GDF15 promotes 5-Fluorouracil and Oxaliplatin resistance by promoting stem cell-like phenotype in colorectal cancer

Hashimoto, Masahiro; Urabe, Shoichiro; Hata, Tsuyoshi; Chinen, Yoshinao; Haruna, Kengo; Takeda, Mitsunobu; Sekido, Yuki; Hamabe, Atsushi; Ogino, Takayuki; Miyoshi, Norikatsu; Tobo, Taro; Mimori, Koshi; Uemura, Mamoru; Eguchi, Hidetoshi; Doki, Yuichiro

doi:https://doi.org/10.1038/s41416-026-03379-0

GDF15 promotes 5-Fluorouracil and Oxaliplatin resistance by promoting stem cell-like phenotype in colorectal cancer

Hashimoto, Masahiro; Urabe, Shoichiro; Hata, Tsuyoshi et al.

British Journal of Cancer, 2026

アクセス数:1,570件（2026-11-15 04:57 集計）

固定URL: https://hdl.handle.net/11094/105105

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タイトル	GDF15 promotes 5-Fluorouracil and Oxaliplatin resistance by promoting stem cell-like phenotype in colorectal cancer
著者	NRID 1000090984021 1000090984021 Scopus Author ID 58951102900 58951102900 著者名 Hashimoto, Masahiro
	著者名 Urabe, Shoichiro
	NRID 1000080749747 1000080749747 ORCID 0000-0001-6616-9069 0000-0001-6616-9069 researchmap permalink tsuyoshi_hata tsuyoshi_hata Scopus Author ID 57189996374 57189996374 著者名 Hata, Tsuyoshi
	著者名 Chinen, Yoshinao
	NRID 1000011001446 1000011001446 ORCID 0009-0000-7656-1128 0009-0000-7656-1128 Scopus Author ID 57215681276 57215681276 著者名 Haruna, Kengo
	NRID 1000090768962 1000090768962 researchmap permalink takeda27832 takeda27832 著者名 Takeda, Mitsunobu
	NRID 1000000781709 1000000781709 ORCID 0000-0003-4281-0047 0000-0003-4281-0047 researchmap permalink 00781709 00781709 Scopus Author ID 57193691322 57193691322 著者名 Sekido, Yuki
	NRID 1000060621034 1000060621034 ORCID 0000-0001-5535-3514 0000-0001-5535-3514 researchmap permalink hamabe_atsushi hamabe_atsushi Scopus Author ID 26435224200 26435224200 著者名 Hamabe, Atsushi
	NRID 1000050597458 1000050597458 ORCID 0000-0001-5435-4144 0000-0001-5435-4144 researchmap permalink togino04 togino04 Scopus Author ID 57200254430 57200254430 著者名 Ogino, Takayuki
	NRID 1000020528624 1000020528624 ORCID 0000-0003-1113-8884 0000-0003-1113-8884 researchmap permalink nor nor Scopus Author ID 9242781300 9242781300 著者名 Miyoshi, Norikatsu
	著者名 Tobo, Taro
	NRID 1000050322748 1000050322748 著者名 Mimori, Koshi
	NRID 1000010528483 1000010528483 ORCID 0000-0001-6285-5619 0000-0001-6285-5619 researchmap permalink mamoruuemura mamoruuemura Scopus Author ID 36796497400 36796497400 著者名 Uemura, Mamoru
	NRID 1000090542118 1000090542118 ORCID 0000-0002-2318-1129 0000-0002-2318-1129 researchmap permalink abcdabcdabcd abcdabcdabcd Scopus Author ID 7101627772 7101627772 著者名 Eguchi, Hidetoshi
	NRID 1000020291445 1000020291445 researchmap permalink ydoki3251 ydoki3251 Scopus Author ID 7006390687 7006390687 著者名 Doki, Yuichiro
内容	Hashimoto M., Urabe S., Hata T., et al. GDF15 promotes 5-Fluorouracil and Oxaliplatin resistance by promoting stem cell-like phenotype in colorectal cancer. British Journal of Cancer (2026); https://doi.org/10.1038/s41416-026-03379-0.
抄録	Background: Despite recent advances in chemotherapy for colorectal cancer (CRC), chemotherapy-sensitive tumours often develop resistance to treatment, which remains a major clinical challenge. This acquired chemoresistance limits the efficacy of subsequent therapies and is associated with a poor prognosis. Therefore, this study identified the mechanisms of acquired chemoresistance in CRC and developed innovative targeted therapies. Methods: 5-fluorouracil (5-FU)-and oxaliplatin (OX)-resistant CRC cells were established through long-term exposure to anticancer drugs, and RNA sequencing (RNA-seq) was performed. RNA-seq data integrated analysis from resistant cells and public single-cell RNA-seq datasets from clinical CRC samples was conducted to identify key drivers of chemoresistance. Prognostic significance was evaluated by immunohistochemical analysis of liver metastasis specimens from patients with CRC who underwent curative resection of the primary tumours. Results: Chemotherapy exposure enriched high stemness and activated TGF-β signalling. GDF15 was identified as a key molecule upregulated in both chemoresistant and high-stemness cells. Clinically, high GDF15 expression is associated with early recurrence and poor prognosis. Functional assays demonstrated that GDF15 overexpression promoted chemoresistance, stemness, and migratory capacity of CRC cells. Conclusions: GDF15 promotes chemoresistance in CRC by promoting stem cell-like properties. These findings provide insights into therapeutic strategies for overcoming acquired chemoresistance and improving outcomes.
出版者	Springer Nature
収録物名	British Journal of Cancer
刊行年月	2026-05-12
言語	英語
ハンドルURL	https://hdl.handle.net/11094/105105
PISSN	00070920
eISSN	15321827
関連情報 (isIdenticalTo)	DOI (出版社版) https://doi.org/10.1038/s41416-026-03379-0
アクセス権	open access
権利情報	This article is licensed under a Creative Commons Attribution 4.0 International License.
出版タイプ	Version of Record
カテゴリ	学術雑誌論文 Journal Article

