in this model exhibited activated Wnt signaling. This model will facilitate further studies of R-spondin signaling and enable development of RSPO-targeted therapy. WW domain containing adaptor with coiled-coil (WAC) is an adaptor protein required for diverse biological processes, including regulation of gene transcription through histone H2B monoubiquitination. Wac was inactivated by transposon insertions in three SB screens for genetic drivers of intestinal tumorigenesis in wild type, Apc-deficient, and Trp53-deficient backgrounds. We found that WAC was somatically mutated and downregulated in human colorectal tumors. Further, mutant versions of WAC identified in human tumors were unable to transcriptionally activate expression of cdkn1a (the gene encoding p21) in a zebrafish embryo model. Depletion of Wac cooperated with Apc and Trp53 inactivation to promote anchorage independent growth of mouse colonic epithelial cells. The results of these studies collectively implicate RSPO2 as an oncogene in multiple wnt-responsive tissues and suggest WAC is a tumor suppressor in the colon that cooperates with APC and TP53. Additional work is warranted to further define the signaling pathways regulated by RSPO2 and WAC in tumorigenesis and to determine if drug targeting of these pathways is a viable strategy for improving the treatment of RSPO2 and WAC-driven cancers.