Loss of myeloid‐specific lamin A/C drives lung metastasis through Gfi‐1 and C/EBPε‐mediated granulocytic differentiation

• Published in: Molecular carcinogenesis 2020-07, Vol.59 (7), p.679-690
• Main Authors: Ishii, Hiroki, Park, Woo‐Yong, So, Jaeyoung, Kuhn, Skyler, Koparde, Vishal N., Pang, Yanli, Greten, Tim F., Hollander, M. Christine, Yang, Li
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Breast cancer; CCAAT-Enhancer-Binding Proteins - genetics; CD11b antigen; Cell Differentiation - genetics; Cells, Cultured; Chemokines; Chemokines - genetics; Chromatin remodeling; Disease Models, Animal; Female; Granulocytes - pathology; granulocytic differentiation; Humans; immunosuppression; Inflammation; Inflammation - genetics; Inflammation - pathology; lamin A/C; Lamin Type A - genetics; Leukocytes, Mononuclear - pathology; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Metastases; Metastasis; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Molecular modelling; Myeloid cells; Myeloid Cells - pathology; Neoplasm Metastasis - genetics; Neoplasm Metastasis - pathology; Peripheral blood; Proto-Oncogene Proteins - genetics; Repressor Proteins - genetics; Transcription factors; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - pathology; Tumor Microenvironment - genetics; Up-Regulation - genetics
• ISSN: 0899-1987; 1098-2744
• DOI: 10.1002/mc.23147

The immune‐suppressive tumor microenvironment promotes metastatic spread and outgrowth. One of the major contributors is tumor‐associated myeloid cells. However, the molecular mechanisms regulating their differentiation and function are not well understood. Here we report lamin A/C, a nuclear lamina protein associated with chromatin remodeling, was one of the critical regulators in cellular reprogramming of tumor‐associated myeloid cells. Using myeloid‐specific lamin A/C knockout mice and triple‐negative breast cancer (TNBC) mouse models, we discovered that the loss of lamin A/C drives CD11b+Ly6G+ granulocytic lineage differentiation, alters the production of inflammatory chemokines, decreases host antitumor immunity, and increases metastasis. The underlying mechanisms involve an increased H3K4me3 leading to the upregulation of transcription factors (TFs) Gfi‐1 and C/EBPε. Decreased lamin A/C and increased Gfi‐1 and C/EBPε were also found in the granulocytic subset in the peripheral blood of human cancer patients. Our data provide a mechanistic understanding of myeloid lineage differentiation and function in the immune‐suppressive microenvironment in TNBC metastasis.