克隆性CNV进化和空间限制性恶性状态的定量耦合将MFGE8确定为癌症中的候选晚期相关靶点
Quantitative coupling of clonal CNV evolution and spatially restricted malignant states identifies MFGE8 as a candidate late-state-associated target in breast cancer.
摘要(中文译文)
乳腺癌进展反映了由克隆演化和微环境选择所塑造的异质性恶性状态，然而基因组不稳定性如何定量地与转录状态转变及空间生态位组织相耦合仍不清楚。我们整合了ER阳性、HER2阳性和三阴性肿瘤的单细胞RNA测序和空间转录组学，并结合了拷贝数变异推断、分支轨迹分析、转录因子调控子建模、细胞间通讯推断和空间生态位定位。轨迹衍生的演化基因程序被转化为bulk肿瘤分层和多队列预后建模。进一步通过基于结构的虚拟筛选结合对接和分子动力学优化，将MFGE8作为治疗靶点进行评估。使用敲低、过表达、回补和体外表型实验对MFGE8进行了功能验证。恶性上皮细胞形成了一个分支三态轨迹，该轨迹与CNV定义的克隆结构强烈耦合，其中三阴性肿瘤中的耦合最为紧密。调控子分析揭示了沿进展过程的转录因子协同重编程，汇聚于一个富含细胞外基质和黏附信号传导的晚期State 3程序。空间转录组学将State 3定位到一个以基质主导的配体-受体相互作用为特征的离散侵袭前沿生态位。MFGE8作为与LHX2活性相关的State 3偏向性输出而出现，计算机模拟的MFGE8扰动诱导了从晚期状态分支的转录回退。结构导向的筛选优先确定了具有稳定相互作用动力学的候选MFGE8结合物。演化基因程序实现了稳健的bulk分层，并支持一个经多队列验证的10基因预后模型，该模型与基因组不稳定性模式和免疫治疗相关特征相关。CNV关联的克隆演化和空间生态位限制与一个晚期恶性程序相关，并优先将MFGE8作为乳腺癌中候选的晚期状态相关治疗靶点。
Abstract
Breast cancer progression reflects heterogeneous malignant states shaped by clonal evolution and microenvironmental selection, yet how genomic instability quantitatively couples to transcriptional state transitions and spatial niche organization remains unclear. We integrated single-cell RNA sequencing and spatial transcriptomics across ER-positive, HER2-positive, and triple-negative tumors, combined with CNV inference, branched trajectory analysis, transcription factor regulon modeling, cell-cell communication inference, and spatial niche mapping. Trajectory-derived evolutionary gene programs were translated to bulk-tumor stratification and multicohort prognostic modeling. MFGE8 was further evaluated as a therapeutic target using structure-based virtual screening with docking and molecular dynamics refinement. Functional validation of MFGE8 was performed using knockdown, overexpression, rescue, and in vitro phenotypic assays. Malignant epithelial cells formed a branched three-state trajectory that was strongly coupled to CNV-defined clonal architecture, with the tightest coupling in triple-negative tumors. Regulon analyses revealed coordinated transcription factor rewiring along progression, converging on a late State 3 program enriched for extracellular matrix and adhesion signaling. Spatial transcriptomics localized State 3 to a discrete invasive-front niche characterized by stromal-dominant ligand-receptor interactions. MFGE8 emerged as a State 3-biased output associated with LHX2 activity, and in silico MFGE8 perturbation induced transcriptional rollback from the late-state branch. Structure-guided screening prioritized candidate MFGE8 binders with stable interaction dynamics. Evolutionary gene programs enabled robust bulk stratification and supported a multicohort-validated 10-gene prognostic model associated with genomic instability patterns and immunotherapy-related signatures. CNV-linked clonal evolution and spatial niche restriction are associated with a late malignant program and prioritize MFGE8 as a candidate late-state-associated therapeutic target in breast cancer.
如何引用
AMA
Zhangwen Ge, Liuxian Wu, Shu Wang, Xukui Li, Tao Wang. Quantitative coupling of clonal CNV evolution and spatially restricted malignant states identifies MFGE8 as a candidate late-state-associated target in breast cancer.. Journal of translational medicine. 2026; doi:10.1186/s12967-026-08308-6.
APA
Zhangwen Ge, Liuxian Wu, Shu Wang, Xukui Li, Tao Wang (2026). Quantitative coupling of clonal CNV evolution and spatially restricted malignant states identifies MFGE8 as a candidate late-state-associated target in breast cancer.. Journal of translational medicine. https://doi.org/10.1186/s12967-026-08308-6
GB/T 7714
Zhangwen Ge, Liuxian Wu, Shu Wang, Xukui Li, Tao Wang. Quantitative coupling of clonal CNV evolution and spatially restricted malignant states identifies MFGE8 as a candidate late-state-associated target in breast cancer.[J]. Journal of translational medicine, 2026 doi:10.1186/s12967-026-08308-6.
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