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An oncogenic phenoscape of colonic stem cell polarization

Qin, Xiao; Cardoso Rodriguez, Ferran; Sufi, Jahangir; Vlckova, Petra; Claus, Jeroen; Tape, Christopher J; (2023) An oncogenic phenoscape of colonic stem cell polarization. Cell , 186 (25) 5554-5568.e18. 10.1016/j.cell.2023.11.004. Green open access

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Abstract

Cancer cells are regulated by oncogenic mutations and microenvironmental signals, yet these processes are often studied separately. To functionally map how cell-intrinsic and cell-extrinsic cues co-regulate cell fate, we performed a systematic single-cell analysis of 1,107 colonic organoid cultures regulated by (1) colorectal cancer (CRC) oncogenic mutations, (2) microenvironmental fibroblasts and macrophages, (3) stromal ligands, and (4) signaling inhibitors. Multiplexed single-cell analysis revealed a stepwise epithelial differentiation phenoscape dictated by combinations of oncogenes and stromal ligands, spanning from fibroblast-induced Clusterin (CLU)+ revival colonic stem cells (revCSCs) to oncogene-driven LRIG1+ hyper-proliferative CSCs (proCSCs). The transition from revCSCs to proCSCs is regulated by decreasing WNT3A and TGF-β-driven YAP signaling and increasing KRASG12D or stromal EGF/Epiregulin-activated MAPK/PI3K flux. We find that APC loss and KRASG12D collaboratively limit access to revCSCs and disrupt stromal-epithelial communication—trapping epithelia in the proCSC fate. These results reveal that oncogenic mutations dominate homeostatic differentiation by obstructing cell-extrinsic regulation of cell-fate plasticity.

Type: Article
Title: An oncogenic phenoscape of colonic stem cell polarization
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.cell.2023.11.004
Publisher version: https://doi.org/10.1016/j.cell.2023.11.004
Language: English
Additional information: ©2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: colonic stem cell, colorectal cancer, CRC, organoid, single-cell analysis, cell plasticity, tumor microenvironment, cell-cell signaling, cell-fate polarization, cue-signal-response
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/10183517
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