Cargando…

MEK inhibition suppresses metastatic progression of KRAS‐mutated gastric cancer

Metastatic progression of tumors is driven by genetic alterations and tumor‐stroma interaction. To elucidate the mechanism underlying the oncogene‐induced gastric tumor progression, we have developed an organoid‐based model of gastric cancer from GAstric Neoplasia (GAN) mice, which express Wnt1 and...

Descripción completa

Detalles Bibliográficos
Autores principales: Yamasaki, Juntaro, Hirata, Yuki, Otsuki, Yuji, Suina, Kentaro, Saito, Yoshiyuki, Masuda, Kenta, Okazaki, Shogo, Ishimoto, Takatsugu, Saya, Hideyuki, Nagano, Osamu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8898706/
https://www.ncbi.nlm.nih.gov/pubmed/34931404
http://dx.doi.org/10.1111/cas.15244
_version_ 1784663716285906944
author Yamasaki, Juntaro
Hirata, Yuki
Otsuki, Yuji
Suina, Kentaro
Saito, Yoshiyuki
Masuda, Kenta
Okazaki, Shogo
Ishimoto, Takatsugu
Saya, Hideyuki
Nagano, Osamu
author_facet Yamasaki, Juntaro
Hirata, Yuki
Otsuki, Yuji
Suina, Kentaro
Saito, Yoshiyuki
Masuda, Kenta
Okazaki, Shogo
Ishimoto, Takatsugu
Saya, Hideyuki
Nagano, Osamu
author_sort Yamasaki, Juntaro
collection PubMed
description Metastatic progression of tumors is driven by genetic alterations and tumor‐stroma interaction. To elucidate the mechanism underlying the oncogene‐induced gastric tumor progression, we have developed an organoid‐based model of gastric cancer from GAstric Neoplasia (GAN) mice, which express Wnt1 and the enzymes COX2 and microsomal prostaglandin E synthase 1 in the stomach. Both p53 knockout (GAN‐p53KO) organoids and KRAS (G12V)‐expressing GAN‐p53KO (GAN‐KP) organoids were generated by genetic manipulation of GAN mouse‐derived tumor (GAN wild‐type [WT]) organoids. In contrast with GAN‐WT and GAN‐p53KO organoids, which manifested Wnt addiction, GAN‐KP organoids showed a Wnt‐independent phenotype and the ability to proliferate without formation of a Wnt‐regulated three‐dimensional epithelial architecture. After transplantation in syngeneic mouse stomach, GAN‐p53KO cells formed only small tumors, whereas GAN‐KP cells gave rise to invasive tumors associated with the development of hypoxia as well as to liver metastasis. Spatial transcriptomics analysis suggested that hypoxia signaling contributes to the metastatic progression of GAN‐KP tumors. In particular, such analysis identified a cluster of stromal cells located at the tumor invasive front that expressed genes related to hypoxia signaling, angiogenesis, and cell migration. These cells were also positive for phosphorylated extracellular signal‐regulated kinase (ERK), suggesting that mitogen‐activated protein kinase (MAPK) signaling promotes development of both tumor and microenvironment. The MEK (MAPK kinase) inhibitor trametinib suppressed the development of GAN‐KP gastric tumors, formation of a hypoxic microenvironment, tumor angiogenesis, and liver metastasis. Our findings therefore establish a rationale for application of trametinib to suppress metastatic progression of KRAS‐mutated gastric cancer.
format Online
Article
Text
id pubmed-8898706
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-88987062022-03-11 MEK inhibition suppresses metastatic progression of KRAS‐mutated gastric cancer Yamasaki, Juntaro Hirata, Yuki Otsuki, Yuji Suina, Kentaro Saito, Yoshiyuki Masuda, Kenta Okazaki, Shogo Ishimoto, Takatsugu Saya, Hideyuki Nagano, Osamu Cancer Sci Original Articles Metastatic progression of tumors is driven by genetic alterations and tumor‐stroma interaction. To elucidate the mechanism underlying the oncogene‐induced gastric tumor progression, we have developed an organoid‐based model