Lipid-laden lung mesenchymal cells foster breast cancer metastasis via metabolic reprogramming of tumor cells and natural killer cells

  • Cell Metab. 2022 Dec 6;34(12):1960-1976.e9. doi: 10.1016/j.cmet.2022.11.003.
Zheng Gong  1 ,  Qing Li  1 ,  Jiayuan Shi  1 ,  Edison T Liu  2 ,  Leonard D Shultz  1 ,  Guangwen Ren  3
Affiliations
  • 1. The Jackson Laboratory, Bar Harbor, ME 04609, USA.
  • 2. The Jackson Laboratory for Genomic Medicine, Farmington, CT 06030, USA.
  • 3. The Jackson Laboratory, Bar Harbor, ME 04609, USA; Tufts University School of Medicine, Boston, MA 02111, USA; Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME 04469, USA. Electronic address: [email protected].
PMID: 36476935 DOI: 10.1016/j.cmet.2022.11.003
Abstract

While the distant organ environment is known to support metastasis of primary tumors, its metabolic roles in this process remain underdetermined. Here, in breast Cancer models, we found lung-resident mesenchymal cells (MCs) accumulating neutral lipids at the pre-metastatic stage. This was partially mediated by interleukin-1β (IL-1β)-induced hypoxia-inducible lipid droplet-associated (HILPDA) that subsequently represses adipose triglyceride Lipase (ATGL) activity in lung MCs. MC-specific ablation of the ATGL or HILPDA genes in mice reinforced and reduced lung metastasis of breast Cancer respectively, suggesting a metastasis-promoting effect of lipid-laden MCs. Mechanistically, lipid-laden MCs transported their lipids to tumor cells and natural killer (NK) cells via exosome-like vesicles, leading to heightened tumor cell survival and proliferation and NK cell dysfunction. Blockage of IL-1β, which was effective singly, improved the efficacy of adoptive NK cell immunotherapy in mitigating lung metastasis. Collectively, lung MCs metabolically regulate tumor cells and anti-tumor immunity to facilitate breast Cancer lung metastasis.

Keywords
IL-1β; NK cells; breast cancer; disseminated tumor cells; inflammation; lipid storage; lung metastasis; mesenchymal cells; metabolic reprograming; triglycerides.
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