Combined Mutation of Apc, Kras , and Tgfbr2 Effectively Drives Metastasis of Intestinal Cancer
Published version of a preprint
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 Trp53R270H 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 upregulated 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.Significance: These findings illuminate how key driver mutations in colon cancer cooperate to drive the development of metastatic disease, with potential implications for the development of suitable prevention strategies. Cancer Res; 78(5); 1334-46. ©2017 AACR.
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Several KRAS alleles had reduced comutation with NRAS and BRAF, and increased comutation with APC and PIK3CA.
“Several KRAS alleles had reduced comutation with NRAS and BRAF, and increased comutation with APC and PIK3CA”
From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [40]
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The origins and genetic interactions of KRAS mutations are allele- and tissue-specific
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- Authors
- 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.
- Affiliations
- Kanazawa University (JP)
- Kyushu University Beppu Hospital (JP)
- Institute of Medical Science, The University of Tokyo (JP)
- National Cancer Center Exploratory Oncology Research & Clinical Trial Center (JP)
- Kyushu University (JP)
- The University of Tokyo (JP)
- Theragen (KR)
- Seoul National University (KR)
- ORCID
- Venue
- Cancer Research
- Published
- 2017-12-27
- Volume
- 78
- Issue
- 5
- Pages
- 1334-1346
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2780751515
- Cited by
- 133
- References
- 49
- Citations by year
- 2026: 10 · 2025: 15 · 2024: 19 · 2023: 20 · 2022: 17 · 2021: 22 · 2020: 14 · 2019: 8 · 2018: 8
- FWCI
- 3.62
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- AMEDDMedical Research and Development, Japan and Grants-in-Aid for Scientific Research ((A) (15H02362), (C) (26430110))
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- APC mutation, KRAS mutation, TGFBR2 mutation, metastasis, intestinal cancer, colorectal cancer, tumor suppressor, oncogenes, TGF-beta signaling
- MeSH terms
- Receptor, Transforming Growth Factor-beta Type II, Animals, Disease Models, Animal, Humans, Intestinal Neoplasms, Liver Neoplasms, Mice, Inbred C57BL, Mutation, Tumor Cells, Cultured, Biomarkers, Tumor, Signal Transduction, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins p21(ras), Mice, SCID, Mice, Inbred NOD, Disease Progression, Gene Expression Profiling, Adenomatous Polyposis Coli Protein, TRPC Cation Channels, Mice
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