An atlas of inter- and intra-tumor heterogeneity of apoptosis competency in colorectal cancer tissue at single-cell resolution

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...

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Bibliographic Details
Published in:Cell death and differentiation 2022-04, Vol.29 (4), p.806-817
Main Authors: Lindner, Andreas Ulrich, Salvucci, Manuela, McDonough, Elizabeth, Cho, Sanghee, Stachtea, Xanthi, O’Connell, Emer P., Corwin, Alex D., Santamaria-Pang, Alberto, Carberry, Steven, Fichtner, Michael, Van Schaeybroeck, Sandra, Laurent-Puig, Pierre, Burke, John P., McNamara, Deborah A., Lawler, Mark, Sood, Anup, Graf, John F., Rehm, Markus, Dunne, Philip D., Longley, Daniel B., Ginty, Fiona, Prehn, Jochen H. M.
Format: Article
Language:English
Subjects:
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Apoptosis
Apoptosis - physiology
Biochemistry
Biomedical and Life Sciences
Cancer
Caspase
Cell Biology
Cell Cycle Analysis
Cell lineage
Colorectal cancer
Colorectal carcinoma
Colorectal Neoplasms - metabolism
DIABLO protein
Human health and pathology
Humans
Immunofluorescence
Life Sciences
Mitochondria
Mitochondria - metabolism
Mitochondrial Proteins - metabolism
Ordinary differential equations
Segmentation
Stem Cells
Stromal cells
Tumors
X-Linked Inhibitor of Apoptosis Protein - metabolism
XIAP protein
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Summary: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.
ISSN:1350-9047
1476-5403
DOI:10.1038/s41418-021-00895-9