Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland University of Medicine and Health Sciences, 123 St. Stephen's Green, Dublin 2, Ireland.
Centre of Systems Medicine, Royal College of Surgeons in Ireland University of Medicine and Health Sciences, 123 St. Stephen's Green, Dublin 2, Ireland.
Cell Death Differ. 2022 Apr;29(4):806-817. doi: 10.1038/s41418-021-00895-9. Epub 2021 Nov 9.
Cancer cells' ability to inhibit apoptosis is key to malignant transformation and limits response to therapy. Here, we performed multiplexed immunofluorescence analysis on tissue microarrays with 373 cores from 168 patients, segmentation of 2.4 million individual cells, and quantification of 18 cell lineage and apoptosis proteins. We identified an enrichment for BCL2 in immune, and BAK, SMAC, and XIAP in cancer cells. Ordinary differential equation-based modeling of apoptosis sensitivity at single-cell resolution was conducted and an atlas of inter- and intra-tumor heterogeneity in apoptosis susceptibility generated. Systems modeling at single-cell resolution identified an enhanced sensitivity of cancer cells to mitochondrial permeabilization and executioner caspase activation compared to immune and stromal cells, but showed significant inter- and intra-tumor heterogeneity.
癌细胞抑制细胞凋亡的能力是恶性转化的关键，限制了对治疗的反应。在这里，我们对来自 168 名患者的 373 个组织微阵列进行了多重免疫荧光分析，对 240 万个单个细胞进行了分割，并对 18 种细胞谱系和凋亡蛋白进行了定量分析。我们发现 BCL2 在免疫细胞中富集，BAK、SMAC 和 XIAP 在癌细胞中富集。我们在单细胞分辨率下对细胞凋亡敏感性进行了基于常微分方程的建模，并生成了细胞凋亡敏感性的肿瘤内和肿瘤间异质性图谱。单细胞分辨率的系统建模发现，与免疫细胞和基质细胞相比，癌细胞对线粒体通透化和效应子半胱天冬酶激活的敏感性增强，但存在显著的肿瘤内和肿瘤间异质性。
