Targeting the LIFR-LCN2 pathway to improve liver cancer therapy

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PROJECT SUMMARY/ABSTRACT Iron is vital for many physiological processes, but excessive iron causes toxicity. Dysregulated iron homeostasis (either iron deficiency or overload) is a harbinger of pathological conditions. The liver stores iron in hepatocytes and is the major organ that controls systemic iron homeostasis. Liver cancer, primarily hepatocellular carcinoma (HCC), is highly lethal with limited treatment options and no biomarkers to predict therapy response. Leukemia inhibitory factor receptor (LIFR) is frequently downregulated in human HCC; however, in vivo and genetic studies of LIFR’s functions in liver cancer development and therapy response were lacking. Recently, by constructing and characterizing hepatocyte-specific and inducible Lifr-knockout mice, we found that loss of Lifr promoted liver tumorigenesis and conferred resistance to sorafenib-induced ferroptosis, a non-apoptotic type of cell death characterized by the iron-dependent accumulation of lipid hydroperoxides. Our data also pointed to a role for LIFR in inhibiting NF-κB signaling in the liver, which in turn downregulates lipocalin 2 (LCN2), an iron- sequestering cytokine. In parallel, our data revealed that in oncogene-induced liver tumors, overexpression of LIFR increased, while knockout of Lifr decreased CD8+ T cell infiltration, which may be mediated by LCN2- dependent downregulation of iron levels, viability, and proliferation of T cells. Altogether, these data support a hypothesis that loss or downregulation of LIFR in liver cancer leads to upregulation of LCN2, which on one hand confers resistance to ferroptosis on liver tumor cells, and on the other hand, deprives T cells of iron that is essential for T cell viability, proliferation, and effector function; both mechanisms contribute to liver cancer progression and therapy resistance. In the proposed work, we will elucidate the molecular mechanisms by which LIFR inhibits NF-κB signaling in liver cells (Specific Aim 1). Further, we will investigate whether LCN2 can serve as a therapeutic target for enhancing sorafenib efficacy in HCC (Specific Aim 2). Finally, we will study whether LIFR or therapeutic LCN2 neutralization can sensitize HCC to immunotherapy (Specific Aim 3). Genetically engineered mouse models, Sleeping Beauty transposon-mediated oncogene-induced liver cancer models, and HCC patient-derived xenograft models will be used to study the therapeutic potential and mechanisms of action of two novel drug combinations, which will illuminate how to improve liver cancer therapy by targeting an iron- sequestering pathway. We envision that low LIFR expression and high LCN2 expression could be used to select HCC patients who will likely benefit from the combination therapy with the LCN2-neutralizing antibody plus sorafenib or immune checkpoint inhibitors.