J Exp Clin Cancer Res|Georgia Konstantinidou团队指出胞外脂质限制促使胰腺癌依赖于自噬

2022年8月3日 0条评论 229次阅读 0人点赞

最新细胞功能及机制文献分享

据报道，KRAS是胰腺导管腺癌（PDAC）突变的主要癌基因，PDAC患者5年生存率约为10%，主要是由于晚期诊断、治疗抵抗和快速复发导致的。尽管目前已有批准的靶向药可用于治疗一些KRAS驱动的肿瘤，例如肺癌和结直肠癌，但尚未发现针对PDAC的有效靶向治疗药。因此，迫切需要新的PDAC治疗方法。

2022年1月8日，瑞士伯尔尼大学药理研究所Georgia Konstantinidou团队在Journal of Experimental and Clinical Cancer Research上发表了题为“Restriction of extracellular lipids renders pancreatic cancer dependent on autophagy”的研究论文。介于突变KRAS驱动的肿瘤可通过代谢重编程程序支持其生长和存活，可用于识别代谢漏洞。在本研究中，团队旨在了解细胞外衍生脂肪酸（FAs）在KRAS驱动PDAC中的作用。揭示了细胞外脂质供应在确保癌细胞中脂肪酸供应方面的核心作用，指出了以前未被发现的PDAC代谢漏洞。

一种已知的KRAS驱动肿瘤代谢适应性就是清除胞外不饱和FAs。团队前期研究发现，ACSL3在KRAS驱动的肺癌和胰腺癌中过度表达。在此项研究中，团队为了评估PDAC细胞对细胞外FAs的依赖性，采用脱脂血清或RNAi介导的ACSL3抑制（抑制细胞外FAs活化和细胞保留）后，进行了细胞增殖测定、qPCR、凋亡测定、免疫印迹和荧光显微镜实验。接下来，为评估体内自噬，团队采用了Kras^G12D/+; p53^flox/flox; Pdx1-Cre^ERT2 (KPC)小鼠与Acsl3基因敲除小鼠杂交，并采用异种移植人源性肿瘤模型评估了ACSL3与自噬抑制联合治疗免疫功能低下小鼠的疗效。

研究结果显示，限制细胞外衍生的FA会降低胰腺癌细胞的增殖，同时对胰腺癌细胞的存活产生不同的影响。限制血脂或抑制ACSL3后，会消耗细胞外衍生的脂质进而触发自噬，即限制细胞外衍生的FAs会导致自噬通量的补偿性增加。接下来的联合细胞外脂质剥夺和自噬抑制在体外对PDAC细胞系表现出抗增殖和促凋亡作用，并促进对小鼠异种移植人胰腺癌细胞衍生肿瘤的抑制。也就是说，自噬的药理学抑制增强了细胞外脂质限制介导的细胞死亡诱导并抑制了PDAC生长。至此，团队为脂质剥夺和自噬阻断作为治疗PDAC的潜在联合靶向策略提供了理论基础。

《J Exp Clin Cancer Res|Georgia Konstantinidou团队指出胞外脂质限制促使胰腺癌依赖于自噬》

图本文部分实验结果图。

期刊及DOI号

J Exp Clin Cancer Res. 2022 Jan 8.

doi: 10.1186/s13046-021-02231-y.

题目

Restriction of extracellular lipids renders pancreatic cancer dependent on autophagy

摘要

背景：KRAS is the predominant oncogene mutated in pancreatic ductal adenocarcinoma (PDAC), the fourth cause of cancer-related deaths worldwide. Mutant KRAS-driven tumors are metabolically programmed to support their growth and survival, which can be used to identify metabolic vulnerabilities. In the present study, we aimed to understand the role of extracellularly derived fatty acids in KRAS-driven pancreatic cancer.

方法：To assess the dependence of PDAC cells on extracellular fatty acids we employed delipidated serum or RNAi-mediated suppression of ACSL3 (to inhibit the activation and cellular retention of extracellular fatty acids) followed by cell proliferation assays, qPCR, apoptosis assays, immunoblots and fluorescence microscopy experiments. To assess autophagy in vivo, we employed the Kras^G12D/+; p53^flox/flox; Pdx1-Cre^ERT2(KPC) mice crossed with Acsl3 knockout mice, and to assess the efficacy of the combination therapy of ACSL3 and autophagy inhibition we used xenografted human cancer cell-derived tumors in immunocompromised mice.

结果：Here we show that depletion of extracellularly derived lipids either by serum lipid restriction or suppression of ACSL3, triggers autophagy, a process that protects PDAC cells from the reduction of bioenergetic intermediates. Combined extracellular lipid deprivation and autophagy inhibition exhibits anti-proliferative and pro-apoptotic effects against PDAC cell lines in vitro and promotes suppression of xenografted human pancreatic cancer cell-derived tumors in mice. Therefore, we propose lipid deprivation and autophagy blockade as a potential co-targeting strategy for PDAC treatment.

结论：Our work unravels a central role of extracellular lipid supply in ensuring fatty acid provision in cancer cells, unmasking a previously unappreciated metabolic vulnerability of PDAC cells.

关键词：Pancreatic cancer, Lipid metabolism, Extracellular lipids, Combination therapy, Tumor metabolic vulnerabilities