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This study applies a graph neural network to routine histology images of colorectal cancer, demonstrating that AI can extract superior prognostic spatial information compared to standard staging. By integrating these image-derived risk scores with multi-omics data, the model identifies specific epithelial-immune axes and therapeutic vulnerabilities relevant to precision oncology.
INSIGHT: Spatially resolved survival modelling from routine histology crosslinked with molecular profiling reveals prognostic epithelial-immune axes in stage II/III colorectal cancer
arXiv:2512.22262v2 Announce Type: replace-cross Abstract: 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.
Abstract: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.
Quantitative Methods (q-bio.QM); Machine Learning (cs.LG)
arXiv:2512.22262 [q-bio.QM]
(or arXiv:2512.22262v2 [q-bio.QM] for this version)
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