吉西他滨
胰腺癌
癌症研究
胰腺导管腺癌
肿瘤科
转移
抗药性
化疗
癌症
肿瘤微环境
内科学
生物
医学
遗传学
作者
Zelin Hou,Jiajing Lin,Yaoguang Ma,Haizong Fang,Yang Wu,Zhijiang Chen,Xianchao Lin,Fang Lü,Wen Pang Su,Xunbin Yu,Heguang Huang,Yu Pan
标识
DOI:10.3389/fphar.2023.1193791
摘要
Introduction: Resistance to gemcitabine is common and critically limits its therapeutic efficacy in pancreatic ductal adenocarcinoma (PDAC). Methods: We constructed 17 patient-derived xenograft (PDX) models from PDAC patient samples and identified the most notable responder to gemcitabine by screening the PDX sets in vivo. To analyze tumor evolution and microenvironmental changes pre- and post-chemotherapy, single-cell RNA sequencing (scRNA-seq) was performed. Results: ScRNA-seq revealed that gemcitabine promoted the expansion of subclones associated with drug resistance and recruited macrophages related to tumor progression and metastasis. We further investigated the particular drug-resistant subclone and established a gemcitabine sensitivity gene panel (GSGP) (SLC46A1, PCSK1N, KRT7, CAV2, and LDHA), dividing PDAC patients into two groups to predict the overall survival (OS) in The Cancer Genome Atlas (TCGA) training dataset. The signature was successfully validated in three independent datasets. We also found that 5-GSGP predicted the sensitivity to gemcitabine in PDAC patients in the TCGA training dataset who were treated with gemcitabine. Discussion and conclusion: Our study provides new insight into the natural selection of tumor cell subclones and remodeling of tumor microenvironment (TME) cells induced by gemcitabine. We revealed a specific drug resistance subclone, and based on the characteristics of this subclone, we constructed a GSGP that can robustly predict gemcitabine sensitivity and prognosis in pancreatic cancer, which provides a theoretical basis for individualized clinical treatment.
科研通智能强力驱动
Strongly Powered by AbleSci AI