Effect of MisMatch repair deficiency on metastasis occurrence in a syngeneic mouse model

Abstract

• Generation of a murine model of MSI metastatic cancer, currently lacking in the field. • In vivo imaging revealed that the 4T1-MSI tumor model exhibits reduced metastatic potential. • MSI metastatic tumors were associated with low-immune transcriptomic activity and an aggressive hybrid epithelial/mesenchymal gene signature. • MSI-specific TANs and TAMs were found at the primary tumors and metastatic sites of MSI tumors. 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. A hybrid epithelial-mesenchymal signature, related to aggressiveness was detected only in metastatic MSI-H tumors. 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.