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.
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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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