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

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

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]
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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