Tumor resistance to ferroptosis driven by Stearoyl-CoA Desaturase-1 (SCD1) in cancer cells and Fatty Acid Biding Protein-4 (FABP4) in tumor microenvironment promote tumor recurrence.
Tumor resistance to ferroptosis driven by Stearoyl-CoA Desaturase-1 (SCD1) in cancer cells and Fatty Acid Biding Protein-4 (FABP4) in tumor microenvironment promote tumor recurrence.
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肿瘤对由癌细胞中的硬脂酰辅酶A去饱和酶-1（SCD 1）和肿瘤微环境中的脂肪酸结合蛋白-4（FABP 4）驱动的铁凋亡的抵抗促进肿瘤复发。
DOI：
10.1016/j.redox.2021.102006
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发表时间：
2021-07
期刊：
影响因子：
11.4
通讯作者：
Sounni NE
中科院分区：
文献类型：
--
作者：
Luis G;Godfroid A;Nishiumi S;Cimino J;Blacher S;Maquoi E;Wery C;Collignon A;Longuespée R;Montero-Ruiz L;Dassoul I;Maloujahmoum N;Pottier C;Mazzucchelli G;Depauw E;Bellahcène A;Yoshida M;Noel A;Sounni NE
肿瘤复发是一个主要的临床问题，代表了癌症相关死亡的主要原因，几乎没有可靶向的共同途径。新辅助治疗后，残留肿瘤在缺氧-复氧之间的持续转换下持续存在和进展的机制尚不清楚。在这项研究中，我们研究了脂质代谢和肿瘤氧化还原平衡在肿瘤复发中的作用。脂质组学、蛋白质组学和质谱成像方法应用于复发的小鼠肿瘤模型。肿瘤中脂质介质的遗传和药理学抑制用于体内和体外功能测定。我们发现，由癌细胞表达的硬脂酰辅酶A去饱和酶-1（SCD 1）和由肿瘤微环境（TME）中的肿瘤内皮细胞（TEC）和脂肪细胞产生的脂肪酸结合蛋白-4（FABP 4）对酪氨酸激酶抑制剂（TKI）和化疗的肿瘤复发至关重要。SCD 1和FABP 4在复发的人乳腺癌样品中也被发现上调，并且与患有不同类型肿瘤的癌症患者的预后较差相关。从机制上讲，SCD 1导致脂肪酸（FA）去饱和，而来自TEM的FABP 4增强了癌细胞中的脂滴（LD），它们协同保护免受氧化应激诱导的铁凋亡。我们发现，脂质动员和去饱和引发肿瘤内在的抗氧化剂和抗铁源生存和再生长在一个苛刻的TME。通过FABP 4抑制剂抑制TME的脂质转运减少了肿瘤再生长，并且通过体内遗传或药理学靶向SCD 1，肿瘤再生长被完全消除。这一发现揭示了利用肿瘤脂质成瘾作为肿瘤的脆弱性来设计新的治疗策略以预防癌症复发是值得的。残余肿瘤中氧化应激标志物和脂质代谢增加。癌细胞中的SCD 1和肿瘤微环境中的FABP 4的表达驱动肿瘤复发。通过SCD 1的脂肪酸去饱和和通过FABP 4的脂质转运赋予对ROS和铁凋亡的抗性。阻断SCD 1和FABP 4可使癌细胞对ROS诱导的铁凋亡敏感，并减少肿瘤复发。
Tumor recurrence is a major clinical issue that represents the principal cause of cancer-related deaths, with few targetable common pathways. Mechanisms by which residual tumors persist and progress under a continuous shift between hypoxia-reoxygenation after neoadjuvent-therapy are unknown. In this study, we investigated the role of lipid metabolism and tumor redox balance in tumor recurrence. Lipidomics, proteomics and mass spectrometry imaging approaches where applied to mouse tumor models of recurrence. Genetic and pharmacological inhibitions of lipid mediators in tumors were used in vivo and in functional assays in vitro. We found that stearoyl-CoA desaturase-1 (SCD1) expressed by cancer cells and fatty acid binding protein-4 (FABP4) produced by tumor endothelial cells (TECs) and adipocytes in the tumor microenvironment (TME) are essential for tumor relapse in response to tyrosine kinase inhibitors (TKI) and chemotherapy. SCD1 and FABP4 were also found upregulated in recurrent human breast cancer samples and correlated with worse prognosis of cancer patients with different types of tumors. Mechanistically, SCD1 leads to fatty acid (FA) desaturation and FABP4 derived from TEM enhances lipid droplet (LD) in cancer cells, which cooperatively protect from oxidative stress-induced ferroptosis. We revealed that lipid mobilization and desaturation elicit tumor intrinsic antioxidant and anti-ferroptotic resources for survival and regrowth in a harsh TME. Inhibition of lipid transport from TME by FABP4 inhibitor reduced tumor regrowth and by genetic — or by pharmacological — targeting SCD1 in vivo, tumor regrowth was abolished completely. This finding unveils that it is worth taking advantage of tumor lipid addiction, as a tumor vulnerability to design novel treatment strategy to prevent cancer recurrence. Increased oxidative stress markers and lipid metabolism in residual tumors. Expression of SCD1 in cancer cells and FABP4 in the tumor microenvironment drive tumor recurrence. Fatty acid desaturation by SCD1 and lipid transport by FABP4 confer resistance to ROS and ferroptosis. Blocking SCD1 and FABP4 sensitized cancer cells to ROS-induced ferroptosis and reduced tumor recurrence.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
46.9
作者：
通讯作者：
--
LKB1 失活会引发氧化还原失衡，从而调节非小细胞肺癌的可塑性和治疗反应。
影响因子：
50.3
作者：
Li F;Han X;Li F;Wang R;Wang H;Gao Y;Wang X;Fang Z;Zhang W;Yao S;Tong X;Wang Y;Feng Y;Sun Y;Li Y;Wong KK;Zhai Q;Chen H;Ji H
通讯作者：
Ji H
影响因子：
19
作者：
Ackerman, Daniel;Simon, M. Celeste
通讯作者：
Simon, M. Celeste
影响因子：
29
作者：
Corbet, Cyril;Pinto, Adan;Feron, Olivier
通讯作者：
Feron, Olivier