ACSL4-Mediated Membrane Phospholipid Remodeling Induces Integrin β1 Activation to Facilitate Triple-Negative Breast Cancer Metastasis

Author:

Qiu Yuxiang123ORCID,Wang Xing4ORCID,Sun Yan5ORCID,Jin Ting2ORCID,Tang Rui2ORCID,Zhou Xinyue2ORCID,Xu Ming2ORCID,Gan Yubi2ORCID,Wang Rui2ORCID,Luo Haojun4ORCID,Liu Manran2ORCID,Tang Xi1ORCID

Affiliation:

1. 1Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.

2. 2Key Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, Chongqing, China.

3. 3Department of Clinical Laboratory, Jiangxi Province Key Laboratory of Laboratory Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.

4. 4Department of Thyroid and Breast Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.

5. 5Department of Cell Biology and Medical Genetics, Basic Medical School, Chongqing Medical University, Chongqing, China.

Abstract

Abstract Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and has a poor prognosis and a high propensity to metastasize. Lipid metabolism has emerged as a critical regulator of tumor progression and metastasis in other cancer types. Characterization of the lipid metabolic features of TNBC could provide important insights into the drivers of TNBC metastasis. Here, we showed that metastatic TNBC tumors harbor more unsaturated phospholipids, especially long-chain polyunsaturated fatty acids, at the sn-2 position of phosphatidylcholine and phosphatidylethanolamine compared with primary tumors. Metastatic TNBC tumors upregulated ACSL4, a long-chain polyunsaturated acyl-CoA synthetase that drives the preferential incorporation of polyunsaturated fatty acids into phospholipids, resulting in the alteration of membrane phospholipid composition and properties. Moreover, ACSL4-mediated phospholipid remodeling of the cell membrane induced lipid-raft localization and activation of integrin β1 in a CD47-dependent manner, which led to downstream focal adhesion kinase phosphorylation that promoted metastasis. Importantly, pharmacologic inhibition of ACSL4 suppressed tumor growth and metastasis and increased chemosensitivity in TNBC models in vivo. These findings indicate that ACSL4-mediated phospholipid remodeling enables TNBC metastasis and can be inhibited as a potential strategy to improve the efficacy of chemotherapy in TNBC. Significance: ACSL4 upregulation in triple-negative breast cancer alters cell membrane phospholipid composition to increase integrin β1 activation and drive metastasis, indicating that targeting ACSL4 could potentially block metastasis and improve patient outcomes.

Funder

National Natural Science Foundation of China

China Postdoctoral Science Foundation

Chongqing Municipal Education Commission

Publisher

American Association for Cancer Research (AACR)

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