用病理图像+空间分析预测结直肠癌生存风险,比传统分期更准。
INSIGHT: Spatially resolved survival modelling from routine histology crosslinked with molecular profiling reveals prognostic epithelial-immune axes in stage II/III colorectal cancer
- 构建图神经网络,从常规病理切片中提取空间风险评分。
- 独立验证显示C指数达0.68-0.69,显著优于pTNM分期。
- 揭示肿瘤细胞与免疫微环境协同演变的高危通路,指导精准治疗。
常规病理切片蕴含大量II/III期结直肠癌预后信息,其核心在于复杂的组织空间结构。我们提出INSIGHT模型,一种图神经网络,可直接从常规病理图像预测患者生存率。在TCGA(n=342)和SURGEN(n=336)数据集上训练并交叉验证,生成个体化空间风险评分。大规模独立验证表明,其预后性能优于传统pTNM分期(C-index 0.68–0.69 vs 0.44–0.58)。空间风险图谱再现经典病理特征,并发现核部固体度与圆形度是定量风险指标。整合空间风险与数据驱动的空间转录组、空间蛋白组、批量RNA-seq及单细胞参考数据,揭示了以肿瘤上皮-免疫交互为核心的预后风险维度,涵盖上皮去分化与胎儿程序、髓系驱动的基质状态(如SPP1+巨噬细胞、LAMP3+树突细胞)以及适应性免疫功能障碍。该分析揭示了患者特异性的上皮异质性,识别出MSI-High肿瘤内部的分层结构,以及CDX2/HNF4A缺失与CEACAM5/6相关增殖程序的高危路径,提示协同治疗靶点。
原文摘要 · Abstract (English)
Routine histology contains rich prognostic information in stage II/III colorectal cancer, much of which is embedded in complex spatial tissue organisation. We present INSIGHT, a graph neural network that predicts survival directly from routine histology images. Trained and cross-validated on TCGA (n=342) and SURGEN (n=336), INSIGHT produces patient-level spatially resolved risk scores. Large independent validation showed superior prognostic performance compared with pTNM staging (C-index 0.68-0.69 vs 0.44-0.58). INSIGHT spatial risk maps recapitulated canonical prognostic histopathology and identified nuclear solidity and circularity as quantitative risk correlates. Integrating spatial risk with data-driven spatial transcriptomic signatures, spatial proteomics, bulk RNA-seq, and single-cell references revealed an epithelium-immune risk manifold capturing epithelial dedifferentiation and fetal programs, myeloid-driven stromal states including $\mathrm{SPP1}^{+}$ macrophages and $\mathrm{LAMP3}^{+}$ dendritic cells, and adaptive immune dysfunction. This analysis exposed patient-specific epithelial heterogeneity, stratification within MSI-High tumours, and high-risk routes of CDX2/HNF4A loss and CEACAM5/6-associated proliferative programs, highlighting coordinated therapeutic vulnerabilities.
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