The role of leukemia inhibitory factor in colorectal cancer

Project Summary Leukemia inhibitory factor (LIF) is a multi-functional cytokine. Our previous studies reveal that LIF is a direct target gene of tumor suppressor p53 and mediates the function of p53 in maternal reproduction, and at the same time, LIF forms a negative feedback loop with p53 to inhibit p53 function in tumor suppression. LIF has a complex role in tumorigenesis; LIF has been reported to suppress or promote tumorigenesis in different types of cancers. Emerging evidence, including ours, has shown that LIF is frequently overexpressed in colorectal cancer (CRC). Further, LIF overexpression is often associated with poor prognosis in CRC patients. These observations strongly suggest a critical role of LIF in promoting colorectal tumorigenesis. Currently, the precise role and mechanism of LIF in colorectal tumorigenesis are poorly defined. Colorectal tumor-initiating stem-like cells (TICs) play a critical role in CRC initiation, progression and resistance to therapy. Eliminating TICs has been actively tested as a therapeutic strategy for CRC. Our recent study shows that LIF is present in the intestinal stem cells (ISC) niche and is essential to maintain ISC number and functions. Oncogenic activation in ISCs plays a critical role in the initiation of CRC. Our preliminary studies further suggest that LIF drives lipid metabolic reprogramming of colorectal TICs as an important mechanism whereby LIF promotes colorectal TIC number and functions. These findings prompt us to hypothesize that LIF is essential for colorectal TIC number and functions, which in turn promotes colorectal tumorigenesis. We further hypothesize that targeting LIF and LIF-driven metabolic reprogramming can suppress colorectal TICs and inhibit colorectal tumorigenesis. In this proposed study, we will determine the role of LIF in colorectal tumorigenesis and colorectal TIC number and functions by using different mouse models (Aim 1). We will determine whether increasing colorectal TIC number and functions through LIF-driven lipid metabolic reprograming is a critical mechanism whereby LIF promotes colorectal tumorigenesis. We will investigate whether LIF regulates the levels and activities of critical transcription factors involved in lipid metabolism in colorectal TICs, including p53, to drive lipid metabolic reprogramming (Aim 2A). We will further test whether the LIF-driven metabolic reprogramming can be targeted for CRC therapy (Aim 2B). The goal of this study is to elucidate the role and mechanism of LIF in CRC, and assess whether targeting LIF-driven lipid metabolic reprogramming is an effective strategy to eliminate TICs and treat CRC with LIF overexpression. If accomplished successfully, this study will establish the critical role of LIF in CRC, reveal its underlying mechanisms, and provide the rationale and base for the development of new therapeutic targets and strategies for CRC with LIF overexpression.