KRAS Controls Pancreatic Cancer Cell Lipid Metabolism and Invasive Potential through the Lipase HSL.
KRAS Controls Pancreatic Cancer Cell Lipid Metabolism and Invasive Potential through the Lipase HSL.
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KRAS通过脂肪酶HSL控制胰腺癌细胞的脂质代谢和侵袭潜力。
DOI：
10.1158/0008-5472.can-20-1255
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发表时间：
2020-11-15
期刊：
影响因子：
11.2
通讯作者：
Razidlo GL
中科院分区：
文献类型：
--
作者：
Rozeveld CN;Johnson KM;Zhang L;Razidlo GL
癌基因诱导的代谢重编程是胰腺癌（PDAC）的标志，但转移的代谢驱动因素尚不清楚。在PDAC中，肥胖和过量脂肪酸加速肿瘤生长并增加转移。在这里，我们报告了储存在称为脂滴（LD）的细胞器中的过量脂质是促进能量密集型转移过程的关键资源。癌基因KRAS通过调节激素敏感脂肪酶（HSL）来控制LD的储存和利用，HSL在人PDAC中下调。KRAS-HSL轴的破坏减少了脂质储存，重编程肿瘤细胞代谢，并抑制体外侵袭性迁移和体内转移。最后，基于显微镜的代谢分析表明，迁移细胞选择性地利用氧化代谢过程中的迁移代谢储存的脂质和燃料侵入性迁移。总之，这些结果揭示了可以靶向减弱PDAC转移的机制。
Oncogene-induced metabolic reprogramming is a hallmark of pancreatic cancer (PDAC), yet the metabolic drivers of metastasis are unclear. In PDAC, obesity and excess fatty acids accelerate tumor growth and increase metastasis. Here, we report that excess lipids, stored in organelles called lipid droplets (LD), are a key resource to fuel the energy-intensive process of metastasis. The oncogene KRAS controlled the storage and utilization of LD through regulation of hormone sensitive lipase (HSL), which was downregulated in human PDAC. Disruption of the KRAS-HSL axis reduced lipid storage, reprogrammed tumor cell metabolism, and inhibited invasive migration in vitro and metastasis in vivo. Finally, microscopy-based metabolic analysis revealed that migratory cells selectively utilize oxidative metabolism during the process of migration to metabolize stored lipids and fuel invasive migration. Taken together, these results reveal a mechanism that can be targeted to attenuate PDAC metastasis.