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

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1334-1346
Number of pages13
JournalCancer Research
Volume78
Issue number5
DOIs
Publication statusPublished - Mar 1 2018

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Sakai, E., Nakayama, M., Oshima, H., Kouyama, Y., Niida, A., Fujii, S., Ochiai, A., Nakayama, K. I., Mimori, K., Suzuki, Y., Hong, C. P., Ock, C. Y., Kim, S. J., & 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