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Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
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SMAD4 is critical in suppression of BRAF-V600E serrated tumorigenesis

Kevin Tong1, Om A Kothari1, Katherine S Haro1

  • 1Department of Genetics, Human Genetics Institute of New Jersey (HGINJ), Rutgers University, Piscataway, NJ, USA.

Oncogene
|August 28, 2021
PubMed

Insights

Loss of Smad4 promotes microsatellite stable serrated colorectal cancer, driven by BRAF-V600E and WNT pathway mutations. This finding advances understanding of this aggressive cancer subtype.

Area of Science:

  • Gastroenterology
  • Oncology
  • Molecular Biology

Background:

  • BRAF-driven colorectal cancer (CRC) has a poor prognosis.
  • Serrated CRC subtypes often show Microsatellite Instability (MSI) and WNT signaling.
  • SMAD4 loss is observed in BRAF-V600E CRC and promotes serrated tumor development in mouse models.

Purpose of the Study:

  • To investigate the role of SMAD4 in early-stage serrated colorectal tumorigenesis.
  • To establish a mouse model for microsatellite stable (MSS) serrated cancers.
  • To identify key genetic drivers in serrated CRC development.

Main Methods:

  • Utilized oncogenic BRAF-V600E mouse models with SMAD4 loss.
  • Assessed tumor development in both microsatellite stable (MSS) and microsatellite instable (MSI) contexts.
  • Performed whole-exome sequencing on serrated tumors.
  • Analyzed human CRC patient data for co-occurring mutations.

Main Results:

  • SMAD4 loss promoted MSS serrated tumors in a BRAF-V600E context.
  • Inactivation of Msh2 accelerated tumor formation.
  • All serrated tumors, both MSS and MSI, acquired oncogenic WNT mutations, primarily in Ctnnb1 (β-catenin).
  • The combination of Ctnnb1, Braf, and Smad4 mutations drives rapid serrated dysplasia.
  • Human CRC data confirmed co-occurrence of BRAF-V600E with WNT and SMAD4/TGFβ pathway mutations.

Conclusions:

  • SMAD4 is a critical factor in early-stage serrated colorectal cancer development.
  • This study provides a model for MSS serrated CRC.
  • Findings expand knowledge of the genetic landscape in this aggressive CRC subset.

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