<br>整合单细胞和批量 RNA 测序揭示了 HBV 相关肝细胞癌中的 CK19 + 癌症干细胞及其特异性 SPP1 + 肿瘤相关巨噬细胞生态位,Hepatology International

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整合单细胞和批量 RNA 测序揭示了 HBV 相关肝细胞癌中的 CK19 + 癌症干细胞及其特异性 SPP1 + 肿瘤相关巨噬细胞生态位
Hepatology International ( IF 5.9 ) Pub Date : 2023-12-30 , DOI: 10.1007/s12072-023-10615-9
Cheng-Lei Yang _{1,

2,

3} , Rui Song _{1,

2,

3} , Jun-Wen Hu _{1,

2,

3} , Jun-Tao Huang _{1,

2,

3} , Nan-Nan Li ₄ , Hang-Hang Ni _{1,

2,

3} , Yuan-Kuan Li _{1,

2,

3} , Jie Zhang _{1,

2,

3} , Zhan Lu _{1,

2,

3} , Min Zhou _{1,

2,

3} , Jun-Duo Wang ₅ , Min-Jun Li _{1,

2,

3} , Guo-Hua Zhan _{1,

2,

3} , Tao Peng _{2,

6} , Hong-Ping Yu _{3,

7} , Lu-Nan Qi _{1,

2,

3} , Qiu-Yan Wang _{8,

9} , Bang-De Xiang _{1,

2,

3}

Affiliation

Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Qingxiu District, 71 He Di Road, Nanning, 530021, Guangxi Province, China.
Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, 530021, Guangxi Province, China.
Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning, 530021, Guangxi Province, China.
Department of Ultrasound, Guangxi Zhuang Autonomous Region Workers' Hospital, Nanning, 530021, Guangxi Province, China.
The First Clinical Medical School, Guangxi Medical University, Nanning, 530021, Guangxi Province, China.
Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, China.
Research Department, Guangxi Medical University Cancer Hospital, Nanning, 530021, Guangxi Province, China.
Department of Biochemistry and Molecular Biology, Guangxi Medical University, Nanning, 530021, Guangxi Province, China.
Center for Genomic and Personalized Medicine, Guangxi Medical University, 22 Shuang Yong Road, Nanning, 530021, Guangxi Province, China.

目的

细胞角蛋白 19 阳性癌症干细胞 (CK19 + CSC) 及其肿瘤相关巨噬细胞 (TAM) 尚未在乙型肝炎病毒 (HBV) 相关肝细胞癌 (HCC) 中得到充分探索。

实验设计

对从 11 名初治 HBV 相关 HCC 患者（包括 8 名 CK19 + 患者）获得的活细胞进行单细胞 RNA 测序，以阐明其转录组状况、CK19 + CSC 异质性和免疫微环境。使用两个内部原发性 HCC 队列（96 例相关 HBV 病例和 89 例复发病例）、TCGA 外部队列以及体外和体内实验来验证结果。

结果

对来自人类 HCC 和邻近正常组织的总共 64,581 个单细胞进行了测序，并鉴定了 11 种细胞类型。结果显示，CK19+CSCs具有表型和转录异质性，共表达多种肝脏CSC标志物，且与较差的预后呈正相关。此外，具有强烈M2样特征和较差预后的SPP1 + TAM（TAM_SPP1）在CK19 + HCC中特异性富集，并通过激活血管生成促进肿瘤侵袭和转移。重要的是，源自 TAM_SPP1 的基质金属蛋白酶 9 (MMP9) 作为 CK19 + HCC 的枢纽基因，被 VEGFA 信号激活。

结论

本研究揭示了 CK19 + CSC 和 CK19 + HCC 中特异性免疫抑制 TAM_SPP1 的异质性和干性特征。 VEGFA信号可以激活TAM_SPP1衍生的MMP9，促进CK19+HCC肿瘤的侵袭和转移。这可能为 HCC 患者的临床治疗提供新的见解。

图形概要

简单总结：细胞角蛋白 19 阳性肝细胞癌是一种高度侵袭性的恶性肿瘤，治疗进展不佳。更好地了解 CK19 + CSC 的特征及其免疫微环境可能有助于开发有效的靶向和免疫治疗。本研究鉴定了 CK19 + CSC 的异质性和特征，并探讨了其独特的免疫抑制 SPP1+TAM 生态位。结果提示，VEGFA信号激活TAM_SPP1衍生的MMP9，促进CK19+HCC肿瘤的侵袭和转移。这项研究可能具有重要的治疗价值。

"点击查看英文标题和摘要"

Integrating single-cell and bulk RNA sequencing reveals CK19 + cancer stem cells and their specific SPP1 + tumor-associated macrophage niche in HBV-related hepatocellular carcinoma

Purpose

Cytokeratin 19-positive cancer stem cells (CK19 + CSCs) and their tumor-associated macrophages (TAMs) have not been fully explored yet in the hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC).

Experimental design

Single-cell RNA sequencing was performed on the viable cells obtained from 11 treatment-naïve HBV-associated HCC patients, including 8 CK19 + patients, to elucidate their transcriptomic landscape, CK19 + CSC heterogeneity, and immune microenvironment. Two in-house primary HCC cohorts (96 cases-related HBV and 89 cases with recurrence), TCGA external cohort, and in vitro and in vivo experiments were used to validate the results.

Results

A total of 64,581 single cells derived from the human HCC and adjacent normal tissues were sequenced, and 11 cell types were identified. The result showed that CK19 + CSCs were phenotypically and transcriptionally heterogeneous, co-expressed multiple hepatics CSC markers, and were positively correlated with worse prognosis. Moreover, the SPP1 + TAMs (TAM_SPP1) with strong M2-like features and worse prognosis were specifically enriched in the CK19 + HCC and promoted tumor invasion and metastasis by activating angiogenesis. Importantly, matrix metalloproteinase 9 (MMP9) derived from TAM_SPP1, as the hub gene of CK19 + HCC, was activated by the VEGFA signal.

Conclusions

This study revealed the heterogeneity and stemness characteristics of CK19 + CSCs and specific immunosuppressive TAM_SPP1 in CK19 + HCC. The VEGFA signal can activate TAM_SPP1-derived MMP9 to promote the invasion and metastasis of CK19 + HCC tumors. This might provide novel insights into the clinical treatment of HCC patients.

Graphical abstract

Lay summary: Cytokeratin 19-positive hepatocellular carcinoma is a highly aggressive malignancy with poor therapeutic progress. Understanding the characteristics of CK19 + CSCs and their immune microenvironment better might facilitate the development of effective targeted and immunotherapy. This study identified the heterogeneity and characteristics of CK19 + CSCs and explored their unique immunosuppressive SPP1+TAM niche. The results suggested that the VEGFA signal activates TAM_SPP1-derived MMP9 to promote the invasion and metastasis of CK19 + HCC tumors. The study might have an important therapeutic value.

更新日期：2023-12-30

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