Metabolomics reveals that CAF-derived lipids promote colorectal cancer peritoneal metastasis by enhancing membrane fluidity.
Metabolomics reveals that CAF-derived lipids promote colorectal cancer peritoneal metastasis by enhancing membrane fluidity.
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代谢组学揭示 CAF 衍生脂质通过增强膜流动性促进结直肠癌腹膜转移
DOI：
10.7150/ijbs.68484
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发表时间：
2022
影响因子：
9.2
通讯作者：
Liu X
中科院分区：
文献类型：
--
作者：
Peng S;Li Y;Huang M;Tang G;Xie Y;Chen D;Hu Y;Yu T;Cai J;Yuan Z;Wang H;Wang H;Luo Y;Liu X
结直肠癌（CRC）腹膜转移（PM）患者的总体生存结果比无腹膜转移患者更差。癌相关成纤维细胞（CAFs）是肿瘤微环境的主要组成部分，介导CRC进展和腹膜转移。识别并开发针对由CAFs驱动的腹膜转移结直肠癌的新型治疗靶点至关重要。利用脂质组学，我们发现临床腹膜转移结直肠癌标本中含不饱和酰基链的磷脂酰胆碱（PC）含量增加。此外，我们发现原发性腹膜转移结直肠癌肿瘤中CAFs的相对丰度较高，并且通过三种独立方法（脂质组学、光漂白后荧光恢复（FRAP）和广义极化）发现，CRC细胞在与CAF条件培养基（CM）孵育后膜流动性增加。然后，我们发现膜流动性增加可增强葡萄糖摄取和代谢，实时生物能量学分析和U - 13C葡萄糖标记结果支持了这一点。有趣的是，硬脂酰辅酶A去饱和酶1（SCD），即不饱和脂肪酸（uS - FAs）生物合成中的限速酶，在腹膜转移中表达水平较低，且与CRC患者的不良预后相关。重要的是，通过非靶向代谢组学分析和脂肪酸（[U - 13C] - 硬脂酸）示踪分析，我们发现CRC细胞摄取CAFs分泌的脂质和类脂质代谢物，这可能弥补了SCD的低表达。体外和体内实验均表明，棕榈酸钠（C16:0）处理可降低CAF诱导的细胞膜流动性变化，限制葡萄糖代谢，抑制细胞侵袭，并损害肿瘤生长和腹腔内播散。研究表明，C16:0浓度增加可诱导与脂毒性相关的细胞凋亡。此外，C16:0在体外有效增强了5 - 氟尿嘧啶（5 - FU）的抗肿瘤活性，在体内具有良好的耐受性。综上所述，这些发现表明，在新辅助化疗中添加饱和脂肪酸（S - FA）C16:0可能为未来治疗腹膜转移结直肠癌开辟新的机会。
Patients with peritoneal metastasis (PM) of colorectal cancer (CRC) have poorer overall survival outcomes than those without PM. Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment and mediate CRC progression and PM. It is imperative to identify and develop novel therapeutic targets for PM-CRC driven by CAFs. Using lipidomics, we reveal that the abundance of phosphatidylcholine (PC) with unsaturated acyl chains was increased in clinical PM-CRC specimens. Additionally, we found that CAFs were present at a higher relative abundance in primary PM-CRC tumors and that membrane fluidity in CRC cells was increased after incubation with CAF-conditioned medium (CM) through three independent methods: lipidomics, fluorescence recovery after photobleaching (FRAP), and generalized polarization. Then, we found that increased membrane fluidity can enhance glucose uptake and metabolism, as supported by real-time bioenergetics analysis and U-13C glucose labeling. Interestingly, stearoyl-CoA desaturase 1 (SCD), the rate-limiting enzyme in the biosynthesis of unsaturated fatty acids (uS-FAs), was expressed at low levels in PM and associated with poor prognosis in CRC patients. Importantly, by untargeted metabolomics analysis and fatty acid ([U-13C]-stearic acid) tracing analyses, we found that CRC cells take up lipids and lipid-like metabolites secreted from CAFs, which may compensate for low SCD expression. Both in vitro and in vivo experiments demonstrated that sodium palmitate (C16:0) treatment could decrease the CAF-induced change in cell membrane fluidity, limit glucose metabolism, suppress cell invasiveness, and impair tumor growth and intraperitoneal dissemination. An increased C16:0 concentration was shown to induce apoptosis linked to lipotoxicity. Furthermore, C16:0 effectively enhanced the antitumor activity of 5-fluorouracil (5-FU) in vitro and was well tolerated in vivo. Taken together, these findings suggest that adding the saturated fatty acid (S-FA) C16:0 to neoadjuvant chemotherapy may open new opportunities for treating PM-CRC in the future.
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单端孢菌素抑制与 SCD-1 介导的代谢物改变相关的结肠癌的侵袭和转移
DOI：
10.1016/j.bbalip.2019.158540
发表时间：
2020-02-01
影响因子：
4.8
作者：
Liao, Chaoliang;Li, Min;Luo, Xiangjian
通讯作者：
Luo, Xiangjian
DOI：
10.1111/j.1440-1746.1989.tb00829.x
发表时间：
1989-05-01
影响因子：
4.1
作者：
BENEDETTI, A;FERRETTI, G;ORLANDI, F
通讯作者：
ORLANDI, F
影响因子：
13.5
作者：
Lin, Ling;Ding, Ying;Shen, Huali
通讯作者：
Shen, Huali
硬脂酰-COA去饱和酶1和旁分泌可扩散信号在促进由癌症相关的成纤维细胞诱导的乳腺癌细胞迁移中起着重要作用。
影响因子：
8.8
作者：
Angelucci, C.;Maulucci, G.;Colabianchi, A.;Iacopino, F.;D'Alessio, A.;Maiorana, A.;Palmieri, V.;Papi, M.;De Spirito, M.;Di Leone, A.;Masetti, R.;Sica, G.
通讯作者：
Sica, G.
影响因子：
29
作者：
Curtis M;Kenny HA;Ashcroft B;Mukherjee A;Johnson A;Zhang Y;Helou Y;Batlle R;Liu X;Gutierrez N;Gao X;Yamada SD;Lastra R;Montag A;Ahsan N;Locasale JW;Salomon AR;Nebreda AR;Lengyel E
通讯作者：
Lengyel E