A novel mouse model of upper tract urothelial carcinoma highlights the impact of dietary intervention on gut microbiota and carcinogenesis prevention despite carcinogen exposure

Yamamoto, Akinaru; Kawashima, Atsunari; Uemura, Toshihiro; Nakano, Kosuke; Matsushita, Makoto; Ishizuya, Yu; Jingushi, Kentaro; Hase, Hiroaki; Katayama, Kotoe; Yamaguchi, Rui; Sassi, Nesrine; Motoyama, Yuichi; Nojima, Satoshi; Mita, Masashi; Kimura, Tomonori; Motooka, Daisuke; Horibe, Yuki; Okuda, Yohei; Oka, Toshiki; Yamamichi, Gaku; Tomiyama, Eisuke; Koh, Yoko; Yamamoto, Yoshiyuki; Kato, Taigo; Hatano, Koji; Uemura, Motohide; Imoto, Seiya; Wada, Hisashi; Morii, Eiichi; Tsujikawa, Kazutake; Nonomura, Norio

doi:https://doi.org/10.1002/ijc.35295

A novel mouse model of upper tract urothelial carcinoma highlights the impact of dietary intervention on gut microbiota and carcinogenesis prevention despite carcinogen exposure

Yamamoto, Akinaru; Kawashima, Atsunari; Uemura, Toshihiro et al.

International Journal of Cancer, 2025, 156(7), 1439-1456

Number of Access:4,866（2025-07-18 12:33 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/100339