資源タイプ	学術雑誌論文
ローカル資源タイプ	学術雑誌論文
DCMI資源タイプ	text
DCTERMS.bibliographicCitation	British Journal of Cancer. 2026
DC.title	GDF15 promotes 5-Fluorouracil and Oxaliplatin resistance by promoting stem cell-like phenotype in colorectal cancer
DC.creator	Hashimoto, Masahiro
	Urabe, Shoichiro
	Hata, Tsuyoshi
	Chinen, Yoshinao
	Haruna, Kengo
	Takeda, Mitsunobu
	Sekido, Yuki
	Hamabe, Atsushi
	Ogino, Takayuki
	Miyoshi, Norikatsu
	Tobo, Taro
	Mimori, Koshi
	Uemura, Mamoru
	Eguchi, Hidetoshi
	Doki, Yuichiro
DC.publisher	Springer Nature
DC.language' scheme='DCTERMS.RFC1766	英語
DC.type' scheme='DCTERMS.DCMIType	text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2026-05-12
DC.identifier	https://doi.org/10.1038/s41416-026-03379-0
DC.description	Hashimoto M., Urabe S., Hata T., et al. GDF15 promotes 5-Fluorouracil and Oxaliplatin resistance by promoting stem cell-like phenotype in colorectal cancer. British Journal of Cancer (2026); https://doi.org/10.1038/s41416-026-03379-0.
DCTERMS.abstract	Background: Despite recent advances in chemotherapy for colorectal cancer (CRC), chemotherapy-sensitive tumours often develop resistance to treatment, which remains a major clinical challenge. This acquired chemoresistance limits the efficacy of subsequent therapies and is associated with a poor prognosis. Therefore, this study identified the mechanisms of acquired chemoresistance in CRC and developed innovative targeted therapies. Methods: 5-fluorouracil (5-FU)-and oxaliplatin (OX)-resistant CRC cells were established through long-term exposure to anticancer drugs, and RNA sequencing (RNA-seq) was performed. RNA-seq data integrated analysis from resistant cells and public single-cell RNA-seq datasets from clinical CRC samples was conducted to identify key drivers of chemoresistance. Prognostic significance was evaluated by immunohistochemical analysis of liver metastasis specimens from patients with CRC who underwent curative resection of the primary tumours. Results: Chemotherapy exposure enriched high stemness and activated TGF-β signalling. GDF15 was identified as a key molecule upregulated in both chemoresistant and high-stemness cells. Clinically, high GDF15 expression is associated with early recurrence and poor prognosis. Functional assays demonstrated that GDF15 overexpression promoted chemoresistance, stemness, and migratory capacity of CRC cells. Conclusions: GDF15 promotes chemoresistance in CRC by promoting stem cell-like properties. These findings provide insights into therapeutic strategies for overcoming acquired chemoresistance and improving outcomes.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	105105
citation_title	GDF15 promotes 5-Fluorouracil and Oxaliplatin resistance by promoting stem cell-like phenotype in colorectal cancer
citation_author	Hashimoto, Masahiro
	Urabe, Shoichiro
	Hata, Tsuyoshi
	Chinen, Yoshinao
	Haruna, Kengo
	Takeda, Mitsunobu
	Sekido, Yuki
	Hamabe, Atsushi
	Ogino, Takayuki
	Miyoshi, Norikatsu
	Tobo, Taro
	Mimori, Koshi
	Uemura, Mamoru
	Eguchi, Hidetoshi
	Doki, Yuichiro
citation_publisher	Springer Nature
citation_language	英語
citation_date	2026-05-12
citation_journal_title	British Journal of Cancer
citation_doi	https://doi.org/10.1038/s41416-026-03379-0
citation_public_url	https://hdl.handle.net/11094/105105

GDF15 promotes 5-Fluorouracil and Oxaliplatin resistance by promoting stem cell-like phenotype in colorectal cancer

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