An atlas of inter- and intra-tumor heterogeneity of apoptosis competency in colorectal cancer tissue at single-cell resolution
Andreas Ulrich Lindner, Manuela Salvucci, Elizabeth McDonough, Sanghee Cho, Xanthi Stachtea, Emer P. O’Connell, Alex D. Corwin, Alberto Santamaria-Pang, Steven Carberry, Michael Fichtner, Sandra Van Schaeybroeck, Pierre Laurent-Puig, John P. Burke, Deborah A. McNamara, Mark Lawler, Anup Sood, John F. Graf, Markus Rehm, Philip D. Dunne, Daniel B. Longley, Fiona Ginty & Jochen H. M. Prehn
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.