RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
结直肠神经内分泌肿瘤伴肝转移的综合单细胞图谱：揭示原发灶与转移灶之间肿瘤微环境异质性
英文原题：Comprehensive single-cell atlas of colorectal neuroendocrine tumors with liver metastases: unraveling tumor microenvironment heterogeneity between primary lesions and metastases.
查看英文原题
Comprehensive single-cell atlas of colorectal neuroendocrine tumors with liver metastases: unraveling tumor microenvironment heterogeneity between primary lesions and metastases.
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研究概要
我们的研究首次对 CRNELM 患者中 PL 与 LM 的细胞和分子差异进行了单细胞分析。我们鉴定出可能驱动 TME 差异并支持转移性肿瘤生长的不同细胞亚群和受体-配体相互作用。这些发现突出了潜在的治疗靶点，并为更好地管理 CRNELM 患者提供了策略依据。
研究思路结论见上方概要
背景
结直肠神经内分泌肿瘤伴肝转移（CRNELM）相比无转移的同类肿瘤，预后更差。全面理解原发灶（PL）与肝转移灶（LM）之间肿瘤微环境（TME）的异质性，可为增强这类患者的临床管理策略提供关键见解。
方法
我们利用单细胞RNA测序分析了CRNELM患者的新鲜组织样本，旨在阐明PL与LM之间TME的差异。通过空间转录组学、bulk RNA测序以及多重免疫组化/免疫荧光实现了互补的多维验证。
结果
我们的单细胞RNA测序分析显示，与PL相比，LM中CD8+ T细胞、CD4+ T细胞、NK细胞、NKT细胞和B细胞的比例更高，且表现出应激样表型。RGS5+周细胞可能在LM内免疫细胞中观察到的应激样表型中发挥作用。PL中的MCs（PL_MCs）和LM中的MCs（LM_MCs）表现出肿瘤相关信号通路的差异性激活。值得注意的是，COLEC11+基质癌相关成纤维细胞（COLEC11_mCAFs）被发现与LM_MCs显著相关。细胞通讯分析揭示了COLEC11_mCAFs与LM_MCs之间潜在的可靶向受体-配体相互作用。多维验证证实了特征性应激样表型的突出性，包括HSPA6_CD8_Tstr、HSPA6_NK和COLEC11_mCAFs在LM中的表现。此外，COLEC11_mCAFs的较高丰度与神经内分泌肿瘤患者队列中较差的生存率相关。
展开英文摘要原文
BACKGROUND
Colorectal neuroendocrine tumors with liver metastases (CRNELM) are associated with a poorer prognosis compared to their nonmetastatic counterparts. A comprehensive understanding of the tumor microenvironment (TME) heterogeneity between primary lesions (PL) and liver metastases (LM) could provide crucial insights for enhancing clinical management strategies for these patients.
METHODS
We utilized single-cell RNA sequencing to analyze fresh tissue samples from CRNELM patients, aiming to elucidate the variations in TME between PL and LM. Complementary multidimensional validation was achieved through spatial transcriptomics, bulk RNA sequencing, and multiplex immunohistochemistry/immunofluorescence.
RESULTS
Our single-cell RNA sequencing analysis revealed that LM harboured a higher proportion of CD8 + T cells, CD4 + T cells, NK cells, NKT cells, and B cells exhibiting a stress-like phenotype compared to PL. RGS5 + pericytes may play a role in the stress-like phenotype observed in immune cells within LM. MCs in PL (PL_MCs) and LM (LM_MCs) exhibit distinct activation of tumor-associated signaling pathways. Notably, COLEC11 + matrix cancer-associated fibroblasts (COLEC11_mCAFs) were found to be significantly associated with LM_MCs. Cell communication analysis unveiled potential targetable receptor-ligand interactions between COLEC11_mCAFs and LM_MCs. Multidimensional validation confirmed the prominence of the characteristic stress-like phenotypes, including HSPA6_CD8_Tstr, HSPA6_NK, and COLEC11_mCAFs in LM. Moreover, a higher abundance of COLEC11_mCAFs correlated with poorer survival rates in the neuroendocrine tumor patient cohort.
CONCLUSION
Overall, our study provides the first single-cell analysis of the cellular and molecular differences between PL and LM in CRNELM patients. We identified distinct cell subsets and receptor-ligand interactions that may drive TME discrepancies and support metastatic tumor growth. These insights highlight potential therapeutic targets and inform strategies for better managing CRNELM patients.
论文信息
- 作者
- Deng Y、Chen Q、Guo C、Chen J、Li X、Li Z、Zhang Y、Zhao J
- 第一作者单位
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.China
- 通讯作者单位
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. zhaohong@cicams.ac.cn.China
- 期刊
- Molecular cancer2025 Jan 21
- 原文标识
- PubMed 39838423 · DOI 10.1186/s12943-025-02231-y
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