The role of leukemia inhibitory factor in colorectal cancer

白血病抑制因子在结直肠癌中的作用

• 批准号: 10364132
• 负责人: Wenwei Hu
• 金额: $ 37.25万
• 依托单位: RBHS -CANCER INSTITUTE OF NEW JERSEY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10364132
• 关键词: ApcMin/+ mice; Azoxymethane; CD36 gene; CDX2 gene; Cancer Etiology; Cell Count; Cell physiology; Cells; Cessation of life; Clinical; Colon; Colonic Neoplasms; Colorectal; Colorectal Cancer; Colorectal Neoplasms; Complex; Data; Development; Epithelial; Fatty Acids; Feedback; Genetic Transcription; Genetically Engineered Mouse; Goals; Human; In Vitro; Internal Ribosome Entry Site; Intestines; Knock-in Mouse; Knock-out; Knockout Mice; LGR5 gene; LIF gene; LIFR gene; Lipids; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Molecular; Mus; Oncogenic; Pathologic Processes; Pathway interactions; Physiological Processes; Play; Prognosis; Reporting; Reproduction; Role; Sampling; Signal Transduction; TP53 gene; Testing; Therapeutic; Time; Tissues; Tumor Suppression; Tumor Suppressor Genes; Work; anti-cancer; base; cancer cell; cancer initiation; cancer type; chemical carcinogen; colon cancer patients; colon tumorigenesis; colorectal cancer treatment; cytokine; enhancing factor; in vivo; leukemia inhibitory factor receptor; lipid metabolism; mouse model; neutralizing antibody; new therapeutic target; overexpression; oxidation; small molecule inhibitor; stem cell niche; stem cells; stem-like cell; stemness; targeted treatment; therapy resistant; transcription factor; tumor; tumorigenesis; uptake

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.

项目摘要 白血病抑制因子（LIF）是一种多功能细胞因子。我们以前的研究表明，LIF是一种 肿瘤抑制基因p53的直接靶基因，并介导p53在母体生殖中的功能， 同时，LIF与p53形成负反馈回路，抑制p53的抑瘤作用。 LIF在肿瘤发生中具有复杂的作用;已报道LIF抑制或促进肿瘤的发生。 不同类型的癌症。新出现的证据，包括我们的，表明LIF经常 在结直肠癌（CRC）中过表达。此外，LIF过表达通常与不良的免疫反应相关。 CRC患者的预后。这些观察结果强烈表明LIF在促进结直肠癌中的关键作用。 肿瘤发生目前，LIF在结直肠肿瘤发生中的确切作用和机制尚不清楚 定义了结直肠肿瘤起始干细胞样细胞（TIC）在结直肠癌的发生、发展和转移中起着关键作用。 和对治疗的抵抗消除TIC已被积极测试作为CRC的治疗策略。 我们最近的研究表明，LIF存在于肠干细胞（ISC）的小生境中，并且是至关重要的， 维护ISC编号和功能。ISCs中的致癌激活在肿瘤的启动中起着关键作用。 《儿童权利公约》。我们的初步研究进一步表明，LIF驱动结直肠癌的脂质代谢重编程， TIC是LIF促进结肠直肠TIC数量和功能的重要机制。这些 这些发现提示我们假设LIF对结肠直肠TIC的数量和功能是必不可少的， turn促进结肠直肠肿瘤发生。我们进一步假设，靶向LIF和LIF驱动的 代谢重编程可以抑制结肠直肠TIC并抑制结肠直肠肿瘤发生。在这 在本研究中，我们将确定LIF在结直肠肿瘤发生和结直肠TIC数量中的作用 和功能通过使用不同的小鼠模型（目的1）。我们将确定是否增加结肠直肠 通过LIF驱动的脂质代谢重编程的TIC数量和功能是一种关键机制， LIF促进结直肠肿瘤发生。我们将研究LIF是否调节 参与结肠直肠TIC中脂质代谢的关键转录因子，包括p53， 代谢重编程（Aim 2A）。我们将进一步测试LIF驱动的代谢重编程是否 可以作为CRC治疗的靶点（Aim 2B）。本研究的目的是阐明其作用和机制 LIF在CRC中的作用，并评估靶向LIF驱动的脂质代谢重编程是否是一种有效的治疗方法。 消除TICs并通过LIF过表达治疗CRC的策略。如果这项研究成功完成， 将确立LIF在CRC中的关键作用，揭示其潜在机制，并提供理论依据 并为开发新的治疗靶点和策略用于具有LIF过表达的CRC奠定基础。