Woodfield Sarah E, Mistretta Brandon J, Patel Roma H, Ibarra Aryana M, Fisher Kevin E, Sarabia Stephen F, Gandhi Ilavarasi, Reuther Jacquelyn, Starosolski Zbigniew, Badachhape Andrew, Epps Jessica, Zorman Barry, Shah Aayushi P, Larson Samuel R, Srivastava Rohit K, Shi Yan, Espinoza Andres F, Govindu Saiabhiroop R, Whitlock Richard S, Holloway Kimberly, Roy Angshumoy, Sumazin Pavel, Ghaghada Ketan B, Lopez-Terrada Dolores, Gunaratne Preethi H, Vasudevan Sanjeev A
Divisions of Pediatric Surgery and Surgical Research, Michael E. DeBakey Department of Surgery, Pediatric Surgical Oncology Laboratory, Texas Children's Surgical Oncology Program, Texas Children's Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA.
Biol Open. 2022 Sep 15;11(9). doi: 10.1242/bio.058973. Epub 2022 Sep 12.
Hepatoblastoma (HB) is the most common pediatric primary liver malignancy, and survival for high-risk disease approaches 50%. Mouse models of HB fail to recapitulate hallmarks of high-risk disease. The aim of this work was to generate murine models that show high-risk features including multifocal tumors, vascular invasion, metastasis, and circulating tumor cells (CTCs). HepT1 cells were injected into the livers or tail veins of mice, and tumor growth was monitored with magnetic resonance and bioluminescent imaging. Blood was analyzed with fluorescence-activated cell sorting to identify CTCs. Intra- and extra-hepatic tumor samples were harvested for immunohistochemistry and RNA and DNA sequencing. Cell lines were grown from tumor samples and profiled with RNA sequencing. With intrahepatic injection of HepT1 cells, 100% of animals grew liver tumors and showed vascular invasion, metastasis, and CTCs. Mutation profiling revealed genetic alterations in seven cancer-related genes, while transcriptomic analyses showed changes in gene expression with cells that invade vessels. Tail vein injection of HepT1 cells resulted in multifocal, metastatic disease. These unique models will facilitate further meaningful studies of high-risk HB. This article has an associated First Person interview with the first author of the paper.
肝母细胞瘤（HB）是最常见的儿童原发性肝脏恶性肿瘤，高危疾病的生存率接近50%。HB的小鼠模型无法重现高危疾病的特征。这项工作的目的是生成具有多灶性肿瘤、血管侵犯、转移和循环肿瘤细胞（CTC）等高风险特征的小鼠模型。将HepT1细胞注入小鼠肝脏或尾静脉，并用磁共振和生物发光成像监测肿瘤生长。通过荧光激活细胞分选分析血液以鉴定CTC。采集肝内和肝外肿瘤样本进行免疫组织化学以及RNA和DNA测序。从肿瘤样本中培养细胞系并用RNA测序进行分析。通过肝内注射HepT1细胞，100%的动物长出肝脏肿瘤，并出现血管侵犯、转移和CTC。突变分析揭示了7个癌症相关基因的基因改变，而转录组分析显示侵袭血管的细胞的基因表达发生了变化。尾静脉注射HepT1细胞导致多灶性转移性疾病。这些独特的模型将有助于对高危HB进行更有意义的进一步研究。本文配有对该论文第一作者的第一人称访谈。
