Abstract
Gallbladder carcinoma (GBC) is a lethal biliary tract malignant neoplasm. Patient-derived primary cancer cell lines (PDPCs) are appropriate models to explore biological characteristics and potential therapeutics; however, there is a lack of PDPCs in GBC. In this study, we aimed to establish and characterize the GBC PDPCs, and further investigated the intra-tumor heterogeneity (ITH). Multi-region sampling (3–9 regions) of the operable tumor tissue samples was used to establish PDPCs. Short tandem repeat genotyping for cell authentication and karyotyping was performed, followed by whole-exome sequencing and RNA sequencing to assess the ITH at the genetic and transcriptional levels, respectively. Thirty-eight PDPCs were successfully established from seven GBC patients and characterized. ITH was observed with a median of 38.3% mutations being heterogeneous (range, 26.6–59.4%) across all patients. Similar with other tumor types, TP53 mutations were always truncal. In addition, there were three genes, KMT2C, CDKN2A, and ARID1A, with truncal mutations in at least two patients. A median of 370 differentially expressed genes (DEGs) was identified per patient. Distinct expression patterns were observed between major histocompatibility complex (MHC) class I and II genes. We found the expression of MHC class II genes in the PDPC samples was closely regulated by CIITA, while that of MHC class I genes were not correlated with CIITA expression. The PDPCs established from GBC patients can serve as novel in vitro models to identify the ITH, which may pave a crucial molecular foundation for enhanced understanding of tumorigenesis and progression.
Highlights
Gallbladder carcinoma (GBC) is one of the lethal biliary tract cancers with limited therapeutic options and unsatisfactory treatments [1, 2]
Thereafter, all Patient-derived primary cancer cell lines (PDPCs) were grown in a 37 °C incubator at 5% C O2 with DMEM/F12 medium supplemented with 10% fetal bovine serum (FBS)
Raw reads from RNA sequencing (RNA-seq) were mapped to the human reference genome hg19 using STAR [39] with default parameters
Summary
Gallbladder carcinoma (GBC) is one of the lethal biliary tract cancers with limited therapeutic options and unsatisfactory treatments [1, 2]. Patients with advanced or metastatic GBCs have a poor prognosis with a 5-year survival rate of less than 10% [5, 6]. Among all the potential reasons, the lack of understanding regarding the tumorigenesis and progression has been proposed as a major obstacle to discovering a new strategy for more precise and effective treatment to improve GBC patients’ prognosis. Several previous studies of GBCs have reported the results of mutational profiling [7,8,9,10,11,12,13]. The recurrently mutated actionable genes and the signaling pathways in Establishment and characterization of 38 novel patient-derived primary cancer cell lines
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