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Colorectal cancer organoid models uncover oxaliplatin-resistant mechanisms at single cell resolution

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A Correction to this article was published on 24 November 2022

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Abstract

Purpose

Oxaliplatin-based chemotherapy is a standard treatment for advanced colorectal cancer (CRC) patients. However, chemoresistance-induced resistance is an essential cause for mortality. Therefore, it is necessary to study the mechanism of drug resistance in CRC.

Methods

Here, we established two strains of patient-derived organoids (PDOs) selected from oxaliplatin-resistant and treatment-naïve CRC patients. To dissect the drug-resistant mechanisms, these CRC-PDOs were subjected to single-cell RNA sequencing (scRNA-Seq).

Results

We found that the drug sensitivity test outcome from these organoids subjected to oxaliplatin and 5-FU exposure was consistent with the clinic readout. CRC-PDOs well recapitulated the morphology and histology of their parental biopsies based on HE and IHC staining of pathological biomarkers. The scRNA-Seq data filtered drug-resistant cell populations and related signaling pathways (e.g. oxidative phosphorylation and ATP metabolic process). The data also revealed several putative drug resistant-driven genes (STMN1, VEGFA and NDRG1) and transcription factors (E2F1, BRCA1, MYBL2, CDX2 and CDX1).

Conclusion

We generated an oxaliplatin-resistant CRC organoid model that was employed to provide potential therapeutic targets for treating CRC patients exhibiting oxaliplatin-resistance.

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Availability of supporting data

The data sets supporting the results of this article are included within the article and its additional files.

Change history

  • 12 November 2022

    The original version of this article was revised: In this article an email address was incorrectly linked to an author name and a minor error occurred in Figure 2. The original article has been corrected.

  • 24 November 2022

    A Correction to this paper has been published: https://doi.org/10.1007/s13402-022-00728-y

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Acknowledgements

The authors thank Shanghai OneTar Biomedicine Co. Ltd. for providing the research environment.

Funding

This research was funded by the Natural Science Foundation of China (82173358, A.H.) and the Henan Health Commission (SB201901104).

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Author notes

    Authors and Affiliations

    1. Department of General Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, PRC, China

      Guanglong Chen, Weijie Zhao, Ye Kong, Huihan Ai, Hang Yang & Zhi Li

    2. Department of Medical Oncology, Tianjin Medical University General Hospital, Tianjin, China

      Ting Gong

    3. Department of Physiology, Second Military Medical University, Shanghai, China

      Zhe Wang

    4. Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

      Zeyu Wang

    5. Department of Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PRC, China

      Xiaolin Lin & Xiuying Xiao

    6. Shanghai OneTar Biomedicine, Shanghai, China

      Sunrui Chen, Chu Sun, Yusheng Liu & Fangyan Wu

    7. College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China

      Jiawei Kang

    8. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, PRC, China

      Shasha Zhao

    9. Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 200025, Shanghai, China

      Jing Sun

    10. Department of Oncology, the Sixth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PRC, China

      Aina He

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    Contributions

    Guanglong Chen, Ting Gong, Zhe Wang, Zeyu Wang, Xiaolin Lin and Sunrui Chen wrote and revised the manuscript; Chu Sun, Weijie Zhao, Ye Kong, Huihan Ai, Jiawei Kang, Hang Yang, Yusheng Liu and Fangyan Wu provided study materials; Shasha Zhao, Xiuying Xiao, Jing Sun, Aina He and Zhi Li reviewed and conceptualized the manuscript. All authors have read and agreed to the published version of the manuscript.

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    Correspondence to Shasha Zhao, Xiuying Xiao, Jing Sun, Aina He or Zhi Li.

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    Ethical approval and Consent to participate

    This study was approved by the Ethical Committee of Zhengzhou University, Affiliated Cancer Hospital (Henan Cancer Hospital)(2019112818. Written informed consent to participate in the study was obtained from all individual participants or their guardians.

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    The authors declare no conflict of interest. S. Chen, Y. Liu and F. Wu served as lab technicians for Shanghai OneTar Biomedicine Co. Ltd.

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    Guanglong Chen, Ting Gong, Zhe Wang, Zeyu Wang, Xiaolin Lin, and Sunrui Chen authors contribute equally to the work.

    The original version of this article was revised: In this article an email address was incorrectly linked to an author name and a minor error occurred in Figure 2. The original article has been corrected.

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    Chen, G., Gong, T., Wang, Z. et al. Colorectal cancer organoid models uncover oxaliplatin-resistant mechanisms at single cell resolution. Cell Oncol. 45, 1155–1167 (2022). https://doi.org/10.1007/s13402-022-00705-5

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