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-¿B 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-¿B 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.