Hepatocellular Carcinoma is a complex cancer with little available targeted therapeutics, in part due to the recently uncovered paradoxical roles of previously defined proto-oncogenes. Our lab and others have identified overexpression and ablation of several proto-oncogenes sensitizes the liver towards HCC development. Previously, our lab demonstrated hepatocyte deletion of Shp2/Ptpn11 in mice (SKO) ablates HCC driven by cMET/Δ90-β-catenin or cMET/PIK3CA mutant yet greatly accelerates chemical carcinogen-induced HCC. To clarify the complex mechanisms of Shp2 function in HCC, we examined the contribution of the proto-oncogene Myc, which acts downstream of Shp2. The aim of my dissertation research is to elucidate the novel murine model of Myc-driven tumorigenesis in SKO background, examining cell-intrinsicand extrinsic factors driving tumor development. Original work in this dissertation shows that Myc-driven hepatocellular carcinoma (HCC) is dramatically aggravated in mice with hepatocyte-specific Ptpn11/Shp2 deletion. Using single-cell RNA-sequencing coupled with functional assays, we show Shp2-knockout livers exhibit defective clearance of tumor-initiating cells by altering macrophage polarization and reducing macrophage phagocytic activity, resulting in an immune-suppressive environment. We uncover that Myc-induced tumors selectively develop from the rare Shp2-positive hepatocytes in Shp2-deficent liver. Myc-driven oncogenesis depends on intact Ras-Erk signaling, driven by Shp2, to sustain Myc stability. Basal Wnt/β-catenin signaling is upregulated in Shp2-deficient liver, which is further augmented by Myc transfection. Ablating Ctnnb1 suppresses Myc-induced HCC in Shp2-deficient livers, revealing an essential role of β- catenin in assisting in Myc-driven HCC. Consistently, Myc overexpression and CTNNB1 mutations are frequently co-detected in HCC patients with poor prognosis. Single cell RNA sequencing and functional in vivo / in vitro data together reveal the complex mechanisms of liver tumorigenesis driven by cell-intrinsic oncogenic signaling of Myc, supported by intrinsic Shp2 and β-catenin signaling, in cooperation with a tumor promoting microenvironment generated by disruption of Shp2 proto-oncogenic signaling.