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

ABSTRACT: 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.

SUBMITTER: Chen WS

PROVIDER: S-EPMC8656042 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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

Chen Wendy S WS Liang Yan Y Zong Min M Liu Jacey J JJ Kaneko Kota K Hanley Kaisa L KL Zhang Kun K Feng Gen-Sheng GS

Cell reports 20211101 6

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 ...[more]

PMID: 34758313

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Dataset Information

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

Publications

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

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