A developmentally prometastatic niche to hepatoblastoma in neonatal liver mediated by the Cxcl1/Cxcr2 axis.
A developmentally prometastatic niche to hepatoblastoma in neonatal liver mediated by the Cxcl1/Cxcr2 axis.
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DOI：
10.1002/hep.32412
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发表时间：
2022-11
期刊：
影响因子：
13.5
通讯作者：
Zhu, Liqin
中科院分区：
文献类型：
--
作者：
Fan, Li;Pan, Qingfei;Yang, Wentao;Koo, Selene C.;Tian, Cheng;Li, Liyuan;Lu, Meifen;Brown, Anthony;Ju, Bensheng;Easton, John;Ranganathan, Sarangarajan;Shin, Soona;Bondoc, Alexander;Yang, Jun J.;Yu, Jiyang;Zhu, Liqin
肝母细胞瘤（HB）是最常见的儿童肝癌。它主要发生在非常年幼的儿童中，这使我们调查新生儿肝脏是否为HB的发展提供了一个致蛋白的生态位。比较出生后第5天建立的原位移植模型和60只小鼠（P5Tx和P60Tx模型）的HB发育情况。使用来自两种模型的肿瘤和肝脏组织进行单细胞rna测序，并研究鉴定出的顶级候选细胞类型和基因在HB细胞生长、迁移和存活中的作用。我们发现，包括HepG2细胞在内的各种HB细胞系在P5Tx模型中的致瘤性和转移性始终比P60Tx模型高得多。P5Tx和P60Tx HepG2模型的Sc-RNAseq结果显示，P5Tx肿瘤缺氧程度更高，肿瘤周围肝脏中活化的肝星状细胞（aHSCs）数量更多，表达的Cxcl1水平显著高于P60Tx模型。我们发现这些差异在正常的P5和P60肝脏中也存在。我们发现Cxcl1/Cxcr2轴介导HB细胞迁移，对HB细胞在缺氧条件下的存活至关重要。用重组CXCL1蛋白处理HepG2 P60Tx模型诱导肝内和肺转移，敲除HepG2细胞中的CXCR2可消除其在P5Tx模型中的转移潜能。最后，我们发现，在转移性HB患者肿瘤中，肿瘤周围肝脏中的aHSCs比局部肿瘤中更多，并且肿瘤缺氧与儿童癌症中HB患者的预后有独特的关系。我们证明新生儿肝脏通过Cxcl1/Cxcr2轴为HB的发展提供了一个前转移性生态位。
Hepatoblastoma (HB) is the most common pediatric liver cancer. Its predominant occurrence in very young children led us to investigating whether the neonatal liver provides a protumorigenic niche to HB development. HB development was compared between orthotopic transplantation models established in postnatal day 5 and 60 mice (P5Tx and P60Tx models). Single-cell RNA-sequencing was performed using tumor and liver tissues from both models and the top candidate cell types and genes identified are investigated for their roles in HB cell growth, migration, and survival. We found that various HB cell lines including HepG2 cells were consistently and considerably more tumorigenic and metastatic in the P5Tx model than in the P60Tx models. Sc-RNAseq of the P5Tx and P60Tx HepG2 models revealed that the P5Tx tumor was more hypoxic and had a larger number of activated hepatic stellate cells (aHSCs) in the tumor-surrounding liver which express significantly higher levels of Cxcl1 than those from the P60Tx model. We found these differences were developmentally present in normal P5 and P60 liver. We showed that the Cxcl1/Cxcr2 axis mediated HB cell migration and was critical to HB cell survival under hypoxia. Treating HepG2 P60Tx model with recombinant CXCL1 protein induced intrahepatic and pulmonary metastasis and CXCR2 knockout in HepG2 cells abolished their metastatic potential in the P5Tx model. Lastly, we showed that in metastatic HB patient tumors there was a similar larger population of aHSCs in the tumor-surrounding liver than in localized tumors, and tumor hypoxia was uniquely associated with HB patient prognosis among pediatric cancers. We demonstrated that the neonatal liver provides a prometastatic niche to HB development via the Cxcl1/Cxcr2 axis.
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