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

Wendy S Chen,Gen-Sheng Feng,Kaisa L Hanley,Kota Kaneko,Kun Zhang,Yan Liang,Jacey J Liu,Min Zong

doi:10.1016/j.celrep.2021.109974

Wendy S Chen, Gen-Sheng Feng + Show 6 more

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https://doi.org/10.1016/j.celrep.2021.109974

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Journal: Cell Reports	Publication Date: Nov 1, 2021
Citations: 32	License type: cc-by

Affiliation: University of California, San Diego

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.

Highlights

Hepatocellular carcinoma (HCC) represents the vast majority of primary liver cancer, a highly fatal disease with rising incidence and mortality worldwide
Myc-driven carcinogenesis is drastically exacerbated in Shp2-deficient liver Based on our recent results that deleting Shp2 in hepatocytes abrogated liver tumorigenesis induced by MET working upstream of Shp2 (Liu et al, 2018), we sought to examine the effect of Shp2 removal on Myc, a nuclear oncoprotein that acts downstream in oncogenic signaling
While Myc-induced tumors in FVB/N mice were classified as hepatoblastomas, we observed that the tumors had hepatoblastomalike high nucleus-to-cytoplasm ratios indicative of high proliferation yet maintained hepatocyte morphology (Table S1) (Chen and Calvisi, 2014; Liu et al, 2017)

Summary

Introduction

Hepatocellular carcinoma (HCC) represents the vast majority of primary liver cancer, a highly fatal disease with rising incidence and mortality worldwide. Liver tumorigenesis results from a series of proliferative, metabolic, and architectural alterations over chronic hepatic disorders (El-Serag, 2011; Llovet et al, 2016). HCC, characteristically resistant to chemotherapy, is often diagnosed at late stages with limited treatment options. A multi-kinase inhibitor sorafenib has remained the frontline drug for advanced HCC for a decade. The U.S Food and Drug Administration (FDA) has only recently approved a combination of atezolizumab and bevacizumab, which achieved significantly better overall and tumor progression-free survival rates than sorafenib in unresectable HCC (Finn et al, 2020). Future development of more efficacious mechanism-based therapeutics requires a deeper understanding of cell-intrinsic and cell-extrinsic tumorigenic signals intertwined in the liver

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