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

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posted on 02.12.2021, 16:25 by Andreas Ulrich LindnerAndreas Ulrich Lindner, Manuela Salvucci, Elizabeth McDonough, Sanghee Cho, Xanthi Stachtea, Emer O'ConnellEmer O'Connell, Alex D Corwin, Alberto Santamaria-Pang, Steven Carberry, Michael Fichtner, Sandra Van Schaeybroeck, Pierre Laurent-Puig, John BurkeJohn Burke, Deborah McNamaraDeborah McNamara, Mark Lawler, Anup Sood, John F Graf, Markus RehmMarkus Rehm, Philip D Dunne, Daniel B Longley, Fiona Ginty, Jochen PrehnJochen 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.

Funding

US-Northern Ireland-Ireland Tripartite grant from Science Foundation Ireland and Health Research Board (16/US/3301)

National Cancer Institute (Systems Modeling of Tumor Heterogeneity and Therapy Response in Colorectal Cancer)

RCSI Bon Secours Hospital MD StAR fellowship

Beaumont Hospital Cancer Research and Development Trust

US-Ireland R01 award (NI Partner supported by HSCNI, STL/5715/15)

History

Comments

The original article is available at https://www.nature.com

Published Citation

Lindner AU. et al. An atlas of inter- and intra-tumor heterogeneity of apoptosis competency in colorectal cancer tissue at single-cell resolution. Cell Death Differ. 2021

Publication Date

9 November 2021

PubMed ID

34754079

Department/Unit

  • Beaumont Hospital
  • Centre for Systems Medicine
  • Physiology and Medical Physics
  • Surgery

Research Area

  • Cancer

Publisher

Springer Nature Limited

Version

  • Published Version (Version of Record)