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

doi:10.1038/s41418-021-00895-9

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 LongleyFiona Ginty, Jochen H M Prehn

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Abstract

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.

Original language	English
Journal	Cell death and differentiation
Early online date	09 Nov 2021
DOIs	https://doi.org/10.1038/s41418-021-00895-9
Publication status	Early online date - 09 Nov 2021

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An atlas of inter- and intra-tumor heterogeneity of apoptosis competency in colorectal cancer tissue at single-cell resolution
Copyright 2021 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 6.21 MBLicence: CC BY

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Lindner, A. U., Salvucci, M., McDonough, E., Cho, S., Stachtea, X., O'Connell, E. P., Corwin, A. D., Santamaria-Pang, A., Carberry, S., Fichtner, M., Van Schaeybroeck, S., Laurent-Puig, P., Burke, J. P., McNamara, D. A., Lawler, M., Sood, A., Graf, J. F., Rehm, M., Dunne, P. D., ... Prehn, J. H. M. (2021). An atlas of inter- and intra-tumor heterogeneity of apoptosis competency in colorectal cancer tissue at single-cell resolution. Cell death and differentiation. Advance online publication. https://doi.org/10.1038/s41418-021-00895-9

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

abstract = "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.",

author = "Lindner, {Andreas Ulrich} and Manuela Salvucci and Elizabeth McDonough and Sanghee Cho and Xanthi Stachtea and O'Connell, {Emer P} and Corwin, {Alex D} and Alberto Santamaria-Pang and Steven Carberry and Michael Fichtner and {Van Schaeybroeck}, Sandra and Pierre Laurent-Puig and Burke, {John P} and McNamara, {Deborah A} and Mark Lawler and Anup Sood and Graf, {John F} and Markus Rehm and Dunne, {Philip D} and Longley, {Daniel B} and Fiona Ginty and Prehn, {Jochen H M}",

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Lindner, AU, Salvucci, M, McDonough, E, Cho, S, Stachtea, X, O'Connell, EP, Corwin, AD, Santamaria-Pang, A, Carberry, S, Fichtner, M, Van Schaeybroeck, S, Laurent-Puig, P, Burke, JP, McNamara, DA, Lawler, M, Sood, A, Graf, JF, Rehm, M, Dunne, PD , Longley, DB, Ginty, F & Prehn, JHM 2021, 'An atlas of inter- and intra-tumor heterogeneity of apoptosis competency in colorectal cancer tissue at single-cell resolution', Cell death and differentiation. https://doi.org/10.1038/s41418-021-00895-9

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T1 - An atlas of inter- and intra-tumor heterogeneity of apoptosis competency in colorectal cancer tissue at single-cell resolution

AU - Lindner, Andreas Ulrich

AU - Salvucci, Manuela

AU - McDonough, Elizabeth

AU - Cho, Sanghee

AU - Stachtea, Xanthi

AU - O'Connell, Emer P

AU - Corwin, Alex D

AU - Santamaria-Pang, Alberto

AU - Carberry, Steven

AU - Fichtner, Michael

AU - Van Schaeybroeck, Sandra

AU - Laurent-Puig, Pierre

AU - Burke, John P

AU - McNamara, Deborah A

AU - Lawler, Mark

AU - Sood, Anup

AU - Graf, John F

AU - Rehm, Markus

AU - Dunne, Philip D

AU - Longley, Daniel B

AU - Ginty, Fiona

AU - Prehn, Jochen H M

PY - 2021/11/9

Y1 - 2021/11/9

N2 - 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.

AB - 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.

U2 - 10.1038/s41418-021-00895-9

DO - 10.1038/s41418-021-00895-9

M3 - Article

C2 - 34754079

SN - 1476-5403

JO - Cell death and differentiation

JF - Cell death and differentiation

ER -

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

Abstract

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