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

Animals Cell Line, Tumor Chemokines Humans Lung / metabolism Mice Neovascularization, Pathologic / drug therapy Triple Negative Breast Neoplasms / drug therapy
FOXC1 chemokine cholesterol lung fibroblasts lung metastasis triple-negative breast cancer

Journal

Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581

Informations de publication

Date de publication:
02 02 2022
Historique:
received: 28 01 2021
revised: 19 05 2021
accepted: 22 06 2021
pubmed: 19 7 2021
medline: 8 4 2022
entrez: 18 7 2021
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.ymthe.2021.07.003 PMID: 34274535 PMC: PMC8821896
pubmed: 34274535
pii: S1525-0016(21)00357-9
doi: 10.1016/j.ymthe.2021.07.003
pmc: PMC8821896
pii:
doi:

Substances chimiques

Chemokines 0

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

672-687

Subventions

Organisme : NCI NIH HHS
ID : R01 CA140995
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA151610
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA258204
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA129822
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA270324
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001881
Pays : United States

Informations de copyright

Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests The authors declare no competing interests.

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Auteurs

Bingchen Han (B)

Department of Surgery, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address: bingchen.han@cshs.org.

Felix Alonso-Valenteen (F)

Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Zhe Wang (Z)

Department of Pathology, Shengjing Hospital of China Medical University, Shenyang 110004, China.

Nan Deng (N)

Biostatistics and Bioinformatics Research Center, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Tian-Yu Lee (TY)

Department of Surgery, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Bowen Gao (B)

Department of Surgery, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Ying Zhang (Y)

Department of Pathology, Shengjing Hospital of China Medical University, Shenyang 110004, China.

Yali Xu (Y)

Department of Breast Surgery, Peking Union Medical College Hospital, Beijing 100730, China.

Xinfeng Zhang (X)

Department of Surgery, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Sandrine Billet (S)

Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Xuemo Fan (X)

Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Stephen Shiao (S)

Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Neil Bhowmick (N)

Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Lali Medina-Kauwe (L)

Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Armando Giuliano (A)

Department of Surgery, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Xiaojiang Cui (X)

Department of Surgery, Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address: xiaojiang.cui@cshs.org.

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Classifications MeSH

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questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Chimiokines › A chemokine regulatory loop induces...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › A chemokine regulatory loop induces...
questionsmedicales.fr › Appareil respiratoire › Poumon › A chemokine regulatory loop induces...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › A chemokine regulatory loop induces...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Métaplasie › Néovascularisation pathologique › A chemokine regulatory loop induces...
questionsmedicales.fr › Maladies de la peau et du tissu conjonctif › Maladies de la peau › Maladies du sein › Tumeurs du sein › Tumeurs du sein triple-négatives › A chemokine regulatory loop induces...