Single-cell transcriptomics reveals opposing roles of Shp2 in Myc-driven liver tumor cells and microenvironment

The mechanisms of Myc-driven liver tumorigenesis are inadequately understood. Herein we show that Myc-driven hepatocellular carcinoma (HCC) is dramatically aggravated in mice with hepatocyte-specific Ptpn11/Shp2 deletion. However, Myc-induced tumors develop selectively from the rare Shp2-positive hepatocytes in Shp2-deficent liver, and Myc-driven oncogenesis depends on an intact Ras-Erk signaling promoted by Shp2 to sustain Myc stability. Despite a stringent requirement of Shp2 cell autonomously, Shp2 deletion induces an immunosuppressive environment, resulting in defective clearance of tumor-initiating cells and aggressive tumor progression. The 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. Consistently, Myc overexpression and CTNNB1 mutations are frequently co-detected in HCC patients with poor prognosis. These data elucidate complex mechanisms of liver tumorigenesis driven by cell-intrinsic oncogenic signaling in cooperation with a tumor-promoting microenvironment generated by disrupting the specific oncogenic pathway. [Display omitted] •Myc alone drives a severe HCC phenotype in Shp2-deficient liver•Shp2 is required cell autonomously for control of Myc stability•Shp2 deficiency induces a tumorigenic environment in the liver•Aberrantly elevated β-catenin signaling promotes Myc-driven HCC Chen et al. demonstrate that Shp2 is required cell intrinsically for Myc-driven hepatocarcinogenesis through maintaining an intact Ras-Erk pathway and Myc stability, although Shp2 deletion in neighboring hepatocytes generates a tumor-promoting immunosuppressive microenvironment by upregulation of β-catenin signaling.