Mutant KRAS Downregulates the Receptor for Leukemia Inhibitory Factor (LIF) to Enhance a Signature of Glycolysis in Pancreatic Cancer and Lung Cancer.
Mutant KRAS Downregulates the Receptor for Leukemia Inhibitory Factor (LIF) to Enhance a Signature of Glycolysis in Pancreatic Cancer and Lung Cancer.
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DOI：
10.1158/1541-7786.mcr-20-0633
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发表时间：
2021-08
期刊：
影响因子：
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通讯作者：
Frank DA
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文献类型：
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作者：
Liu S;Gandler HI;Tošić I;Ye DQ;Giaccone ZT;Frank DA
胰腺癌的特点是致癌KRAS的异常活性，在90%的胰腺腺癌中发生突变。由于KRAS本身是一个具有挑战性的治疗靶点，我们专注于了解KRAS驱动的关键信号通路，以此作为揭示治疗干预依赖性的一种方式。对原发性人类胰腺癌和模型系统的分析显示，突变的KRAS下调了细胞因子白血病抑制因子（LIF）的受体。此外，下调LIF受体（LIFR）对于kras介导的肿瘤转化是必要的。我们发现LIFR通过抑制葡萄糖转运蛋白GLUT1的表达对kras介导的转化有抑制作用，GLUT1是kras驱动的恶性肿瘤中糖酵解增强的关键介质。LIFR表达降低导致GLUT1升高，糖酵解和线粒体呼吸增加。LIFR对GLUT1的抑制是由转录因子STAT3介导的，这表明STAT3在KRAS突变的癌细胞中具有肿瘤抑制作用。最后，在KRAS突变的胰腺癌患者中，LIFR表达降低与较短的生存期相关，这反映了LIFR在临床上重要的肿瘤抑制作用。在KRAS突变驱动的非小细胞肺癌中也发现了类似的结果，这表明沉默LIFR是KRAS介导的细胞转化的一种普遍机制。这些结果表明，根据肿瘤细胞的遗传背景，LIFR/STAT3通路可能介导促瘤或抑瘤信号通路，并可能在肿瘤微环境的其他细胞中发挥不同的作用。
Pancreatic cancer is characterized by aberrant activity of oncogenic KRAS, which is mutated in 90% of pancreatic adenocarcinomas. Since KRAS itself is a challenging therapeutic target, we focused on understanding key signaling pathways driven by KRAS as a way to reveal dependencies that are amenable to therapeutic intervention. Analyses in primary human pancreatic cancers and model systems revealed that the receptor for the cytokine leukemia inhibitory factor (LIF) is down-regulated by mutant KRAS. Furthermore, down-regulation of the LIF receptor (LIFR) is necessary for KRAS-mediated neoplastic transformation. We found LIFR exerts inhibitory effects on KRAS-mediated transformation by inhibiting expression of the glucose transporter GLUT1, a key mediator of the enhanced glycolysis found in KRAS-driven malignancies. Decreased LIFR expression leads to increased GLUT1 as well as increases in glycolysis and mitochondrial respiration. The repression of GLUT1 by LIFR is mediated by the transcription factor STAT3, indicating a tumor suppressive role for STAT3 within cancer cells with mutated KRAS. Finally, reflecting a clinically important tumor suppressive role of LIFR, decreased LIFR expression correlates with shorter survival in pancreatic cancer patients with mutated KRAS. Similar findings were found in non-small cell lung cancers driven by mutated KRAS, suggesting that silencing LIFR is a generalized mechanism of KRAS-mediated cellular transformation. These results indicate that the LIFR/STAT3 pathway may mediate either tumor promoting or tumor suppressive signaling pathways depending on the genetic background of tumor cells, and may play diverse roles within other cells in the tumor microenvironment.