RESUMEN
Primary liver cancer represents a major health problem. It comprises hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), which differ markedly with regards to their morphology, metastatic potential and responses to therapy. However, the regulatory molecules and tissue context that commit transformed hepatic cells towards HCC or ICC are largely unknown. Here we show that the hepatic microenvironment epigenetically shapes lineage commitment in mosaic mouse models of liver tumorigenesis. Whereas a necroptosis-associated hepatic cytokine microenvironment determines ICC outgrowth from oncogenically transformed hepatocytes, hepatocytes containing identical oncogenic drivers give rise to HCC if they are surrounded by apoptotic hepatocytes. Epigenome and transcriptome profiling of mouse HCC and ICC singled out Tbx3 and Prdm5 as major microenvironment-dependent and epigenetically regulated lineage-commitment factors, a function that is conserved in humans. Together, our results provide insight into lineage commitment in liver tumorigenesis, and explain molecularly why common liver-damaging risk factors can lead to either HCC or ICC.
Asunto(s)
Apoptosis , Carcinoma Hepatocelular/patología , Linaje de la Célula , Colangiocarcinoma/patología , Neoplasias Hepáticas/patología , Necrosis , Microambiente Tumoral , Animales , Apoptosis/genética , Carcinogénesis/genética , Carcinoma Hepatocelular/genética , Diferenciación Celular , Linaje de la Célula/genética , Colangiocarcinoma/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/deficiencia , Citocinas/metabolismo , Elementos Transponibles de ADN/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Modelos Animales de Enfermedad , Epigénesis Genética/genética , Femenino , Perfilación de la Expresión Génica , Genes myc , Genes ras , Hepatocitos/metabolismo , Hepatocitos/patología , Humanos , Neoplasias Hepáticas/genética , Masculino , Ratones , Mosaicismo , Necrosis/genética , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
In this Article, the pCaMIN construct consisted of 'mouse MYC and mouse NrasG12V' instead of 'mouse Myc and human NRASG12V; and the pCAMIA construct consisted of 'mouse Myc and human AKT1' instead of 'mouse Myc and Akt1' this has been corrected online.