A chemokine regulatory loop induces cholesterol synthesis in lung-colonizing triple-negative breast cancer cells to fuel metastatic growth

Bingchen Han; Felix Alonso-Valenteen; Zhe Wang; Nan Deng; Tian-Yu Lee; Bowen Gao; Ying Zhang; Yali Xu; Xinfeng Zhang; Sandrine Billet; Xuemo Fan; Stephen Shiao; Neil Bhowmick; Lali Medina-Kauwe; Armando Giuliano; Xiaojiang Cui

doi:10.1016/j.ymthe.2021.07.003

A chemokine regulatory loop induces cholesterol synthesis in lung-colonizing triple-negative breast cancer cells to fuel metastatic growth

Mol Ther. 2022 Feb 2;30(2):672-687. doi: 10.1016/j.ymthe.2021.07.003. Epub 2021 Jul 16.

Authors

Bingchen Han¹, Felix Alonso-Valenteen², Zhe Wang³, Nan Deng⁴, Tian-Yu Lee⁵, Bowen Gao⁵, Ying Zhang³, Yali Xu⁶, Xinfeng Zhang⁵, Sandrine Billet⁷, Xuemo Fan⁸, Stephen Shiao⁹, Neil Bhowmick⁷, Lali Medina-Kauwe², Armando Giuliano⁵, Xiaojiang Cui¹⁰

Affiliations

¹ Department of Surgery, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address: [email protected].
² Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
³ Department of Pathology, Shengjing Hospital of China Medical University, Shenyang 110004, China.
⁴ Biostatistics and Bioinformatics Research Center, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁵ Department of Surgery, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁶ Department of Breast Surgery, Peking Union Medical College Hospital, Beijing 100730, China.
⁷ Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁸ Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁹ Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
¹⁰ Department of Surgery, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address: [email protected].

Abstract

Triple-negative breast cancer (TNBC) has a high propensity for organ-specific metastasis. However, the underlying mechanisms are not well understood. Here we show that the primary TNBC tumor-derived C-X-C motif chemokines 1/2/8 (CXCL1/2/8) stimulate lung-resident fibroblasts to produce the C-C motif chemokines 2/7 (CCL2/7), which, in turn, activate cholesterol synthesis in lung-colonizing TNBC cells and induce angiogenesis at lung metastatic sites. Inhibiting cholesterol synthesis in lung-colonizing breast tumor cells by pulmonary administration of simvastatin-carrying HER3-targeting nanoparticles reduces angiogenesis and growth of lung metastases in a syngeneic TNBC mouse model. Our findings reveal a novel, chemokine-regulated mechanism for the cholesterol synthesis pathway and a critical role of metastatic site-specific cholesterol synthesis in the pulmonary tropism of TNBC metastasis. The study has implications for the unresolved epidemiological observation that use of cholesterol-lowering drugs has no effect on breast cancer incidence but can unexpectedly reduce breast cancer mortality, suggesting interventions of cholesterol synthesis in lung metastases as an effective treatment to improve survival in individuals with TNBC.

Keywords: FOXC1; chemokine; cholesterol; lung fibroblasts; lung metastasis; triple-negative breast cancer.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Cell Line, Tumor
Chemokines
Humans
Lung / metabolism
Mice
Neovascularization, Pathologic / drug therapy
Neovascularization, Pathologic / genetics
Triple Negative Breast Neoplasms* / drug therapy
Triple Negative Breast Neoplasms* / genetics

Substances

Chemokines

Abstract

Publication types

MeSH terms

Substances

Grants and funding