Mutant KRAS Downregulates the Receptor for Leukemia Inhibitory Factor (LIF) to Enhance a Signature of Glycolysis in Pancreatic Cancer and Lung Cancer

Abstract

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 KRASmediated 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.

STAT3 as a mediator of oncogenic cellular metabolism: Pathogenic and therapeutic implications

“…However, Ras-transformation and STAT3 signaling are found to be mutually exclusive in pancreatic cancers, in which KRAS mutation occurs at a 90% frequency ( 90 ). Analyses of primary human pancreatic adenocarcinomas and pancreatic cancer cellular systems showed that the LIF receptor is significantly downregulated in cancers with mutated KRAS, and this downregulation of LIFR was necessary for KRAS-mediated neoplastic transformation.…”

Cancer-Associated Fibroblasts and Tumor Cells in Pancreatic Cancer Microenvironment and Metastasis: Paracrine Regulators, Reciprocation and Exosomes

“…Increased serum LIF is a biomarker to predict lymph node metastasis and distant metastasis in pancreatic cancer patients [43]. Another study, however, showed that expression of LIFR was associated with longer overall survival of pancreatic cancer patients [44]. Oncogenic KRAS downregulates LIFR.…”

“…Oncogenic KRAS downregulates LIFR. Downregulation of LIFR is important for KRAS-mediated neoplastic transformation [44]. Wang et al showed that oncogenic KRAS induced LIF expression in pancreatic cancer cells, where the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling is essential [45].…”

Long Noncoding RNAs and Circular RNAs in the Metabolic Reprogramming of Lung Cancer: Functions, Mechanisms, and Clinical Potential

“…KRAS is an important oncogene in various cancers; mutant KRAS induces an increase in the expression of GLUT1, glycolysis, and mitochondrial respiration [ 68 ]. As a cellular energy sensor and modulator, AMP-activated protein kinase (AMPK) behavior in tumorigenesis remains largely unsolved.…”