Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Mol Cancer Res. 2021 Aug;19(8):1283-1295. doi: 10.1158/1541-7786.MCR-20-0633. Epub 2021 Apr 30.
Pancreatic cancer is characterized by aberrant activity of oncogenic KRAS, which is mutated in 90% of pancreatic adenocarcinomas. Because 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 downregulated by mutant KRAS. Furthermore, downregulation 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. IMPLICATIONS: Mutant KRAS drives downregulation of the receptor for LIF, thereby allowing an increase in expression of the glucose transporter GLUT1 and increases in glycolysis and mitochondrial respiration.
胰腺癌的特征是致癌基因 KRAS 的异常活性，90%的胰腺腺癌都存在 KRAS 突变。由于 KRAS 本身是一个具有挑战性的治疗靶点，我们专注于理解 KRAS 驱动的关键信号通路，以此揭示可通过治疗干预来解决的依赖性。对原发性人胰腺肿瘤和模型系统的分析表明，细胞因子白血病抑制因子（LIF）的受体被突变的 KRAS 下调。此外，LIF 受体（LIFR）的下调对于 KRAS 介导的肿瘤转化是必需的。我们发现 LIFR 通过抑制葡萄糖转运蛋白 GLUT1 的表达来抑制 KRAS 介导的转化，GLUT1 是 KRAS 驱动的恶性肿瘤中增强的糖酵解的关键介质。LIFR 表达的降低导致 GLUT1 以及糖酵解和线粒体呼吸的增加。LIFR 通过转录因子 STAT3 抑制 GLUT1 的表达，表明突变的 KRAS 中的癌细胞中的 STAT3 具有肿瘤抑制作用。最后，反映 LIFR 的临床上重要的肿瘤抑制作用，LIFR 表达的降低与 KRAS 突变的胰腺癌患者的生存时间缩短相关。在由 KRAS 突变驱动的非小细胞肺癌中也发现了类似的发现，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，LIFR/STAT3 通路可能根据肿瘤细胞的遗传背景介导促进肿瘤或抑制肿瘤的信号通路，并可能在肿瘤微环境中的其他细胞中发挥多样化的作用。意义：突变的 KRAS 驱动 LIF 受体的下调，从而允许葡萄糖转运蛋白 GLUT1 的表达增加以及糖酵解和线粒体呼吸的增加。
