Hou Pei-Pei, Zheng Chong-Ming, Wu Si-Hong, Liu Xi-Xiao, Xiang Guang-Xin, Cai Wei-Yang, Chen Gang, Lou Yong-Liang
Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, P.R. China.
Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, P.R. China.
Cancer Res. 2024 Dec 2;84(23):3953-3966. doi: 10.1158/0008-5472.CAN-24-0832.
Extracellular vesicles (EV) derived from cancer cells are crucial mediators of intercellular communication during tumor progression. The cargo in tumor-derived EVs that facilitates the establishment of a tumor-supportive microenvironment could serve as a therapeutic target to improve cancer treatment. Here, we demonstrated that hepatocellular carcinoma (HCC) cells secreted the acyl-CoA synthetase long-chain family member 4 (ACSL4) in large EVs (lEV) to modulate tumor-microenvironment interactions that promote HCC progression. HCC-derived lEV ACSL4 increased the intracellular abundance of polyunsaturated fatty acid-containing lipids and remodeled the lipid profile to potentiate lipid peroxidation in peritumoral hepatocytes, resulting in hepatocyte senescence accompanied by the senescence-associated secretory phenotype. Depletion of senescent hepatocytes by senolytic treatment suppressed tumor progression. In HCC cells, SREBP2-mediated transcriptional activation upregulated ACSL4 expression, and Akt-mediated phosphorylation of ACSL4 induced its packaging into lEVs by augmenting its interaction with Annexin A2. This study identified the critical regulatory function of ACSL4 secreted from HCC cells in inducing lipid remodeling and senescence in hepatocytes to support HCC progression, suggesting that targeting lEV ACSL4 is a potential therapeutic strategy for HCC. Significance: Peritumoral hepatocyte senescence mediated by ACSL4 secreted from hepatocellular carcinoma cells in extracellular vesicles promotes tumor progression through a senescence secretome and represents a therapeutic target in liver cancer.
癌细胞衍生的细胞外囊泡（EV）是肿瘤进展过程中细胞间通讯的关键介质。肿瘤来源的EV中的货物促进了肿瘤支持性微环境的建立，可作为改善癌症治疗的治疗靶点。在此，我们证明肝细胞癌（HCC）细胞在大型EV（lEV）中分泌酰基辅酶A合成酶长链家族成员4（ACSL4），以调节促进HCC进展的肿瘤-微环境相互作用。HCC来源的lEV ACSL4增加了含多不饱和脂肪酸脂质的细胞内丰度，并重塑脂质谱以增强肿瘤周围肝细胞中的脂质过氧化，导致肝细胞衰老并伴有衰老相关分泌表型。通过衰老细胞溶解疗法清除衰老肝细胞可抑制肿瘤进展。在HCC细胞中，SREBP2介导的转录激活上调了ACSL4的表达，而Akt介导的ACSL4磷酸化通过增强其与膜联蛋白A2的相互作用诱导其包装到lEV中。本研究确定了HCC细胞分泌的ACSL4在诱导肝细胞脂质重塑和衰老以支持HCC进展中的关键调节功能，表明靶向lEV ACSL4是HCC的一种潜在治疗策略。意义：细胞外囊泡中肝细胞癌细胞分泌的ACSL4介导的肿瘤周围肝细胞衰老通过衰老分泌组促进肿瘤进展，是肝癌的一个治疗靶点。
