Combined mutation of Apc, Kras, and Tgfbr2 effectively drives metastasis of intestinal cancer

Eri Sakai, Mizuho Nakayama, Hiroko Oshima, Yuta Kouyama, Atsushi Niida, Satoshi Fujii, Atsushi Ochiai, Keiichi I. Nakayama, Koshi Mimori, Yutaka Suzuki, Chang Pyo Hong, Chan Young Ock, Seong Jin Kim, Masanobu Oshima

研究成果: ジャーナルへの寄稿記事

11 引用 (Scopus)

抄録

Colorectal cancer is driven by the accumulation of driver mutations, but the contributions of specific mutations to different steps in malignant progression are not fully understood. In this study, we generated mouse models harboring different combinations of key colorectal cancer driver mutations (Apc, Kras, Tgfbr2, Trp53, Fbxw7) in intestinal epithelial cells to comprehensively investigate their roles in the development of primary tumors and metastases. Apcδ716 mutation caused intestinal adenomas and combination with Trp53R270 mutation or Tgfbr2 deletion induced submucosal invasion. The addition of KrasG12D mutation yielded epithelial-mesenchymal transition (EMT)-like morphology and lymph vessel intravasation of the invasive tumors. In contrast, combinations of Apcδ716 with KrasG12D and Fbxw7 mutation were insufficient for submucosal invasion, but still induced EMT-like histology. Studies using tumor-derived organoids showed that KrasG12D was critical for liver metastasis following splenic transplantation, when this mutation was combined with either Apcδ716 plus Trp53R270H or Tgfbr2 deletion, with the highest incidence of metastasis displayed by tumors with a Apcδ716 KrasG12D Tgfbr2-/- genotype. RNA sequencing analysis of tumor organoids defined distinct gene expression profiles characteristic for the respective combinations of driver mutations, with upre-gulated genes in Apcδ716 KrasG12D Tgfbr2-/- tumors found to be similarly upregulated in specimens of human metastatic colorectal cancer. Our results show how activation of Wnt and Kras with suppression of TGFβ signaling in intestinal epithelial cells is sufficient for colorectal cancer metastasis, with possible implications for the development of metastasis prevention strategies.

元の言語英語
ページ(範囲)1334-1346
ページ数13
ジャーナルCancer Research
78
発行部数5
DOI
出版物ステータス出版済み - 3 1 2018

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Intestinal Neoplasms
Neoplasm Metastasis
Mutation
Colorectal Neoplasms
Organoids
Neoplasms
Epithelial-Mesenchymal Transition
Epithelial Cells
RNA Sequence Analysis
Lymph
Transcriptome
Adenoma
Histology
Transplantation
Genotype
Liver
Incidence

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

これを引用

Sakai, E., Nakayama, M., Oshima, H., Kouyama, Y., Niida, A., Fujii, S., ... Oshima, M. (2018). Combined mutation of Apc, Kras, and Tgfbr2 effectively drives metastasis of intestinal cancer. Cancer Research, 78(5), 1334-1346. https://doi.org/10.1158/0008-5472.CAN-17-3303

Combined mutation of Apc, Kras, and Tgfbr2 effectively drives metastasis of intestinal cancer. / Sakai, Eri; Nakayama, Mizuho; Oshima, Hiroko; Kouyama, Yuta; Niida, Atsushi; Fujii, Satoshi; Ochiai, Atsushi; Nakayama, Keiichi I.; Mimori, Koshi; Suzuki, Yutaka; Hong, Chang Pyo; Ock, Chan Young; Kim, Seong Jin; Oshima, Masanobu.

:: Cancer Research, 巻 78, 番号 5, 01.03.2018, p. 1334-1346.

研究成果: ジャーナルへの寄稿記事

Sakai, E, Nakayama, M, Oshima, H, Kouyama, Y, Niida, A, Fujii, S, Ochiai, A, Nakayama, KI, Mimori, K, Suzuki, Y, Hong, CP, Ock, CY, Kim, SJ & Oshima, M 2018, 'Combined mutation of Apc, Kras, and Tgfbr2 effectively drives metastasis of intestinal cancer', Cancer Research, 巻. 78, 番号 5, pp. 1334-1346. https://doi.org/10.1158/0008-5472.CAN-17-3303
Sakai, Eri ; Nakayama, Mizuho ; Oshima, Hiroko ; Kouyama, Yuta ; Niida, Atsushi ; Fujii, Satoshi ; Ochiai, Atsushi ; Nakayama, Keiichi I. ; Mimori, Koshi ; Suzuki, Yutaka ; Hong, Chang Pyo ; Ock, Chan Young ; Kim, Seong Jin ; Oshima, Masanobu. / Combined mutation of Apc, Kras, and Tgfbr2 effectively drives metastasis of intestinal cancer. :: Cancer Research. 2018 ; 巻 78, 番号 5. pp. 1334-1346.
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abstract = "Colorectal cancer is driven by the accumulation of driver mutations, but the contributions of specific mutations to different steps in malignant progression are not fully understood. In this study, we generated mouse models harboring different combinations of key colorectal cancer driver mutations (Apc, Kras, Tgfbr2, Trp53, Fbxw7) in intestinal epithelial cells to comprehensively investigate their roles in the development of primary tumors and metastases. Apcδ716 mutation caused intestinal adenomas and combination with Trp53R270 mutation or Tgfbr2 deletion induced submucosal invasion. The addition of KrasG12D mutation yielded epithelial-mesenchymal transition (EMT)-like morphology and lymph vessel intravasation of the invasive tumors. In contrast, combinations of Apcδ716 with KrasG12D and Fbxw7 mutation were insufficient for submucosal invasion, but still induced EMT-like histology. Studies using tumor-derived organoids showed that KrasG12D was critical for liver metastasis following splenic transplantation, when this mutation was combined with either Apcδ716 plus Trp53R270H or Tgfbr2 deletion, with the highest incidence of metastasis displayed by tumors with a Apcδ716 KrasG12D Tgfbr2-/- genotype. RNA sequencing analysis of tumor organoids defined distinct gene expression profiles characteristic for the respective combinations of driver mutations, with upre-gulated genes in Apcδ716 KrasG12D Tgfbr2-/- tumors found to be similarly upregulated in specimens of human metastatic colorectal cancer. Our results show how activation of Wnt and Kras with suppression of TGFβ signaling in intestinal epithelial cells is sufficient for colorectal cancer metastasis, with possible implications for the development of metastasis prevention strategies.",
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AU - Sakai, Eri