of gastric cancer from GAstric Neoplasia (GAN) mice, which express Wnt1 and the enzymes COX2 and microsomal prostaglandin E synthase 1 in the stomach. Both p53 knockout (GAN‐p53KO) organoids and KRAS (G12V)‐expressing GAN‐p53KO (GAN‐KP) organoids were generated by genetic manipulation of GAN mouse‐derived tumor (GAN wild‐type [WT]) organoids. In contrast with GAN‐WT and GAN‐p53KO organoids, which manifested Wnt addiction, GAN‐KP organoids showed a Wnt‐independent phenotype and the ability to proliferate without formation of a Wnt‐regulated three‐dimensional epithelial architecture. After transplantation in syngeneic mouse stomach, GAN‐p53KO cells formed only small tumors, whereas GAN‐KP cells gave rise to invasive tumors associated with the development of hypoxia as well as to liver metastasis. Spatial transcriptomics analysis suggested that hypoxia signaling contributes to the metastatic progression of GAN‐KP tumors. In particular, such analysis identified a cluster of stromal cells located at the tumor invasive front that expressed genes related to hypoxia signaling, angiogenesis, and cell migration. These cells were also positive for phosphorylated extracellular signal‐regulated kinase (ERK), suggesting that mitogen‐activated protein kinase (MAPK) signaling promotes development of both tumor and microenvironment. The MEK (MAPK kinase) inhibitor trametinib suppressed the development of GAN‐KP gastric tumors, formation of a hypoxic microenvironment, tumor angiogenesis, and liver metastasis. Our findings therefore establish a rationale for application of trametinib to suppress metastatic progression of KRAS‐mutated gastric cancer. John Wiley and Sons Inc. 2022-01-07 2022-03 /pmc/articles/PMC8898706/ /pubmed/34931404 http://dx.doi.org/10.1111/cas.15244 Text en © 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Articles
Yamasaki, Juntaro
Hirata, Yuki
Otsuki, Yuji
Suina, Kentaro
Saito, Yoshiyuki
Masuda, Kenta
Okazaki, Shogo
Ishimoto, Takatsugu
Saya, Hideyuki
Nagano, Osamu
MEK inhibition suppresses metastatic progression of KRAS‐mutated gastric cancer
title MEK inhibition suppresses metastatic progression of KRAS‐mutated gastric cancer
title_full MEK inhibition suppresses metastatic progression of KRAS‐mutated gastric cancer
title_fullStr MEK inhibition suppresses metastatic progression of KRAS‐mutated gastric cancer
title_full_unstemmed MEK inhibition suppresses metastatic progression of KRAS‐mutated gastric cancer
title_short MEK inhibition suppresses metastatic progression of KRAS‐mutated gastric cancer
title_sort mek inhibition suppresses metastatic progression of kras‐mutated gastric cancer
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8898706/
https://www.ncbi.nlm.nih.gov/pubmed/34931404
http://dx.doi.org/10.1111/cas.15244
work_keys_str_mv AT yamasakijuntaro mekinhibitionsuppressesmetastaticprogressionofkrasmutatedgastriccancer
AT hiratayuki mekinhibitionsuppressesmetastaticprogressionofkrasmutatedgastriccancer
AT otsukiyuji mekinhibitionsuppressesmetastaticprogressionofkrasmutatedgastriccancer
AT suinakentaro mekinhibitionsuppressesmetastaticprogressionofkrasmutatedgastriccancer
AT saitoyoshiyuki mekinhibitionsuppressesmetastaticprogressionofkrasmutatedgastriccancer
AT masudakenta mekinhibitionsuppressesmetastaticprogressionofkrasmutatedgastriccancer
AT okazakishogo mekinhibitionsuppressesmetastaticprogressionofkrasmutatedgastriccancer
AT ishimototakatsugu mekinhibitionsuppressesmetastaticprogressionofkrasmutatedgastriccancer
AT sayahideyuki mekinhibitionsuppressesmetastaticprogressionofkrasmutatedgastriccancer
AT naganoosamu mekinhibitionsuppressesmetastaticprogressionofkrasmutatedgastriccancer