One of the hallmarks of pancreatic cancer is aberrant activity of oncogenic KRAS, which is mutated and constitutively activated in greater than 90% of pancreatic adenocarcinomas. While KRAS itself is a challenging therapeutic target, we have focused on understanding the key signaling pathways driven by KRAS, which may reveal dependencies that are amenable to therapeutic intervention. By performing bioinformatics analysis on primary human pancreatic cancers coupled with validation in cancer cell lines, we found that the receptor for the cytokine leukemia inhibitory factor (LIF) was downregulated by mutant KRAS. Furthermore, downregulation of the LIF receptor (LIFR) was necessary for KRAS-mediated neoplastic transformation. One of the key features of KRAS-driven cancer is enhanced glycolysis. 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. Interestingly, this downregulation 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 findings highlight the intriguing concept that the LIFR/STAT3 pathway may mediate either tumor-promoting or tumor-suppressive signaling pathways, depending on cellular genetic background and specific cell types, even within one cancerous tissue. For example, while LIF in the tumor microenvironment may act on pancreatic stellate cells to promote dense stromal formation, activation of LIFR/STAT3 within pancreatic cancer cells limits cell survival. The inhibition of LIFR expression in pancreatic cancer cells upregulates GLUT1 levels in order to support the enhanced glycolysis necessary for malignant transformation. This selective silencing of LIFR within cancer cells allows the pancreatic cancer cells to evade the inhibitory effects of LIF, while other cells in the tumor microenvironment have increased function in the presence of LIF. Therefore, the elucidation of the complex role of the LIF/LIFR/STAT3 axis in pancreatic cancer is essential to allow the design of rational therapeutic interventions for patients with pancreatic cancer.
Citation Format: Suhu Liu, Helen I. Gandler, Sarah R. Walker, Darwin Q. Ye, Zachary T. Giaccone, Jonathan A. Nowak, Andrew J. Aguirre, Brian M. Wolpin, David A. Frank. Mutant KRAS downregulates LIFR to enhance glycolysis in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B32.