Convergent genomic diversity and novel BCAA metabolism in intrahepatic cholangiocarcinoma.
Br J Cancer
; 128(12): 2206-2217, 2023 06.
Article
de En
| MEDLINE
| ID: mdl-37076565
ABSTRACT
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.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Tumeurs des canaux biliaires
/
Cholangiocarcinome
Type d'étude:
Prognostic_studies
Limites:
Humans
Langue:
En
Journal:
Br J Cancer
Année:
2023
Type de document:
Article
Pays d'affiliation:
Japon