# Integrin α3β1 Is Not Required for Onset of Dysplasia in Genetic Model of Colon Cancer but Promotes Motility of Colon Cancer Cells

## TL;DR

This study shows that integrin α3β1 is not needed for early colon cancer development but helps cancer cells move, suggesting it's important in later stages.

## Contribution

The study reveals a stage-specific role of integrin α3β1 in colorectal cancer progression, highlighting its potential as a therapeutic target at later stages.

## Key findings

- Genetic deletion of integrin α3β1 does not affect pre-cancerous colonic dysplasia in a murine model.
- Suppression of integrin α3β1 reduces motility and invasion of human colorectal cancer cells by 40-60%.
- Integrin α3β1 may play a pro-migratory role in later stages of colorectal cancer progression.

## Abstract

Integrin α3β1 is an extracellular matrix receptor with pro-tumorigenic/pro-metastatic roles on many tumor/cancer cells, and its expression has been correlated with poor prognosis, indicating its potential value as a therapeutic target and/or prognostic marker. However, α3β1 has also been linked to tumor-suppressive roles in some cancer types/subtypes, and it may even switch from tumor-supportive to cancer-suppressive during disease progression, which highlights the need to investigate this integrin in different cancers and at different stages. In the current study, we assessed roles for α3β1 in colorectal cancer, where its value as a therapeutic target is underexplored. Using a genetic approach to delete α3β1 in a murine model of colorectal cancer, we showed that it is dispensable for pre-cancerous colonic dysplasia. However, using RNAi to suppress α3β1, we showed that it promotes the motility/invasion of human colorectal cancer cells. These findings indicate that α3β1 may be important at specific stages of colorectal cancer progression.

Background/Objectives: The progression of colorectal cancer through clinically and histopathologically well-defined stages is driven by specific mutations that activate oncogenes or inactivate tumor-suppressor genes. In addition, pre-cancerous/cancer cells respond to cues from the tissue microenvironment that support tumorigenesis and progression, many of which are transmitted through integrin receptors for the extracellular matrix. Integrin α3β1 has pro-tumorigenic/pro-metastatic roles in many cancers, but it also has suppressive roles in some cancers or at specific stages of progression, indicating that its potential value as a therapeutic target cannot be extrapolated across cancer types or stages. In this study, we investigated roles for α3β1 in colorectal cancer using cellular and genetic models that represent different stages. Methods: We generated mice with colon-specific α3 knockout in a tamoxifen-inducible model of KRAS-mutated colorectal cancer to assess the effects of α3β1 ablation on early dysplasia. We also used siRNA to suppress α3β1 in human colorectal cancer cells, then assessed effects on motility and invasion in vitro. Results: Genetic deletion of α3β1 in the colon did not alter dysplasia in mice predisposed to KRAS-mutated colorectal cancer, and it was accompanied by an increase in the colocalization of α6 integrin with laminin-332 (a matrix ligand for both integrins), suggesting functional compensation. However, suppression of α3β1 caused an approximately 40% to 60% reduction in the motility/invasion of human colorectal cancer cells. Conclusions: Our findings that α3β1 is not required for pre-cancerous dysplasia but promotes colorectal cancer cell motility/invasion indicate an important role for pro-migratory functions of this integrin at later stages of progression when cells invade from the primary tumor, suggesting that strategies to target α3β1 in colorectal cancer should be aimed at distinct stages of disease progression.