Molecular Biomarker of Drug Resistance Developed From Patient-Derived Organoids Predicts Survival of Colorectal Cancer Patients

Lifeng Chen; Bo Tian; Wen Liu; Haitao Liang; Yong You; Weizhen Liu

doi:10.3389/fonc.2022.855674

Molecular Biomarker of Drug Resistance Developed From Patient-Derived Organoids Predicts Survival of Colorectal Cancer Patients

Front Oncol. 2022 Mar 29:12:855674. doi: 10.3389/fonc.2022.855674. eCollection 2022.

Authors

Lifeng Chen¹, Bo Tian², Wen Liu¹, Haitao Liang³, Yong You¹, Weizhen Liu⁴

Affiliations

¹ Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
² Department of Orthopaedic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
³ Shenzhen Second People's Hospital (The First Hospital Affiliated to Shenzhen University, Health Science Center), Shenzhen, China.
⁴ Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Abstract

The drug 5-fluorouracil (5-Fu) is the critical composition of colorectal cancer (CRC) treatments. Prognostic and predictive molecular biomarkers for CRC patients (CRCpts) treated with 5-Fu-based chemotherapy can provide assistance for tailoring treatment approach. Here, we established a molecular biomarker of 5-Fu resistance derived from colorectal cancer organoids (CRCOs) for predicting the survival of CRCpts. Forty-one CRCO cultures were generated from 50 CRC tumor tissues after surgery (82%). The following experiments revealed a great diversity in drug sensitivity for 10 μM 5-Fu treatment tested by using organoid size change. Fourteen cases (34.1%) were 5-Fu sensitive and the other 27 (65.9%) were resistant. Then, differentially expressed genes (DEGs) associated with 5-Fu resistance were outputted by transcriptome sequencing. In particular, DEGs were generated in two comparison groups: 1) 5-Fu sensitive and resistant untreated CRCOs; 2) CRCOs before 5-Fu treatment and surviving CRCOs after 5-Fu treatment. Some molecules and most of the pathways that have been reported to be involved in 5-Fu resistance were identified in the current research. By using DEGs correlated with 5-Fu resistance and survival of CRCpts, the gene signature and drug-resistant score model (DRSM) containing five molecules were established in The Cancer Genome Atlas (TCGA)-CRC cohort by least absolute shrinkage and selection operator (LASSO) regression analysis and 5-fold cross-validation. Multivariate analysis revealed that drug-resistant score (DRS) was an independent prognostic factor for overall survival (OS) in CRCpts in TCGA-CRC cohort (P < 0.001). Further validation results from four Gene Expression Omnibus (GEO) cohorts elucidated that the DRSM based on five genes related to 5-Fu chemosensitivity and developed from patient-derived organoids can predict survival of CRCpts. Meanwhile, our model could predict the survival of CRCpts in different subgroups. Besides, the difference of molecular pathways, tumor mutational burden (TMB), immune response-related pathways, immune score, stromal score, and immune cell proportion were dissected between DRS-high and DRS-low patients in TCGA-CRC cohort.

Keywords: 5-fluorouracil; colorectal cancer; drug resistance; molecular biomarker; organoids; predict; survival.