Loss of Lamin A/C in myeloid cells promotes lung metastasis through Gfi-1 and C/EBPe-mediated granulocytic differentiation

The immune suppressive tumor microenvironment contributes to metastatic spread. In particular, tumor-associated myeloid cells, which differ from normal myeloid cells, suppress cytotoxic T lymphocyte-mediated anti-tumor immunity. However, the underlying molecular mechanisms for tumor-associated myeloid lineage differentiation and functional properties are not well understood. Here we report a lack of Lamin A/C, a nuclear lamina protein associated with chromatin remodeling, in tumor-associated granulocytic myeloid cells. Using mouse models of myeloid specific Lamin A/C knockout, and mouse models of triple negative breast cancer (TNBC), we discovered that the loss of Lamin A/C drives CD11b+Ly6G+ granulocytic lineage differentiation. Mechanistically, loss of Lamin A/C increased H3K4me3 and led to the up-regulation of transcription factors C/EBPe and Gfi-1, which are critical for granulocytic lineage differentiation. In addition, loss of Lamin A/C changes the production of inflammatory chemokines and decreases anti-tumor immunity, leading to increased lung metastasis. Our data provide mechanistic understanding of myeloid lineage differentiation and function in the immune suppressive microenvironment in TNBC metastasis. CD11b+Ly6C+ or CD11b+Ly6G+ myeloid cells were sorted from spleens of wt or myeloid-specific Lmna knockout mice by the FACSAria flow cytometer. Total RNA was extracted from sorted cells, and RNA-seq was performed to clarify the influence of loss of Lamin A/C in myeloid cells on myeloid differentiation.