单细胞转录组学揭示了 Shp2 在 Myc 驱动的肝肿瘤细胞和微环境中的相反作用。
Single-cell transcriptomics reveals opposing roles of Shp2 in Myc-driven liver tumor cells and microenvironment.
机构信息
Division of Biological Sciences, University of California at San Diego, La Jolla, CA 92093, USA; Department of Pathology, University of California at San Diego, La Jolla, CA 92093, USA.
Department of Pathology, University of California at San Diego, La Jolla, CA 92093, USA.
出版信息
Cell Rep. 2021 Nov 9;37(6):109974. doi: 10.1016/j.celrep.2021.109974.
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.
Myc 驱动的肝肿瘤发生机制尚未充分阐明。在此，我们发现，肝细胞特异性 Ptpn11/Shp2 缺失会显著加剧 Myc 驱动的肝细胞癌（HCC）。然而，Myc 诱导的肿瘤选择性地从 Shp2 缺陷肝脏中的罕见 Shp2 阳性肝细胞中发展，并且 Myc 驱动的致癌作用取决于 Shp2 促进的完整 Ras-Erk 信号，以维持 Myc 的稳定性。尽管 Shp2 在细胞自主方面有严格的要求，但 Shp2 的缺失会诱导免疫抑制环境，导致肿瘤起始细胞清除缺陷和侵袭性肿瘤进展。Shp2 缺陷肝脏中的基础 Wnt/β-catenin 信号被上调，而 Myc 转染进一步增强了这种信号。敲除 Ctnnb1 可抑制 Shp2 缺陷肝脏中的 Myc 诱导 HCC，表明 β-catenin 发挥了重要作用。一致地，Myc 过表达和 CTNNB1 突变在预后不良的 HCC 患者中经常同时检测到。这些数据阐明了由细胞内在致癌信号驱动的肝肿瘤发生的复杂机制，该机制与通过破坏特定致癌途径产生的促进肿瘤的微环境协同作用。
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