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Peer-reviewedCC BY 4.0eLife

Impacts of mutation accumulation and order on tumor initiation revealed by engineered murine colorectal cancer organoids

  • Yanping Li1,2,3
  • Xiaoxin Xie1,2,3
  • Daqi Deng3
  • Zhiyuan Sun1,2,3
  • Zhaoan Huang1,2,3
  • Yisen Tang3
  • Liang Fang1,2,3,4
  • Wei Chen1,2,3,4
  • Qionghua Zhu1,2,3,4
4 affiliations
  1. 1Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China
  2. 2Innovative Center for RNA Therapeutics (ICRT), School of Life Sciences, Southern University of Science and Technology, Shenzhen, China
  3. 3Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China
  4. 4Guangming Advanced Research Institute, Southern University of Science and Technology, Shenzhen, China
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Abstract

Tumorigenesis typically follows a multi-hit trajectory, driven by accumulating oncogenic mutations. Colorectal cancer (CRC) has long served as a paradigmatic model of multi-hit tumorigenesis, characterized by adenoma-carcinoma transition accompanied by acquisition of specific oncogene and tumor suppressor mutations. However, how the temporal order of early mutations influences CRC initiation remains poorly understood. To address this, we established a CRC tumorigenesis model using murine intestinal organoids. By introducing defined combinations of key CRC driver mutations (Kras, Apc, and Trp53) in distinct orders, we systematically investigated how the order of mutation accumulation affects tumor initiation. Our results reveal that the mutation accumulation confers growth advantages in both in vitro and in vivo models. Strikingly, mutation order also influenced the tumorigenic properties of the organoids. Whereas organoids with Trp53 loss before or after Apc loss similarly affected organoid phenotypes in vitro or tumorigenicity in immunodeficient mice, organoids with Trp53 loss preceding Apc inactivation exhibited reduced tumor-forming potential in immunocompetent mice, likely due to their distinct immunological features. Collectively, our study reveals a critical role of ordered mutation accumulation in CRC initiation, an insight that may hold clinical relevance.

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Cite

BibTeXRIS
BibTeX
@article{li2026impacts,
  title = {{Impacts of mutation accumulation and order on tumor initiation revealed by engineered murine colorectal cancer organoids}},
  author = {Yanping Li and Xiaoxin Xie and Daqi Deng and Zhiyuan Sun and Zhaoan Huang and Yisen Tang and Liang Fang and Wei Chen and Qionghua Zhu},
  journal = {eLife},
  year = {2026},
  month = nov,
  doi = {10.7554/elife.110070},
  url = {https://elifesciences.org/articles/110070},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Impacts of mutation accumulation and order on tumor initiation revealed by engineered murine colorectal cancer organoids
AU  - Yanping Li
AU  - Xiaoxin Xie
AU  - Daqi Deng
AU  - Zhiyuan Sun
AU  - Zhaoan Huang
AU  - Yisen Tang
AU  - Liang Fang
AU  - Wei Chen
AU  - Qionghua Zhu
PY  - 2026
DA  - 2026/11/03
JO  - eLife
DO  - 10.7554/elife.110070
UR  - https://elifesciences.org/articles/110070
AB  - Tumorigenesis typically follows a multi-hit trajectory, driven by accumulating oncogenic mutations. Colorectal cancer (CRC) has long served as a paradigmatic model of multi-hit tumorigenesis, characterized by adenoma-carcinoma transition accompanied by acquisition of specific oncogene and tumor suppressor mutations. However, how the temporal order of early mutations influences CRC initiation remains poorly understood. To address this, we established a CRC tumorigenesis model using murine intestinal organoids. By introducing defined combinations of key CRC driver mutations (Kras, Apc, and Trp53) in distinct orders, we systematically investigated how the order of mutation accumulation affects tumor initiation. Our results reveal that the mutation accumulation confers growth advantages in both in vitro and in vivo models. Strikingly, mutation order also influenced the tumorigenic properties of the organoids. Whereas organoids with Trp53 loss before or after Apc loss similarly affected organoid phenotypes in vitro or tumorigenicity in immunodeficient mice, organoids with Trp53 loss preceding Apc inactivation exhibited reduced tumor-forming potential in immunocompetent mice, likely due to their distinct immunological features. Collectively, our study reveals a critical role of ordered mutation accumulation in CRC initiation, an insight that may hold clinical relevance.
SN  - 2050-084X
ER  -