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

Document Type

Article

Publication Date

12-6-2022

Publication Title

Cell Metab

Keywords

JGM, JMG, Animals, Mice, Killer Cells, Natural, Lung Neoplasms, Lung, Lipids

JAX Source

Cell Metab. 2022;34(12):1960-76.e9.

Volume

34

Issue

12

First Page

1960

Last Page

1976

ISSN

1932-7420

PMID

36476935

DOI

https://doi.org/10.1016/j.cmet.2022.11.003

Grant

This work was supported by grants from National Institutes of Health, United States (R00-CA188093, R37-CA237307, R01-CA251433, and P30-CA034196 to G.R. and R24-OD026440 to L.D.S.). Z.G. is supported by the Brooks Scholar Award Program at The Jackson Laboratory, United States.

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.

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