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BRAF-driven serrated colon cancers are among the most aggressive subsets of colorectal cancers. Smad4 is a critical tumor suppressor found mutated in many late-stage cancers, yet the role of Smad4 in serrated cancer invasion is still relatively understudied. This study seeks to address this gap by using organoids as an in vitro system for invasive behavior. Organoids derived from BRAF-driven tumors have invasive capabilities, and the re-expression of SMAD4 directly suppresses the invasive behavior. Furthermore, expression of SMAD4 transcriptionally alters genes associated with the extracellular space, providing evidence that Smad4 regulates the environment surrounding tumors. These results provide new models to study serrated cancer invasion and reveal a role of SMAD4 in manipulating the tumor microenvironment to suppress invasion.

Colon cancer is the third most prominent cancer and second leading cause of cancer-related deaths in the United States. Up to 20% of colon cancers follow the serrated tumor pathway driven by mutations in the MAPK pathway. Loss of SMAD4 function occurs in the majority of late-stage colon cancers and is associated with aggressive cancer progression. Therefore, it is important to develop technology to accurately model and better understand the genetic mechanisms behind cancer invasion. Organoids derived from tumors found in the Smad4^KO BRAF^V600E/+ mouse model present multiple phenotypes characteristic of invasion both in ex vivo and in vivo systems. Smad4^KO BRAF^V600E/+ tumor organoids can migrate through 3D culture …