de Duve Institute, Université catholique de Louvain, Avenue Hippocrate 75, Brussels, B1-7503, 1200, Belgium.
Department of Imaging & Pathology, UZ Herestraat 49, Leuven, 3000, Belgium.
BMC Cancer. 2024 Aug 20;24(1):1025. doi: 10.1186/s12885-024-12770-0.
Most studies on tumour progression from precursor lesion toward gallbladder adenocarcinoma investigate lesions sampled from distinct patients, providing an overarching view of pathogenic cascades. Whether this reflects the tumourigenic process in individual patients remains insufficiently explored. Genomic and epigenomic studies suggest that a subset of gallbladder cancers originate from biliary intraepithelial neoplasia (BilIN) precursor lesions, whereas others form independently from BilINs. Spatial transcriptomic data supporting these conclusions are missing. Moreover, multiple areas with precursor or adenocarcinoma lesions can be detected within the same pathological sample. Yet, knowledge about intra-patient variability of such lesions is lacking.
To characterise the spatial transcriptomics of gallbladder cancer tumourigenesis in individual patients, we selected two patients with distinct cancer aetiology and whose samples simultaneously displayed multiple areas of normal epithelium, BilINs and adenocarcinoma. Using GeoMx digital spatial profiling, we characterised the whole transcriptome of a high number of regions of interest (ROIs) per sample in the two patients (24 and 32 ROIs respectively), with each ROI covering approximately 200 cells of normal epithelium, low-grade BilIN, high-grade BilIN or adenocarcinoma. Human gallbladder organoids and cell line-derived tumours were used to investigate the tumour-promoting role of genes.
Spatial transcriptomics revealed that each type of lesion displayed limited intra-patient transcriptomic variability. Our data further suggest that adenocarcinoma derived from high-grade BilIN in one patient and from low-grade BilIN in the other patient, with co-existing high-grade BilIN evolving via a distinct process in the latter case. The two patients displayed distinct sequences of signalling pathway activation during tumour progression, but Semaphorin 4 A (SEMA4A) expression was repressed in both patients. Using human gallbladder-derived organoids and cell line-derived tumours, we provide evidence that repression of SEMA4A promotes pseudostratification of the epithelium and enhances cell migration and survival.
Gallbladder adenocarcinoma can develop according to patient-specific processes, and limited intra-patient variability of precursor and cancer lesions was noticed. Our data suggest that repression of SEMA4A can promote tumour progression. They also highlight the need to gain gene expression data in addition to histological information to avoid understimating the risk of low-grade preneoplastic lesions.
大多数关于从癌前病变到胆囊腺癌进展的肿瘤研究都调查了来自不同患者的病变样本，从而提供了发病机制级联的全面视图。但这是否反映了个体患者的肿瘤发生过程仍未得到充分探索。基因组和表观基因组研究表明，一部分胆囊癌起源于胆管上皮内肿瘤（BilIN）前体病变，而其他肿瘤则独立于 BilIN 形成。缺乏支持这些结论的空间转录组学数据。此外，在同一个病理样本中可以检测到多个具有前体或腺癌病变的区域。然而，关于此类病变的患者内变异性的知识还很缺乏。
为了描述个体患者胆囊癌肿瘤发生的空间转录组学，我们选择了两名具有不同癌症病因的患者，他们的样本同时显示出多个正常上皮、BilIN 和腺癌区域。使用 GeoMx 数字空间分析，我们对两名患者的每个样本中的大量感兴趣区域（ROI）进行了全转录组分析（分别为 24 和 32 个 ROI），每个 ROI 覆盖大约 200 个正常上皮、低级别 BilIN、高级别 BilIN 或腺癌细胞。使用人类胆囊类器官和细胞系衍生的肿瘤来研究基因的肿瘤促进作用。
空间转录组学显示，每种病变类型在患者内的转录组变异性有限。我们的数据进一步表明，一名患者的腺癌源自高级别 BilIN，另一名患者的腺癌源自低级别 BilIN，而在后一种情况下，共存的高级别 BilIN 则通过不同的过程演变。两名患者在肿瘤进展过程中表现出不同的信号通路激活序列，但 SEMA4A 在两名患者中均受到抑制。使用人类胆囊衍生的类器官和细胞系衍生的肿瘤，我们提供了证据表明 SEMA4A 的抑制促进了上皮的假复层化，并增强了细胞迁移和存活。
胆囊腺癌可以根据患者特定的过程发展，并且前体和癌症病变的患者内变异性有限。我们的数据表明，SEMA4A 的抑制可以促进肿瘤进展。它们还强调需要获得基因表达数据，除了组织学信息，以避免低估低级别癌前病变的风险。
