Λεπτομέρειες βιβλιογραφικής εγγραφής
| Τίτλος: |
Pan‐cancer atlas of cellular architecture reveals a nearest‐neighbour distance‐associated biomechanical‐immune axis involving CD4+ memory T cells. |
| Συγγραφείς: |
Huang, Linglong, Östman, Arne, Sun, Yunfan |
| Πηγή: |
Clinical & Translational Medicine; Jul2026, Vol. 16 Issue 7, p1-27, 27p |
| Θεματικοί όροι: |
Mechanotransduction (Cytology), Tumor-infiltrating immune cells, Tumor microenvironment, RNA sequencing, CD4 antigen, Cancer prognosis, Cell aggregation |
| Περίληψη: |
Background: The systematic link between cellular spatial organization and its biomechanical consequences remains a critical knowledge gap in human oncology. Objective: To quantitatively map the cellular architecture of solid tumours and elucidate its mechanistic impact on mechanical signalling, immune infiltration, and patient survival. Methods: We developed a scalable digital pathology framework, processing 7910 H&E whole‐slide images across 21 solid tumours. A deep learning pipeline was employed to segment over 4.7 billion nuclei, enabling the calculation of cell density and nearest neighbour distance (NND) as key spatial metrics. To bridge morphology and function, we integrated these metrics with bulk RNA‐seq data from 19 TCGA cohorts (n = 7401) using rigorous histological matching. Furthermore, to resolve microenvironmental heterogeneity, we performed unsupervised clustering of over 60 000 T‐cell transcriptomes from independent cohorts. These findings were validated through high‐resolution Visium‐HD spatial transcriptomics to correlate physical proximity with localized gene expression. Results: While tumours exhibited significant heterogeneity, NND, but not cell density, emerged as a primary determinant of biomechanical and immune signatures. A trend‐level association was observed between lower NND and higher Hippo/YAP/TAZ pathway activity across nine matched cancer types (Spearman's ρ = ‐.65, p =.058, n = 9). In addition, lower NND was significantly correlated with increased CD4+ memory T‐cell (CD4+ TMem cell) abundance (Spearman's ρ = ‐.86, p <.01). Single‐cell analyses confirmed that CD4+ TMem cells intrinsically express mechanical stress signalling markers, which spatial transcriptomics localized to CD4+ TMem cell aggregation zones characterized by high pathway activity. Clinically, this spatial‐mechanical‐CD4+ TMem cell axis was associated with prognosis in breast, oesophageal, liver, and lung adenocarcinomas, where high mechanical signalling generally predicted poor outcomes but could be modulated by CD4+ TMem infiltration levels. Conclusion: Our study identifies low NND as a spatial correlate of biomechanical crowding that is associated with CD4+ TMem cell programming and adverse clinical outcomes. By integrating deep learning‐based spatial metrics with multi‐omics, we highlight spatial mechanics as a critical, potentially targetable dimension of the tumour microenvironment for future immunotherapies. Highlights: NND extracted from routine H&E slides serves as a spatial proxy for mechanical crowding across 21 cancer types.Low NND is associated with Hippo/YAP/TAZ pathway activation and CD4+ TMem cell enrichment, validated by single‐cell and spatial transcriptomics.This spatial‐mechanical‐immune axis carries prognostic significance, with potential implications for spatially informed immunotherapy. [ABSTRACT FROM AUTHOR] |
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| Βάση Δεδομένων: |
Complementary Index |