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

Springer Science and Business Media LLC - Tập 45 - Trang 1155-1167 - 2022
Guanglong Chen1, Ting Gong2, Zhe Wang3, Zeyu Wang4, Xiaolin Lin5, Sunrui Chen6, Chu Sun6, Weijie Zhao1, Ye Kong1, Huihan Ai1, Hang Yang1, Yusheng Liu6, Fangyan Wu6, Jiawei Kang7, Shasha Zhao8, Xiuying Xiao5, Jing Sun9, Aina He10, Zhi Li1
1Department of General Surgery, The Affiliated Cancer Hospital of Zhengzhou University/Henan Cancer Hospital, Zhengzhou, China
2Department of Medical Oncology, Tianjin Medical University General Hospital, Tianjin, China
3Department of Physiology, Second Military Medical University, Shanghai, China
4Department of Gastrointestinal Surgery, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
5Department of Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
6Shanghai OneTar Biomedicine, Shanghai, China
7College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China
8State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, China
9Department of General Surgery, RuiJin Hospital, Shanghai Jiaotong University School of Medicine, ShangHai, China
10Department of Oncology, the Sixth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

Tóm tắt

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. 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). 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). 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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