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Title	A novel mouse model of upper tract urothelial carcinoma highlights the impact of dietary intervention on gut microbiota and carcinogenesis prevention despite carcinogen exposure
Creator	NRID 1000050909653 1000050909653 ORCID 0000-0002-3565-5870 0000-0002-3565-5870 researchmap permalink ayamamoto ayamamoto CreatorName Yamamoto, Akinaru
	NRID 1000050746568 1000050746568 researchmap permalink akawashima akawashima Scopus Author ID 9846139400 9846139400 CreatorName Kawashima, Atsunari
	NRID 1000060905941 1000060905941 CreatorName Uemura, Toshihiro
	NRID 1000000804410 1000000804410 researchmap permalink uro.med.osaka-u uro.med.osaka-u CreatorName Nakano, Kosuke
	NRID 1000040824785 1000040824785 ORCID 0000-0002-7491-9410 0000-0002-7491-9410 researchmap permalink mmatsushita mmatsushita CreatorName Matsushita, Makoto
	NRID 1000000783854 1000000783854 researchmap permalink okiishi okiishi CreatorName Ishizuya, Yu
	NRID 1000080707571 1000080707571 ORCID 0000-0002-2274-4962 0000-0002-2274-4962 researchmap permalink _kj _kj Scopus Author ID 13807151700 13807151700 CreatorName Jingushi, Kentaro
	NRID 1000080779926 1000080779926 researchmap permalink hase-h hase-h Scopus Author ID 55360273600 55360273600 CreatorName Hase, Hiroaki
	NRID 1000040581195 1000040581195 CreatorName Katayama, Kotoe
	NRID 1000090380675 1000090380675 CreatorName Yamaguchi, Rui
	CreatorName Sassi, Nesrine
	NRID 1000060948074 1000060948074 researchmap permalink y_motoyama y_motoyama Scopus Author ID 57208337832 57208337832 CreatorName Motoyama, Yuichi
	NRID 1000040528791 1000040528791 ORCID 0000-0002-5124-0026 0000-0002-5124-0026 researchmap permalink snojima snojima Scopus Author ID 16224082000 16224082000 CreatorName Nojima, Satoshi
	CreatorName Mita, Masashi
	NRID 1000000631300 1000000631300 ORCID 0000-0001-8186-094X 0000-0001-8186-094X researchmap permalink KimuraUNM KimuraUNM CreatorName Kimura, Tomonori
	NRID 1000010636830 1000010636830 researchmap permalink daisukem daisukem Scopus Author ID 35315737900 35315737900 CreatorName Motooka, Daisuke
	NRID 1000080981977 1000080981977 CreatorName Horibe, Yuki
	NRID 1000010964372 1000010964372 ORCID 0000-0001-9909-4200 0000-0001-9909-4200 researchmap permalink okudayohei okudayohei CreatorName Okuda, Yohei
	NRID 1000060964385 1000060964385 CreatorName Oka, Toshiki
	NRID 1000040882262 1000040882262 researchmap permalink urology-osaka-japan urology-osaka-japan CreatorName Yamamichi, Gaku
	NRID 1000040845244 1000040845244 researchmap permalink uro.med.osaka uro.med.osaka CreatorName Tomiyama, Eisuke
	NRID 1000070824754 1000070824754 researchmap permalink uro-koh uro-koh CreatorName Koh, Yoko
	NRID 1000090759557 1000090759557 researchmap permalink yoshi229 yoshi229 CreatorName Yamamoto, Yoshiyuki
	NRID 1000070648021 1000070648021 researchmap permalink taigokato taigokato Scopus Author ID 55414697500 55414697500 ORCID 0000-0002-8681-1407 0000-0002-8681-1407 CreatorName Kato, Taigo
	NRID 1000060762234 1000060762234 researchmap permalink koji_hatano koji_hatano Scopus Author ID 14627167600 14627167600 CreatorName Hatano, Koji
	NRID 1000040631015 1000040631015 researchmap permalink urourouro urourouro CreatorName Uemura, Motohide
	NRID 1000010345027 1000010345027 CreatorName Imoto, Seiya
	NRID 1000070243459 1000070243459 researchmap permalink hwada hwada Scopus Author ID 7402917501 7402917501 CreatorName Wada, Hisashi
	NRID 1000010283772 1000010283772 ORCID 0000-0001-8490-3650 0000-0001-8490-3650 researchmap permalink read0046454 read0046454 Scopus Author ID 7003914326 7003914326 CreatorName Morii, Eiichi
	NRID 1000010207376 1000010207376 researchmap permalink read0014359 read0014359 Scopus Author ID 7004354760 7004354760 CreatorName Tsujikawa, Kazutake
	NRID 1000030263263 1000030263263 researchmap permalink read0185096 read0185096 Scopus Author ID 7005880662 7005880662 CreatorName Nonomura, Norio
Subject	animal model
	cancer prevention
	microbiome
	N-butyl-N-(4-hydroxybutyl) nitrosamine
	upper tract urothelial carcinoma
Description	Yamamoto A., Kawashima A., Uemura T., et al. A novel mouse model of upper tract urothelial carcinoma highlights the impact of dietary intervention on gut microbiota and carcinogenesis prevention despite carcinogen exposure. International Journal of Cancer 156, 1439 (2025); https://doi.org/10.1002/ijc.35295.
Abstract	Animal models of N-butyl-N-(4-hydroxy butyl) nitrosamine (BBN)-induced urothelial carcinoma (UC), particularly bladder cancer (BC), have long been established. However, the rare incidence of BBN-induced upper urinary tract UC (UTUC), which originates from the same urothelium as BC, remains elusive. The scarcity of animal models of UTUC has made it challenging to study the biology of UTUC. To address this problem, we tried to establish a novel mouse model of UTUC by treating multiple mice strains and sexes with BBN. The molecular consistency between the UTUC mouse model and human UTUC was confirmed using multi-omics analyses, including whole-exome, whole-transcriptome, and spatial transcriptome sequencing. 16S ribosomal RNA metagenome sequencing, metabolome analysis, and dietary interventions were employed to assess changes in the gut microbiome, metabolome, and carcinogenesis of UTUC. Of all treated mice, only female BALB/c mice developed UTUC over BC. Multi-omics analyses confirmed that the UTUC model reflected the molecular characteristics and heterogeneity of human UTUC with poor prognosis. Furthermore, the model exhibited increased Tnf-related inflammatory gene expression in the upper urinary tract and a low relative abundance of Parabacteroides distasonis in the gut. Dietary intervention, mainly without alanine, led to P. distasonis upregulation and successfully prevented UTUC, as well as suppressed Tnf-related inflammatory gene expression in the upper urinary tract despite the exposure to BBN. This is the first report to demonstrate a higher incidence of UTUC than BC in a non-engineered mouse model using BBN. Overall, this model could serve as a useful tool for comprehensively investigating UTUC in future studies.
