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BACKGROUND

Driver alterations may represent novel candidates for driver gene-guided therapy; however, intrahepatic cholangiocarcinoma (ICC) with multiple genomic aberrations makes them intractable. Therefore, the pathogenesis and metabolic changes of ICC need to be understood to develop new treatment strategies. We aimed to unravel the evolution of ICC and identify ICC-specific metabolic characteristics to investigate the metabolic pathway associated with ICC development using multiregional sampling to encompass the intra- and inter-tumoral heterogeneity.

METHODS

We performed the genomic, transcriptomic, proteomic and metabolomic analysis of 39-77 ICC tumour samples and eleven normal samples. Further, we analysed their cell proliferation and viability.

RESULTS

We demonstrated that intra-tumoral heterogeneity of ICCs with distinct driver genes per case exhibited neutral evolution, regardless of their tumour stage. Upregulation of BCAT1 and BCAT2 indicated the involvement of 'Val Leu Ile degradation pathway'. ICCs exhibit the accumulation of ubiquitous metabolites, such as branched-chain amino acids including valine, leucine, and isoleucine, to negatively affect cancer prognosis. We revealed that this metabolic pathway was almost ubiquitously altered in all cases with genomic diversity and might play important roles in tumour progression and overall survival.

CONCLUSIONS

We propose a novel ICC onco-metabolic pathway that could enable the development of new therapeutic interventions.

背景

驱动基因改变可能代表着驱动基因指导治疗的新候选者；然而，具有多种基因组改变的肝内胆管癌（ICC）使其难以治疗。因此，需要了解 ICC 的发病机制和代谢变化，以制定新的治疗策略。我们旨在揭示 ICC 的演变，并确定 ICC 的特异性代谢特征，以使用多区域采样来研究与 ICC 发展相关的代谢途径，从而涵盖肿瘤内和肿瘤间的异质性。

方法

我们对 39-77 个 ICC 肿瘤样本和 11 个正常样本进行了基因组、转录组、蛋白质组和代谢组学分析。此外，我们还分析了它们的细胞增殖和活力。

结果

我们表明，每个病例中具有不同驱动基因的 ICC 肿瘤内异质性表现出中性进化，而与肿瘤分期无关。BCAT1 和 BCAT2 的上调表明“缬氨酸、亮氨酸、异亮氨酸降解途径”的参与。ICC 表现出普遍代谢物的积累，如支链氨基酸（包括缬氨酸、亮氨酸和异亮氨酸），从而对癌症预后产生负面影响。我们揭示，这种代谢途径在具有基因组多样性的所有病例中几乎普遍改变，可能在肿瘤进展和总生存中发挥重要作用。