肺腺癌远处转移的机制与治疗靶点
Mechanisms and therapeutic targets in distant metastasis of lung adenocarcinoma.
作者
作者单位
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
- State Key Laboratory of Molecular Oncology, Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
- State Key Laboratory of Molecular Oncology, Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. jmying@cicams.ac.cn.
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. lijunling@cicams.ac.cn.
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. xingpuyuan@cicams.ac.cn.
摘要
中文
远处转移具有器官趋向性,是肺腺癌(LUAD)患者死亡的主要原因。本研究整合了52例LUAD患者的数字空间转录组学(DSP)、多重免疫荧光(mIF)及临床数据,构建器官特异性转移风险模型,并探讨转移器官趋向性背后的分子机制。基于原发肿瘤空间转录组的随机森林模型可准确预测脑(AUC = 0.974)、肝(AUC = 0.975)、肾上腺(AUC = 0.929)及骨(AUC = 0.907)转移。研究鉴定了与器官趋向性转移相关的关键区室特异性基因表达特征,包括肿瘤中表达的基因(如脑转移的FKBP1A、肝转移的MOCOS)、免疫细胞中表达的基因(如肝转移的ADAMTSL2)及基质细胞中表达的基因(如脑转移的CKAP2)。通路分析揭示了与器官趋向性相关的不同生物学过程,如脑转移中富集的细胞死亡通路及肝转移中的细胞外基质(ECM)重塑。转移后生存模型强调了基质基因表达(如OS相关的PKM和PFS相关的VCAM1)及免疫抑制微环境(如M2型巨噬细胞浸润)作为关键预后因素。本研究建立的高精度预测模型及关键分子特征,加深了对"种子-土壤"相互作用动力学的理解,为未来临床应用提供了有前景的生物标志物和治疗靶点。
English
Distant metastasis, characterized by organotropism, is a major cause of mortality in lung adenocarcinoma (LUAD). In this study, digital spatial profiling (DSP), multiplex immunofluorescence (mIF), and clinical data from 52 LUAD patients were integrated to develop organ-specific metastasis risk models, and the molecular mechanisms underlying metastatic organotropism were investigated. Random forest models based on primary tumor spatial transcriptomics accurately predicted metastasis to the brain (AUC = 0.974), liver (AUC = 0.975), adrenal gland (AUC = 0.929), and bone (AUC = 0.907). Key compartment-specific gene expression signatures associated with organotropic metastasis were identified, including those expressed in tumors (e.g., FKBP1A for the brain and MOCOS for the liver), immune cells (e.g., ADAMTSL2 for the liver), and stromal cells (e.g., CKAP2 for the brain). Pathway analyses revealed distinct biological processes associated with organotropism, such as enriched cell death pathways in brain metastasis and extracellular matrix (ECM) remodeling in liver metastasis. Postmetastasis survival models highlight stromal gene expression (e.g., PKM for OS and VCAM1 for PFS) and immunosuppressive microenvironments (e.g., M2 macrophage infiltration) as critical prognostic factors. The high-precision prediction models and key molecular signatures identified in this study enhance our understanding of "seed-soil" interaction dynamics and offer promising biomarkers and therapeutic targets for future clinical use.
分类与指标
- 研究类型
- 基础研究
- 病种
- 肺癌
- JCR 分区
- Q1
- 影响因子
- 81.2
- 新锐分区
- 1区