Characterization of ILEI/LIFR Axis-induced Intracellular Signaling

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Project Summary Our lab has previously identified a mechanism of transforming growth factor beta (TGFβ)-mediated epithelial-to-mesenchymal transition (EMT) in murine mammary epithelium. We have shown that expression of the interleukin-like EMT inducer (ILEI) protein is necessary to induce EMT in murine mammary gland cells following exposure to TGFβ. ILEI has also been shown to increase the self-renewal capacity of epithelial cells following EMT, through its interaction with leukemia inhibitory factor receptor (LIFR), suggesting that the ILEI/LIFR signaling axis promotes breast cancer stem-cell (BCSC) phenotype. Further, our lab has shown that TGFβ-induced upregulation of LIFR is ILEI-dependent. In cells derived from a mouse tumor progression model created by our lab, spheroid formation capacity in non-adherent cell culture conditions is attenuated following either ILEI or LIFR knockdown. Additionally, orthotopic grafts of cells with ILEI or LIFR knockdown display a decrease in tumor growth and metastasis relative to control cells. We hypothesize that TGFβ-induced LIFR regulation contributes to metastases. The precise mechanisms of ILEI-mediated EMT and BCSC induction are unknown. Herein we aim to interrogate ILEI/LIFR axis-mediated mechanisms downstream of TGFβ exposure that influence (1) the regulation of LIFR protein expression and (2) the ensuing maintenance of self-renewal capacity and disease progression in our model. In Specific Aim 1, the LIFR promoter sequence will be examined to identify key factors regulating LIFR expression. In Specific Aim 2, transcriptomic data will be examined following ILEI/LIFR knockout to identify a signature of ILEI/LIFR-regulated gene expression and its association with self-renewal capacity. In Specific Aim 3, the role of LIFR will be examined in vivo to determine the impact of its expression upon outgrowth of pulmonary tumors following tail vein injection of cells into immunodeficient mice. Data from our experiments will characterize a signaling pathway associated with BCSC maintenance and will potentially identify novel therapeutic targets. Our findings may translate to novel treatments for dormancy and relapse in human metastatic breast cancer.