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 Mycdriven 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/beta-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 beta-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.

Automated summary

The mechanisms of Myc-driven liver tumorigenesis involve complex interactions between cell-intrinsic oncogenic signaling and a tumor-promoting microenvironment generated by disrupting specific oncogenic pathways. While Myc-induced tumors are aggravated in mice with hepatocyte-specific Ptpn11/Shp2 deletion, the development of tumors selectively from Shp2-positive hepatocytes in Shp2-deficient liver highlights the crucial role of Shp2 in promoting Ras-Erk signaling and sustaining Myc stability. Despite a stringent requirement of Shp2 cell autonomously, its deletion induces an immunosuppressive environment leading to defective clearance of tumor-initiating cells and aggressive tumor progression. Additionally, upregulation of basal Wnt/beta-catenin signaling in Shp2-deficient liver further augmented by Myc transfection underscores the essential role of beta-catenin in Myc-induced HCC progression.