Effect of MisMatch Repair Deficiency on metastasis occurrence modelized in a syngeneic mouse model

Abstract

Mismatch repair deficiency leads to high mutation rates and microsatellite instability (MSI-H), associated with immune infiltration and responsiveness to immunotherapies. In early stages, MSI-H tumors generally have a better prognosis and lower metastatic potential than microsatellite-stable (MSS) tumors, especially in colorectal cancer. However, in advanced stages, MSI-H tumors lose this survival advantage for reasons that remain unclear. We developed a syngeneic mouse model of MSI cancer by knocking out the MMR gene Msh2 in the metastatic 4T1 breast cancer cell line. This model mirrored genomic features of MSI-H cancers and showed reduction in metastatic incidence compared to their MSS counterparts. In MSI-H tumors, we observed an enrichment of immune gene-signatures that negatively correlated with metastasis incidence. Importantly, a hybrid epithelial-mesenchymal signature, related to aggressiveness was detected only in metastatic MSI-H tumors which may explain the worse outcomes after recurrence of MSI tumors compared to MSS. Interestingly, we identified immature myeloid cells at primary and metastatic sites in MSI-H tumor-bearing mice, suggesting that MMR deficiency elicits specific immune responses beyond T-cell activation. SignificanceA novel syngeneic mouse model of MSI cancer demonstrates that the immune system regulates MSI cancer cell dissemination, offering an important tool to model advanced stages of human MSI-driven disease.