Convergent genomic diversity and novel BCAA metabolism in intrahepatic cholangiocarcinoma
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Published:2023-04-19
Issue:12
Volume:128
Page:2206-2217
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ISSN:0007-0920
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Container-title:British Journal of Cancer
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language:en
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Short-container-title:Br J Cancer
Author:
Kitagawa AkihiroORCID, Osawa TsuyoshiORCID, Noda Miwa, Kobayashi Yuta, Aki Sho, Nakano Yusuke, Saito Tomoko, Shimizu Dai, Komatsu Hisateru, Sugaya Maki, Takahashi JunichiORCID, Kosai Keisuke, Takao Seiichiro, Motomura Yushi, Sato KuniakiORCID, Hu Qingjiang, Fujii Atsushi, Wakiyama Hiroaki, Tobo Taro, Uchida Hiroki, Sugimachi Keishi, Shibata Kohei, Utsunomiya Tohru, Kobayashi Shogo, Ishii HideshiORCID, Hasegawa Takanori, Masuda Takaaki, Matsui Yusuke, Niida Atsushi, Soga TomoyoshiORCID, Suzuki Yutaka, Miyano Satoru, Aburatani Hiroyuki, Doki Yuichiro, Eguchi Hidetoshi, Mori Masaki, Nakayama Keiichi I., Shimamura Teppei, Shibata TatsuhiroORCID, Mimori KoshiORCID
Abstract
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.
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology
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