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

Autor: Guanglong Chen, Ting Gong, Zhe Wang, Zeyu Wang, Xiaolin Lin, Sunrui Chen, Chu Sun, Weijie Zhao, Ye Kong, Huihan Ai, Hang Yang, Yusheng Liu, Fangyan Wu, Jiawei Kang, Shasha Zhao, Xiuying Xiao, Jing Sun, Aina He, Zhi Li
Rok vydání: 2022
Předmět:
Zdroj: Cellular Oncology.
ISSN: 2211-3436
2211-3428
DOI: 10.1007/s13402-022-00705-5
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: