DNA and RNA sequencing of mouse 4T1 knocked out for MSH2
Mismatch repair deficiency (MMRD) leads to the inability of cells to correct errors during DNA replication, causing a high mutational burden and the accumulation of insertions/deletions (indels) at microsatellite sites. This results in high microsatellite instability (MSI-H), immune infiltration, and responsiveness to immunotherapies. The MMRD phenotype is present in over 15 types of cancers, especially colorectal (CRC) and endometrial cancers. MSI-H tumors generally have a better prognosis in early stages and are less likely to metastasize than microsatellite-stable (MSS) tumors, as seen in CRC. However, in advanced stages, MSI-H tumors lose this survival advantage, with the underlying remaining unclear. Leveraging the tumor-agnostic features of the MMRD phenotype, we established a syngeneic mouse model of MSI cancer using the highly metastatic 4T1 breast cancer cell line, knocked out for the MMR gene Msh2. This model recapitulated the genomic features common to all MSI-H cancers, showed a 17.3% reduction in metastatic incidence and fewer lesion-bearing sites in the MSI metastatic group compared to the MSS group, which mirrors findings from human MSI CRC data. Interestingly, primary MSI-H tumors showed enrichment of immune-related gene expression signatures that negatively correlated with metastatic status. Moreover, primary MSI-H tumors that develop metastasis exhibited a distinct enrichment of a hybrid epithelial-mesenchymal signature, indicating greater aggressiveness compared to MSS tumors. Furthermore, we identified a unique population of immature myeloid cells present at both primary and metastatic sites in MSI-H tumor-bearing mice, suggesting that the deficiency in MMR pathway elicits a specific immune response beyond T-cell activation.