Zhang, Xiaoyan;
Yang, Ling;
Lei, Wanjun;
Hou, Qiang;
Huang, Ming;
Zhou, Rongjing;
Enver, Tariq;
(2022)
Single-cell sequencing reveals CD133+CD44--originating evolution and novel stemness related variants in human colorectal cancer.
EBioMedicine
, 82
, Article 104125. 10.1016/j.ebiom.2022.104125.
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Abstract
BACKGROUND: Tumor heterogeneity of human colorectal cancer (CRC)-initiating cells (CRCICs) in cancer tissues often represents aggressive features of cancer progression. For high-resolution examination of CRCICs, we performed single-cell whole-exome sequencing (scWES) and bulk cell targeted exome sequencing (TES) of CRCICs to investigate stemness-specific somatic alterations or clonal evolution. METHODS: Single cells of three subpopulations of CRCICs (CD133+CD44+, CD133-CD44+, and CD133+CD44- cells), CRC cells (CRCCs), and control cells from one CRC tissue were sorted for scWES. Then, we set up a mutation panel from scWES data and TES was used to validate mutation distribution and clonal evolution in additional 96 samples (20 patients) those were also sorted into the same three groups of CRCICs and CRCCs. The knock-down experiments were used to analyze stemness-related mutant genes. Neoantigens of these mutant genes and their MHC binding affinity were also analyzed. FINDINGS: Clonal evolution analysis of scWES and TES showed that the CD133+CD44- CRCICs were the likely origin of CRC before evolving into other groups of CRCICs/CRCCs. We revealed that AHNAK2, PLIN4, HLA-B, ALK, CCDC92 and ALMS1 genes were specifically mutated in CRCICs followed by the validation of their functions. Furthermore, four predicted neoantigens of AHNAK2 were identified and validated, which might have applications in immunotherapy for CRC patients. INTERPRETATION: All the integrative analyses above revealed clonal evolution of CRC and new markers for CRCICs and demonstrate the important roles of CRCICs in tumorigenesis and progression of CRCs. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.
| Type: | Article |
|---|---|
| Title: | Single-cell sequencing reveals CD133+CD44--originating evolution and novel stemness related variants in human colorectal cancer |
| Location: | Netherlands |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.ebiom.2022.104125 |
| Publisher version: | https://doi.org/10.1016/j.ebiom.2022.104125 |
| Language: | English |
| Additional information: | Copyright © 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) |
| Keywords: | Cancer initiating cells, Clonal evolution, Colorectal cancer, Mutation, Single-cell sequencing |
| UCL classification: | 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 > Research Department of Cancer Bio UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10151860 |
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