LIF/LIFR oncogenic signaling is a novel therapeutic target in endometrial cancer

Abstract

Endometrial cancer (EC) is the fourth most common cancer in women. Advanced-stage EC has limited treatment options with a poor prognosis. There is an unmet need for the identification of actionable drivers for the development of targeted therapies in EC. Leukemia inhibitory factor receptor (LIFR) and its ligand LIF play a major role in cancer progression, metastasis, stemness, and therapy resistance. However, little is known about the functional significance of the LIF/LIFR axis in EC progression. In this study using endometrial tumor tissue arrays, we identified that expression of LIF, LIFR is upregulated in EC. Knockout of LIFR using CRISPR/Cas9 in two different EC cells resulted in a significant reduction of their cell viability and cell survival. In vivo studies demonstrated that LIFR-KO significantly reduced EC xenograft tumor growth. Treatment of established and primary patient-derived EC cells with a novel LIFR inhibitor, EC359 resulted in the reduction of cell viability with an IC50 in the range of 20–100 nM and induction of apoptosis. Further, treatment with EC359 reduced the spheroid formation of EC cancer stem cells and reduced the levels of cancer stem cell markers SOX2, OCT4, NANOG, and Axin2. Mechanistic studies demonstrated that EC359 treatment attenuated the activation of LIF-LIFR driven pathways, including STAT3 and AKT/mTOR signaling in EC cells. Importantly, EC359 treatment resulted in a significant reduction of the growth of EC patient-derived explants ex vivo, EC cell line-derived xenografts, and patient-derived xenografts in vivo. Collectively, our work revealed the oncogenic potential of the LIF/LIFR axis in EC and support the utility of LIFR inhibitor, EC359, as a novel targeted therapy for EC via the inhibition of LIF/LIFR oncogenic signaling.

Knockdown of Lamin B1 and the Corresponding Lamin B Receptor Leads to Changes in Heterochromatin State and Senescence Induction in Malignant Melanoma

“…Some of the defined target genes of LMNB1 like LIFR and IL6R are already reported to be cancer associated [ 60 , 61 ]. LIFR belongs to the type I cytokine receptor family and could form a receptor complex which is involved in important cellular processes like differentiation, proliferation, and survival [ 62 ]. The LIF/LIFR axis is reported to be involved in the maintenance of stem cells [ 62 ].…”

“…LIFR belongs to the type I cytokine receptor family and could form a receptor complex which is involved in important cellular processes like differentiation, proliferation, and survival [ 62 ]. The LIF/LIFR axis is reported to be involved in the maintenance of stem cells [ 62 ]. Maybe the loss of LIFR due to LMNB1 knockdown results in reduction of the stemness like properties of melanoma cells leading to senescence.…”

Inhibition of LIFR Blocks Adiposity-Driven Endometrioid Endometrial Cancer Growth

“…Human EC cell lines HEC-1-A, AN3 CA and RL95-2 were purchased from the American Type Culture Collection (ATCC, Manassas, VA, USA) and cultured as described [ 16 ]. Ishikawa cells were purchased from Sigma (Millipore Sigma, St. Louis, MO, USA).…”

The ILEI/LIFR complex induces EMT via the Akt and ERK pathways in renal interstitial fibrosis

“…It is involved in maintaining hepatocyte pluripotency, protecting the liver, promoting glucose absorption and utilization, regulating cellular proliferation and differentiation, and other biological processes. Studies have reported that LIFR activates the JAK/STAT, ERK/MAPK, and Akt/PI3K pathways in tumor formation, inflammation, and cardiac function [ 15 – 17 ]. Woosley, et al found that ILEI forms a ligand-receptor complex by binding to the extracellular binding factor region of LIFR [ 18 ], suggesting that LIFR may be a key downstream effector molecule for many functions of ILEI.…”