Convergent genomic diversity and novel BCAA metabolism in intrahepatic cholangiocarcinoma

Akihiro Kitagawa; Tsuyoshi Osawa; Miwa Noda; Yuta Kobayashi; Sho Aki; Yusuke Nakano; Tomoko Saito; Dai Shimizu; Hisateru Komatsu; Maki Sugaya; Junichi Takahashi; Keisuke Kosai; Seiichiro Takao; Yushi Motomura; Kuniaki Sato; Qingjiang Hu; Atsushi Fujii; Hiroaki Wakiyama; Taro Tobo; Hiroki Uchida; Keishi Sugimachi; Kohei Shibata; Tohru Utsunomiya; Shogo Kobayashi; Hideshi Ishii; Takanori Hasegawa; Takaaki Masuda; Yusuke Matsui; Atsushi Niida; Tomoyoshi Soga; Yutaka Suzuki; Satoru Miyano; Hiroyuki Aburatani; Yuichiro Doki; Hidetoshi Eguchi; Masaki Mori; Keiichi Nakayama; Teppei Shimamura; Tatsuhiro Shibata; Koshi Mimori

doi:10.1038/s41416-023-02256-4

Convergent genomic diversity and novel BCAA metabolism in intrahepatic cholangiocarcinoma

Akihiro Kitagawa, Tsuyoshi Osawa, Miwa Noda, Yuta Kobayashi, Sho Aki, Yusuke Nakano, Tomoko Saito, Dai Shimizu, Hisateru Komatsu, Maki Sugaya, Junichi Takahashi, Keisuke Kosai, Seiichiro Takao, Yushi Motomura, Kuniaki Sato, Qingjiang Hu, Atsushi Fujii, Hiroaki Wakiyama, Taro Tobo, Hiroki UchidaKeishi Sugimachi, Kohei Shibata, Tohru Utsunomiya, Shogo Kobayashi, Hideshi Ishii, Takanori Hasegawa, Takaaki Masuda, Yusuke Matsui, Atsushi Niida, Tomoyoshi Soga, Yutaka Suzuki, Satoru Miyano, Hiroyuki Aburatani, Yuichiro Doki, Hidetoshi Eguchi, Masaki Mori, Keiichi Nakayama, Teppei Shimamura, Tatsuhiro Shibata, Koshi Mimori

Research output: Contribution to journal › Article › peer-review

6 Citations (Scopus)

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. [Figure not available: see fulltext.]

Original language	English
Pages (from-to)	2206-2217
Number of pages	12
Journal	British journal of cancer
Volume	128
Issue number	12
DOIs	https://doi.org/10.1038/s41416-023-02256-4
Publication status	Published - Jun 29 2023

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Oncology
Cancer Research

UN SDGs

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10.1038/s41416-023-02256-4

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Kitagawa, A., Osawa, T., Noda, M., Kobayashi, Y., Aki, S., Nakano, Y., Saito, T., Shimizu, D., Komatsu, H., Sugaya, M., Takahashi, J., Kosai, K., Takao, S., Motomura, Y., Sato, K., Hu, Q., Fujii, A., Wakiyama, H., Tobo, T., ... Mimori, K. (2023). Convergent genomic diversity and novel BCAA metabolism in intrahepatic cholangiocarcinoma. British journal of cancer, 128(12), 2206-2217. https://doi.org/10.1038/s41416-023-02256-4

Kitagawa, A, Osawa, T, Noda, M, Kobayashi, Y, Aki, S, Nakano, Y, Saito, T, Shimizu, D, Komatsu, H, Sugaya, M, Takahashi, J, Kosai, K, Takao, S, Motomura, Y, Sato, K, Hu, Q, Fujii, A, Wakiyama, H , Tobo, T, Uchida, H, Sugimachi, K, Shibata, K, Utsunomiya, T, Kobayashi, S, Ishii, H, Hasegawa, T, Masuda, T, Matsui, Y, Niida, A, Soga, T, Suzuki, Y, Miyano, S, Aburatani, H, Doki, Y, Eguchi, H, Mori, M, Nakayama, K, Shimamura, T, Shibata, T & Mimori, K 2023, 'Convergent genomic diversity and novel BCAA metabolism in intrahepatic cholangiocarcinoma', British journal of cancer, vol. 128, no. 12, pp. 2206-2217. https://doi.org/10.1038/s41416-023-02256-4

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title = "Convergent genomic diversity and novel BCAA metabolism in intrahepatic cholangiocarcinoma",

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 {\textquoteleft}Val Leu Ile degradation pathway{\textquoteright}. 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. [Figure not available: see fulltext.]",

author = "Akihiro Kitagawa and Tsuyoshi Osawa and Miwa Noda and Yuta Kobayashi and Sho Aki and Yusuke Nakano and Tomoko Saito and Dai Shimizu and Hisateru Komatsu and Maki Sugaya and Junichi Takahashi and Keisuke Kosai and Seiichiro Takao and Yushi Motomura and Kuniaki Sato and Qingjiang Hu and Atsushi Fujii and Hiroaki Wakiyama and Taro Tobo and Hiroki Uchida and Keishi Sugimachi and Kohei Shibata and Tohru Utsunomiya and Shogo Kobayashi and Hideshi Ishii and Takanori Hasegawa and Takaaki Masuda and Yusuke Matsui and Atsushi Niida and Tomoyoshi Soga and Yutaka Suzuki and Satoru Miyano and Hiroyuki Aburatani and Yuichiro Doki and Hidetoshi Eguchi and Masaki Mori and Keiichi Nakayama and Teppei Shimamura and Tatsuhiro Shibata and Koshi Mimori",

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doi = "10.1038/s41416-023-02256-4",

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TY - JOUR

T1 - Convergent genomic diversity and novel BCAA metabolism in intrahepatic cholangiocarcinoma

AU - Kitagawa, Akihiro

AU - Osawa, Tsuyoshi

AU - Noda, Miwa

AU - Kobayashi, Yuta

AU - Aki, Sho

AU - Nakano, Yusuke

AU - Saito, Tomoko

AU - Shimizu, Dai

AU - Komatsu, Hisateru

AU - Sugaya, Maki

AU - Takahashi, Junichi

AU - Kosai, Keisuke

AU - Takao, Seiichiro

AU - Motomura, Yushi

AU - Sato, Kuniaki

AU - Hu, Qingjiang

AU - Fujii, Atsushi

AU - Wakiyama, Hiroaki

AU - Tobo, Taro

AU - Uchida, Hiroki

AU - Sugimachi, Keishi

AU - Shibata, Kohei

AU - Utsunomiya, Tohru

AU - Kobayashi, Shogo

AU - Ishii, Hideshi

AU - Hasegawa, Takanori

AU - Masuda, Takaaki

AU - Matsui, Yusuke

AU - Niida, Atsushi

AU - Soga, Tomoyoshi

AU - Suzuki, Yutaka

AU - Miyano, Satoru

AU - Aburatani, Hiroyuki

AU - Doki, Yuichiro

AU - Eguchi, Hidetoshi

AU - Mori, Masaki

AU - Nakayama, Keiichi

AU - Shimamura, Teppei

AU - Shibata, Tatsuhiro

AU - Mimori, Koshi

PY - 2023/6/29

Y1 - 2023/6/29

N2 - 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. [Figure not available: see fulltext.]

AB - 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. [Figure not available: see fulltext.]

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JO - British journal of cancer

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ER -

Convergent genomic diversity and novel BCAA metabolism in intrahepatic cholangiocarcinoma

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