AU - Nakayama, Mizuho

AU - Oshima, Hiroko

AU - Kouyama, Yuta

AU - Niida, Atsushi

AU - Fujii, Satoshi

AU - Ochiai, Atsushi

AU - Nakayama, Keiichi I.

AU - Mimori, Koshi

AU - Suzuki, Yutaka

AU - Hong, Chang Pyo

AU - Ock, Chan Young

AU - Kim, Seong Jin

AU - Oshima, Masanobu

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N2 - Colorectal cancer is driven by the accumulation of driver mutations, but the contributions of specific mutations to different steps in malignant progression are not fully understood. In this study, we generated mouse models harboring different combinations of key colorectal cancer driver mutations (Apc, Kras, Tgfbr2, Trp53, Fbxw7) in intestinal epithelial cells to comprehensively investigate their roles in the development of primary tumors and metastases. Apcδ716 mutation caused intestinal adenomas and combination with Trp53R270 mutation or Tgfbr2 deletion induced submucosal invasion. The addition of KrasG12D mutation yielded epithelial-mesenchymal transition (EMT)-like morphology and lymph vessel intravasation of the invasive tumors. In contrast, combinations of Apcδ716 with KrasG12D and Fbxw7 mutation were insufficient for submucosal invasion, but still induced EMT-like histology. Studies using tumor-derived organoids showed that KrasG12D was critical for liver metastasis following splenic transplantation, when this mutation was combined with either Apcδ716 plus Trp53R270H or Tgfbr2 deletion, with the highest incidence of metastasis displayed by tumors with a Apcδ716 KrasG12D Tgfbr2-/- genotype. RNA sequencing analysis of tumor organoids defined distinct gene expression profiles characteristic for the respective combinations of driver mutations, with upre-gulated genes in Apcδ716 KrasG12D Tgfbr2-/- tumors found to be similarly upregulated in specimens of human metastatic colorectal cancer. Our results show how activation of Wnt and Kras with suppression of TGFβ signaling in intestinal epithelial cells is sufficient for colorectal cancer metastasis, with possible implications for the development of metastasis prevention strategies.

AB - Colorectal cancer is driven by the accumulation of driver mutations, but the contributions of specific mutations to different steps in malignant progression are not fully understood. In this study, we generated mouse models harboring different combinations of key colorectal cancer driver mutations (Apc, Kras, Tgfbr2, Trp53, Fbxw7) in intestinal epithelial cells to comprehensively investigate their roles in the development of primary tumors and metastases. Apcδ716 mutation caused intestinal adenomas and combination with Trp53R270 mutation or Tgfbr2 deletion induced submucosal invasion. The addition of KrasG12D mutation yielded epithelial-mesenchymal transition (EMT)-like morphology and lymph vessel intravasation of the invasive tumors. In contrast, combinations of Apcδ716 with KrasG12D and Fbxw7 mutation were insufficient for submucosal invasion, but still induced EMT-like histology. Studies using tumor-derived organoids showed that KrasG12D was critical for liver metastasis following splenic transplantation, when this mutation was combined with either Apcδ716 plus Trp53R270H or Tgfbr2 deletion, with the highest incidence of metastasis displayed by tumors with a Apcδ716 KrasG12D Tgfbr2-/- genotype. RNA sequencing analysis of tumor organoids defined distinct gene expression profiles characteristic for the respective combinations of driver mutations, with upre-gulated genes in Apcδ716 KrasG12D Tgfbr2-/- tumors found to be similarly upregulated in specimens of human metastatic colorectal cancer. Our results show how activation of Wnt and Kras with suppression of TGFβ signaling in intestinal epithelial cells is sufficient for colorectal cancer metastasis, with possible implications for the development of metastasis prevention strategies.

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