结直肠癌类器官模型在单细胞分辨率下揭示了奥沙利铂耐药机制。

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

作者信息

Chen Guanglong, Gong Ting, Wang Zhe, Wang Zeyu, Lin Xiaolin, Chen Sunrui, Sun Chu, Zhao Weijie, Kong Ye, Ai Huihan, Yang Hang, Liu Yusheng, Wu Fangyan, Kang Jiawei, Zhao Shasha, Xiao Xiuying, Sun Jing, He Aina, Li Zhi

机构信息

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

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

出版信息

Cell Oncol (Dordr). 2022 Dec;45(6):1155-1167. doi: 10.1007/s13402-022-00705-5. Epub 2022 Sep 22.

DOI:10.1007/s13402-022-00705-5

PMID:36136268

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.

摘要

目的

基于奥沙利铂的化疗是晚期结直肠癌（CRC）患者的标准治疗方法。然而，化疗耐药导致的抗性是死亡率的重要原因。因此，有必要研究CRC中的耐药机制。

方法

在此，我们建立了两株源自患者的类器官（PDO），分别选自对奥沙利铂耐药和未接受过治疗的CRC患者。为了剖析耐药机制，对这些CRC-PDO进行了单细胞RNA测序（scRNA-Seq）。

结果

我们发现，这些接受奥沙利铂和5-氟尿嘧啶处理的类器官的药敏试验结果与临床结果一致。基于病理生物标志物的HE和IHC染色，CRC-PDO很好地重现了其亲本活检组织的形态和组织学特征。scRNA-Seq数据筛选出了耐药细胞群体和相关信号通路（如氧化磷酸化和ATP代谢过程）。数据还揭示了几个假定的耐药驱动基因（STMN1、VEGFA和NDRG1）和转录因子（E2F1、BRCA1、MYBL2、CDX2和CDX1）。