SMAD4 is critical in suppression of BRAF-V600E serrated tumorigenesis
- 27 August 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 40 (41), 6034-6048
- https://doi.org/10.1038/s41388-021-01997-x
Abstract
BRAF-driven colorectal cancer is among the poorest prognosis subtypes of colon cancer. Previous studies suggest that BRAF-mutant serrated cancers frequently exhibit Microsatellite Instability (MSI) and elevated levels of WNT signaling. The loss of tumor-suppressor Smad4 in oncogenic BRAF-V600E mouse models promotes rapid serrated tumor development and progression, and SMAD4 mutations co-occur in human patient tumors with BRAF-V600E mutations. This study assesses the role of SMAD4 in early-stage serrated tumorigenesis. SMAD4 loss promotes microsatellite stable (MSS) serrated tumors in an oncogenic BRAF-V600E context, providing a model for MSS serrated cancers. Inactivation of Msh2 in these mice accelerated tumor formation, and whole-exome sequencing of both MSS and MSI serrated tumors derived from these mouse models revealed that all serrated tumors developed oncogenic WNT mutations, predominantly in the WNT-effector gene Ctnnb1 (β-catenin). Mouse models mimicking the oncogenic β-catenin mutation show that the combination of three oncogenic mutations (Ctnnb1, Braf, and Smad4) are critical to drive rapid serrated dysplasia formation. Re-analysis of human tumor data reveals BRAF-V600E mutations co-occur with oncogenic mutations in both WNT and SMAD4/TGFβ pathways. These findings identify SMAD4 as a critical factor in early-stage serrated cancers and helps broaden the knowledge of this rare but aggressive subset of colorectal cancer.Keywords
Funding Information
- U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK121915)
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (5R01CA190558, P30CA072720, 5K99CA245123, 1F32CA235829, 1R01CA243547)
- U.S. Department of Health & Human Services | NIH | National Cancer Institute
- U.S. Department of Health & Human Services | NIH | National Cancer Institute
- U.S. Department of Health & Human Services | NIH | National Cancer Institute
- Rutgers, The State University of New Jersey
- U.S. Department of Health & Human Services | NIH | National Cancer Institute
- U.S. Department of Defense
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