Publisher	John Wiley and Sons Inc
Source Title	International Journal of Cancer
Volume (Issue)	156(7)
Page	1439-1456
Date of Issued	2025-04-01
Language	English
Handle URL	https://hdl.handle.net/11094/100339
PISSN	00207136
eISSN	10970215
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1002/ijc.35295
Access Rights	open access
CopyRight	This article is licensed under a Creative Commons Attribution 4.0 International License.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCTERMS.bibliographicCitation	International Journal of Cancer. 2025, 156(7), p. 1439-1456
DC.title	A novel mouse model of upper tract urothelial carcinoma highlights the impact of dietary intervention on gut microbiota and carcinogenesis prevention despite carcinogen exposure
DC.creator	Yamamoto, Akinaru
	Kawashima, Atsunari
	Uemura, Toshihiro
	Nakano, Kosuke
	Matsushita, Makoto
	Ishizuya, Yu
	Jingushi, Kentaro
	Hase, Hiroaki
	Katayama, Kotoe
	Yamaguchi, Rui
	Sassi, Nesrine
	Motoyama, Yuichi
	Nojima, Satoshi
	Mita, Masashi
	Kimura, Tomonori
	Motooka, Daisuke
	Horibe, Yuki
	Okuda, Yohei
	Oka, Toshiki
	Yamamichi, Gaku
	Tomiyama, Eisuke
	Koh, Yoko
	Yamamoto, Yoshiyuki
	Kato, Taigo
	Hatano, Koji
	Uemura, Motohide
	Imoto, Seiya
	Wada, Hisashi
	Morii, Eiichi
	Tsujikawa, Kazutake
	Nonomura, Norio
DC.publisher	John Wiley and Sons Inc
DC.language' scheme='DCTERMS.RFC1766	English
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2025-04-01
DC.identifier	https://doi.org/10.1002/ijc.35295
DC.subject	animal model
	cancer prevention
	microbiome
	N-butyl-N-(4-hydroxybutyl) nitrosamine
	upper tract urothelial carcinoma
DC.description	Yamamoto A., Kawashima A., Uemura T., et al. A novel mouse model of upper tract urothelial carcinoma highlights the impact of dietary intervention on gut microbiota and carcinogenesis prevention despite carcinogen exposure. International Journal of Cancer 156, 1439 (2025); https://doi.org/10.1002/ijc.35295.
DCTERMS.abstract	Animal models of N-butyl-N-(4-hydroxy butyl) nitrosamine (BBN)-induced urothelial carcinoma (UC), particularly bladder cancer (BC), have long been established. However, the rare incidence of BBN-induced upper urinary tract UC (UTUC), which originates from the same urothelium as BC, remains elusive. The scarcity of animal models of UTUC has made it challenging to study the biology of UTUC. To address this problem, we tried to establish a novel mouse model of UTUC by treating multiple mice strains and sexes with BBN. The molecular consistency between the UTUC mouse model and human UTUC was confirmed using multi-omics analyses, including whole-exome, whole-transcriptome, and spatial transcriptome sequencing. 16S ribosomal RNA metagenome sequencing, metabolome analysis, and dietary interventions were employed to assess changes in the gut microbiome, metabolome, and carcinogenesis of UTUC. Of all treated mice, only female BALB/c mice developed UTUC over BC. Multi-omics analyses confirmed that the UTUC model reflected the molecular characteristics and heterogeneity of human UTUC with poor prognosis. Furthermore, the model exhibited increased Tnf-related inflammatory gene expression in the upper urinary tract and a low relative abundance of Parabacteroides distasonis in the gut. Dietary intervention, mainly without alanine, led to P. distasonis upregulation and successfully prevented UTUC, as well as suppressed Tnf-related inflammatory gene expression in the upper urinary tract despite the exposure to BBN. This is the first report to demonstrate a higher incidence of UTUC than BC in a non-engineered mouse model using BBN. Overall, this model could serve as a useful tool for comprehensively investigating UTUC in future studies.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	100339
citation_title	A novel mouse model of upper tract urothelial carcinoma highlights the impact of dietary intervention on gut microbiota and carcinogenesis prevention despite carcinogen exposure
citation_author	Yamamoto, Akinaru
	Kawashima, Atsunari
	Uemura, Toshihiro
	Nakano, Kosuke
	Matsushita, Makoto
	Ishizuya, Yu
	Jingushi, Kentaro
	Hase, Hiroaki
	Katayama, Kotoe
	Yamaguchi, Rui
	Sassi, Nesrine
	Motoyama, Yuichi
	Nojima, Satoshi
	Mita, Masashi
	Kimura, Tomonori
	Motooka, Daisuke
	Horibe, Yuki
	Okuda, Yohei
	Oka, Toshiki
	Yamamichi, Gaku
	Tomiyama, Eisuke
	Koh, Yoko
	Yamamoto, Yoshiyuki
	Kato, Taigo
	Hatano, Koji
	Uemura, Motohide
	Imoto, Seiya
	Wada, Hisashi
	Morii, Eiichi
	Tsujikawa, Kazutake
	Nonomura, Norio
citation_publisher	John Wiley and Sons Inc
citation_language	English
citation_date	2025-04-01
citation_journal_title	International Journal of Cancer
citation_volume	156
citation_issue	7
citation_firstpage	1439
citation_lastpage	1456
citation_doi	https://doi.org/10.1002/ijc.35295
citation_public_url	https://hdl.handle.net/11094/100339

A novel mouse model of upper tract urothelial carcinoma highlights the impact of dietary intervention on gut microbiota and carcinogenesis prevention despite carcinogen exposure

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