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

Author:

Ishii, Hiroki

Park, Woo-Yong

So, Jaeyoung

Kuhn,Skyler

Koparde,Vishal

Pang, Yanli

Greten, Tim F

Hollander, M Christine

Yang, Li [ORCID]
Author Address

Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland., CCR Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland., Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research Sponsored by the National Cancer Institute, NIH, Frederick, Maryland., Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.,

Abstract:

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/EBPe. Decreased lamin A/C and increased Gfi-1 and C/EBPe 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. © 2020 The Authors. Molecular Carcinogenesis Published by Wiley Periodicals, Inc.

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