Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, P. R. China.
School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, P. R. China.
Hepatology. 2024 Jun 1;79(6):1293-1309. doi: 10.1097/HEP.0000000000000673. Epub 2023 Nov 16.
Microvascular invasion (MVI) is a crucial pathological hallmark of HCC that is closely associated with poor outcomes, early recurrence, and intrahepatic metastasis following surgical resection and transplantation. However, the intricate tumor microenvironment and transcriptional programs underlying MVI in HCC remain poorly understood.
We performed single-cell RNA sequencing of 46,789 individual cells from 10 samples of MVI+ (MVI present) and MVI- (MVI absent) patients with HCC. We conducted comprehensive and comparative analyses to characterize cellular and molecular features associated with MVI and validated key findings using external bulk, single-cell, and spatial transcriptomic datasets coupled with multiplex immunofluorescence assays. The comparison identified specific subtypes of immune and stromal cells critical to the formation of the immunosuppressive and pro-metastatic microenvironment in MVI+ tumors, including cycling T cells, lysosomal associated membrane protein 3+ dendritic cells, triggering receptor expressed on myeloid cells 2+ macrophages, myofibroblasts, and arterial i endothelial cells. MVI+ malignant cells are characterized by high proliferation rates, whereas MVI- malignant cells exhibit an inflammatory milieu. Additionally, we identified the midkine-dominated interaction between triggering receptor expressed on myeloid cells 2+ macrophages and malignant cells as a contributor to MVI formation and tumor progression. Notably, we unveiled a spatially co-located multicellular community exerting a dominant role in shaping the immunosuppressive microenvironment of MVI and correlating with unfavorable prognosis.
This study provides a comprehensive single-cell atlas of MVI in HCC, shedding light on the complex multicellular ecosystem and molecular features associated with MVI. These findings deepen our understanding of the underlying mechanisms driving MVI and provide valuable insights for improving clinical diagnosis and developing more effective treatment strategies.
微血管侵犯（MVI）是 HCC 的关键病理标志，与手术切除和移植后不良预后、早期复发和肝内转移密切相关。然而，MVI 背后复杂的肿瘤微环境和转录程序仍知之甚少。
我们对 10 例 MVI+（存在 MVI）和 MVI-（不存在 MVI）HCC 患者的 46789 个单个细胞进行了单细胞 RNA 测序。我们进行了全面和比较分析，以描述与 MVI 相关的细胞和分子特征，并使用外部批量、单细胞和空间转录组数据集以及多重免疫荧光测定验证了关键发现。比较确定了特定的免疫和基质细胞亚型，这些亚型对于 MVI+肿瘤中免疫抑制和促转移微环境的形成至关重要，包括循环 T 细胞、溶酶体相关膜蛋白 3+树突状细胞、髓样细胞触发受体 2+巨噬细胞、肌成纤维细胞和动脉 i 内皮细胞。MVI+恶性细胞的特征是高增殖率，而 MVI-恶性细胞则表现出炎症环境。此外，我们发现髓样细胞触发受体 2+巨噬细胞和恶性细胞之间以中期因子为主的相互作用是 MVI 形成和肿瘤进展的一个贡献因素。值得注意的是，我们揭示了一个空间上共存的多细胞群落，它在塑造 MVI 的免疫抑制微环境方面发挥着主导作用，并与不良预后相关。
本研究提供了 HCC 中 MVI 的全面单细胞图谱，揭示了与 MVI 相关的复杂多细胞生态系统和分子特征。这些发现加深了我们对驱动 MVI 的潜在机制的理解，并为改善临床诊断和开发更有效的治疗策略提供了有价值的见解。
