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

作者全名：Qiu, Yuxiang; Wang, Xing; Sun, Yan; Jin, Ting; Tang, Rui; Zhou, Xinyue; Xu, Ming; Gan, Yubi; Wang, Rui; Luo, Haojun; Liu, Manran; Tang, Xi

作者地址：[Qiu, Yuxiang; Tang, Xi] Chongqing Med Univ, Affiliated Hosp 1, Dept Lab Med, 1 Youyi Rd, Chongqing 400016, Peoples R China; [Qiu, Yuxiang; Jin, Ting; Tang, Rui; Zhou, Xinyue; Xu, Ming; Gan, Yubi; Wang, Rui; Liu, Manran] Chongqing Med Univ, Key Lab Lab Med Diagnost, Chinese Minist Educ, 1 Yi Xue Yuan Rd, Chongqing 400016, Peoples R China; [Qiu, Yuxiang] Nanchang Univ, Dept Clin Lab, Jiangxi Prov Key Lab Lab Med, Affiliated Hosp 2, Nanchang, Jiangxi, Peoples R China; [Wang, Xing; Luo, Haojun] Chongqing Med Univ, Affiliated Hosp 2, Dept Thyroid & Breast Surg, Chongqing, Peoples R China; [Sun, Yan] Chongqing Med Univ, Basic Med Sch, Dept Cell Biol & Med Genet, Chongqing, Peoples R China

通信作者：Tang, X (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Lab Med, 1 Youyi Rd, Chongqing 400016, Peoples R China.; Liu, MR (通讯作者)，Chongqing Med Univ, Key Lab Lab Med Diagnost, Chinese Minist Educ, 1 Yi Xue Yuan Rd, Chongqing 400016, Peoples R China.

来源：CANCER RESEARCH

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001238377200007

JCR分区：Q1

影响因子：12.5

年份：2024

卷号：84

期号：11

开始页：1856

结束页：1871

文献类型：Article

关键词：　

摘要：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 beta 1 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.

基金机构：National Natural Science Foundation of China (NSFC) [NSFC82173155, NSFC81874199]; National Natural Science Foundation of China [2023YNFY12035, 2022MD723743]; National Natural Science Foundation Incubation Project of The Second Affiliated Hospital of Nanchang University [MOST 2018YFE0113700]; National Key Projects of the Ministry of Science and Technology of China [CXQT20012]; Innovation Research Group in Colleges and Universities Program of Chongqing Municipal Education Commission; Outstanding Professorship Program of Chongqing Medical University [CSTB2023NSCQ-MSX0081]; Foundation of Chongqing

基金资助正文：This work was supported in part by the National Natural Science Foundation of China (NSFC81802653) to Xi Tang; National Natural Science Foundation Incubation Project of The Second Affiliated Hospital of Nanchang University (2023YNFY12035) to Yuxiang Qiu; China Postdoctoral Science Foundation (2022MD723743) to Xing Wang; and also partly supported by the National Key Projects of the Ministry of Science and Technology of China (MOST 2018YFE0113700), National Natural Science Foundation of China (NSFC82173155, NSFC81874199), Innovation Research Group in Colleges and Universities Program of Chongqing Municipal Education Commission (No. CXQT20012), the Outstanding Professorship Program of Chongqing Medical University to Manran Liu. Natural Science, and Foundation of Chongqing to Xing Wang (CSTB2023NSCQ-MSX0081).