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MiRNA profiling of biliary intraepithelial neoplasia reveals step-wise tumorigenesis in cholangiocarcinoma

ABSTRACT: Biliary intraepithelial neoplasia (BilIN) is a common precursor lesion of distal cholangiocarcinoma (dCCA). However, the sequence leading from a single epithelial layer in normal biliary epithelia to intraepithelial precursor lesions and finally to the invasive tumor is poorly understood. Here, we aimed to elucidate key miRNAs involved in this stepwise process and to identify their possible mRNA target genes in distal cholangiocarcinogenesis. As basis of our study, we conducted Laser Capture Microdissection of FFPE tissue sections of 12 patients with distal cholangiocarcinoma. For each patient, we isolated three matched sample sets, including non-neoplastic biliary epithelia, high grade BilIN (grade 3), and invasive dCCA, thereby representing different stages of distal cholangiocarcinogenesis. This resulted in a total of 36 samples. Total RNA was extracted and the expression of ~800 miRNAs was assessed using the Nanostring® technology. Significantly deregulated miRNAs were validated by quantitative RT-PCR. Target genes were identified using miRWalk2.0 and validated by qRT-PCR and Western blot.

ORGANISM(S): Homo sapiens

PROVIDER: GSE140001 | GEO | 2020/08/07

REPOSITORIES: GEO

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Project description:Genomic and epigenomic studies support that adenocarcinomas of the gallbladder develop according to a metaplasia-biliary intraepithelial neoplasia (BilIN)-adenocarcinoma histogenic sequence, in which metaplasia and BilIN are non-cancerous lesions of the epithelium. Moreover, recent genomic data suggest that adenocarcinoma can develop in a BilIN-dependent or -independent way, pointing toward patient-specific tumourigenic processes. Spatial transcriptomic data addressing these processes are still missing. Here, using GeoMx digital spatial profiling (NanoString), we characterized the spatial transcriptome of normal gallbladder epithelium, BilINs and adenocarcinoma coexisting within the same samples. To address intra-patient variability we profiled the whole transcriptome of a high number of regions of interest (ROIs) per sample in two patients (Patient #1, 81 year old woman: 24 ROIs; Patient #2, 53-year old man:32 ROIs), with each ROI covering approximately 200 cells of normal epithelium, low-grade BilIN, high-grade BilIN or adenocarcinoma. Our results showed that each type of lesion displayed little transcriptomic variability within the same patient, but differed significantly between patients. They also suggested that adenocarcinoma can derive from high-grade BilIN or from low-grade BilIN, with co-existing high-grade BilIN evolving via a distinct process in the latter case. We also provide strong evidence for patient-specific tumourigenic mechanisms, characterized by distinct sequences of signalling pathway activation. Among those pathways, we functionally investigated SEMAPHORIN 4A (SEMA4A) and provided evidence that repression of SEMA4A expression, as is observed in the gallbladder samples of the two patients, can enhance cell migration and survival, and perturb polarisation of the epithelial cells. In conclusion, our results support that gallbladder adenocarcinoma develops according to patient-specific processes that can be promoted by repression of SEMA4A. They underscore the need to gain gene expression data in addition to histological information to evaluate the risk of low-grade preneoplastic lesions.

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MiRNA profiling of biliary intraepithelial neoplasia reveals step-wise tumorigenesis in cholangiocarcinoma

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