Cancer Research Institute, First People's Hospital of Foshan, Foshan, 528000, Guangdong, China.
The First Affiliated Hospital/School of Clinical Medicineof, Guangdong Pharmaceutical University, Guangzhou, 510080, Guangdong, China.
J Exp Clin Cancer Res. 2023 Jan 23;42(1):28. doi: 10.1186/s13046-023-02598-0.
Cervical cancer (CC) is the 3 most common cancer in women and the 4 leading cause of deaths in gynaecological malignancies, yet the exact progression of CC is inconclusive, mainly due to the high complexity of the changing tumour microenvironment (TME) at different stages of tumorigenesis. Importantly, a detailed comparative single-nucleus transcriptomic analysis of tumour microenvironment (TME) of CC patients at different stages is lacking.
In this study, a total of 42,928 and 29,200 nuclei isolated from the tumour tissues of stage-I and II CC patients and subjected to single-nucleus RNA sequencing (snRNA-seq) analysis. The cell heterogeneity and functions were comparatively investigated using bioinformatic tools. In addition, label-free quantitative mass spectrometry based proteomic analysis was carried out. The proteome profiles of stage-I and II CC patients were compared, and an integrative analysis with the snRNA-seq was performed.
Compared with the stage-I CC (CCI) patients, the immune response relevant signalling pathways were largely suppressed in various immune cells of the stage-II CC (CCII) patients, yet the signalling associated with cell and tissue development was enriched, as well as metabolism for energy production suggested by the upregulation of genes associated with mitochondria. This was consistent with the quantitative proteomic analysis that showed the dominance of proteins promoting cell growth and intercellular matrix development in the TME of CCII group. The interferon-α and γ responses appeared the most activated pathways in many cell populations of the CCI patients. Several collagens, such as COL12A1, COL5A1, COL4A1 and COL4A2, were found significantly upregulated in the CCII group, suggesting their roles in diagnosing CC progression. A novel transcript AC244205.1 was detected as the most upregulated gene in CCII patients, and its possible mechanistic role in CC may be investigated further.
Our study provides important resources for decoding the progression of CC and set the foundation for developing novel approaches for diagnosing CC and tackling the immunosuppressive TME.
宫颈癌（CC）是女性中第三常见的癌症，也是妇科恶性肿瘤中第四大死亡原因，但 CC 的确切进展尚不清楚，主要是由于肿瘤发生的不同阶段肿瘤微环境（TME）的高度复杂性。重要的是，缺乏对不同阶段 CC 患者肿瘤微环境（TME）的详细比较性单细胞转录组分析。
在这项研究中，总共从 I 期和 II 期 CC 患者的肿瘤组织中分离出 42928 个和 29200 个细胞核，并进行单细胞 RNA 测序（snRNA-seq）分析。使用生物信息学工具比较了细胞异质性和功能。此外，还进行了无标记定量质谱的蛋白质组分析。比较了 I 期和 II 期 CC 患者的蛋白质组谱，并与 snRNA-seq 进行了综合分析。
与 I 期 CC（CCI）患者相比，在各种免疫细胞中，II 期 CC（CCII）患者的免疫反应相关信号通路受到了很大的抑制，但与细胞和组织发育相关的信号通路被富集，以及与线粒体相关的基因上调表明能量产生的代谢增强。这与定量蛋白质组分析结果一致，即 CCII 组 TME 中促进细胞生长和细胞外基质发育的蛋白质占主导地位。干扰素-α和γ反应似乎是 CCI 患者许多细胞群体中最活跃的途径。在 CCII 组中，几种胶原蛋白，如 COL12A1、COL5A1、COL4A1 和 COL4A2，被发现明显上调，表明它们在诊断 CC 进展中的作用。在 CCII 患者中检测到一个新的转录本 AC244205.1 是上调最明显的基因，其在 CC 中的可能作用机制可能进一步研究。
我们的研究为破译 CC 的进展提供了重要资源，并为开发诊断 CC 和解决免疫抑制性 TME 的新方法奠定了基础。
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