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A patient-derived organoid model captures fetal-like plasticity in colorectal cancer

Liang Xiong^1,† , Ying Xu^1,† , Zhaoya Gao^2,3,† , Jingyi Shi⁴ , Yunfan Wang⁵ , Xiaodong Wang⁶ , Wensheng Huang^2,3 , Ming Li^2,3 , Longteng Wang⁷ , Jun Xu¹ , Cheng Li⁷ , Jin Gu^2,3,4,8,9,* , Hongkui Deng^1,* , Molong Qu^1,*

¹School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
²Department of Gastrointestinal Surgery, Peking University Shougang Hospital, Beijing, China
³Center for Precision Diagnosis and Treatment of Colorectal Cancer and Inflammatory Diseases, Peking University Health Science Center, Beijing, China
⁴Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Surgery, Peking University Cancer Hospital & Institute, Beijing, China
⁵Department of Pathology, Peking University Shougang Hospital, Beijing, China
⁶Department of Oncology, Peking University Shougang Hospital, Beijing, China
⁷Center for Bioinformatics, School of Life Sciences, Center for Statistical Science, Peking University, Beijing, China
⁸Peking University International Cancer Institute, Peking University, Beijing, China
⁹Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
^†These authors contributed equally: Liang Xiong, Ying Xu, Zhaoya Gao
* Correspondence: Jin Gu(zlguj@bjmu.edu.cn)Hongkui Deng(hongkui_deng@pku.edu.cn)Molong Qu(qumolong@163.com)

Phenotypic plasticity is a hallmark feature driving cancer progression, metastasis, and therapy resistance. Fetal-like transcriptional programs have been increasingly implicated in promoting plastic cell states, yet their roles remain difficult to study due to limitations of existing culture models. Here, we establish a chemically defined patient-derived organoid system that enables long-term expansion of colorectal cancer (CRC) cells while preserving fetal-like features associated with phenotypic plasticity. Using this model, we identify an oncofetal state (OnFS) that is enriched in advanced tumors and linked to key features of plasticity, including epithelial-mesenchymal plasticity, as well as increased metastasis and treatment resistance. Mechanistically, we show that FGF2-AP-1 signaling maintains the OnFS program and associated phenotypic plasticity in CRC. This model offers a powerful platform for studying the fetal-like features underlying cancer cell plasticity and their role in tumor progression and treatment resistance in CRC.

https://doi.org/10.1038/s41422-025-01139-y

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