IL4-Regulated Metabolic Changes Contribute to Metastatic Capability

描述（由申请人提供）：作为美国男性和女性合并癌症相关死亡的第二大原因，结直肠癌既致命又普遍。患有转移性疾病的结直肠癌患者的5年生存率仅为12%。FDA批准的针对VEGF或EGFR的靶向治疗只能提高患者的生存期6个月或更短。此外，其中一些治疗对肿瘤具有特定蛋白质突变（如K-Ras）的患者无效。结肠癌患者迫切需要新的靶向治疗，特别是那些转移性疾病。白细胞介素-4（IL-4），一种Th 2细胞因子，与IL-4/IL-4受体（IL-4 R）相互作用具有良好的调节作用。 在免疫系统中的作用。然而，IL 4 R在包括结肠癌在内的许多上皮癌中过表达，并且可能是抗肿瘤治疗的有希望的靶点。我们已经证明，IL 4 R IL 4受体的一种成分，促进结肠癌转移的生长，但IL 4 R是如何促进转移性肿瘤生长的尚不清楚。通过增强葡萄糖代谢的代谢重编程可支持增加的转移定植（存活和增殖）。我们已经表明，信号转导和转录激活因子6（Stat 6）在结肠癌细胞中响应于IL 4被激活，并且可能是介导控制结肠癌细胞中IL 4 R增强代谢的基因转录的关键参与者。我们假设IL 4 R β-活化的Stat 6信号传导用于增强结肠癌细胞中增加的葡萄糖摄取和利用，以促进肝转移的定殖。除了先前产生的IL 4 R敲低克隆，我们将使用表达显性阴性或组成型活性Stat 6的结肠癌克隆来测试这一假设。将通过在存在或不存在IL 4的情况下靶向糖酵解酶来证实IL 4/IL 4 R诱导的葡萄糖代谢与结肠癌生长之间的因果关系。利用这些工具，我们将回答三个主要问题：1）什么是Stat 6介导的基因转录的变化，促进葡萄糖代谢响应IL 4; 2）是IL 4/IL 4 R？诱导依赖于Stat 6的葡萄糖代谢的改变;和3）IL 4 R的贡献是什么？诱导葡萄糖代谢转移定植？在这些研究完成时，我们将首次确定免疫细胞因子（IL 4）是否可以重新编程上皮细胞的代谢以实现特定目标（转移性肿瘤生长）。最终，这些结果将有助于确定转移性结肠癌患者治疗的新靶点。

DESCRIPTION (provided by applicant): As the second leading cause of cancer-related deaths in the U.S. among men and women combined, colorectal cancer is both lethal and prevalent. The 5-year survival rate for colorectal cancer patients with metastatic disease is a dismal 12%. FDA approved targeted therapies against either VEGF or EGFR only improve patient survival by six months or less. In addition, some of these therapies are not effective in patients whose tumors have specific mutations in proteins such as K-Ras. Novel targeted therapies are desperately needed for colon cancer patients, particularly those with metastatic disease. Interleukin-4 (IL4), a Th2 cytokine, and the IL4/IL4 receptor (IL4R) interaction have well defined roles in the immune system. Yet, IL4Rs are overexpressed in many epithelial cancers including colon cancer, and could be a promising target for antitumor therapy. We have shown that IL4R¿, a component of the IL4 receptor, promotes the growth of colon cancer metastases, yet how IL4R¿ contributes to metastatic tumor growth is unknown. Metabolic reprogramming through the enhancement of glucose metabolism may support increased metastatic colonization (survival and proliferation). We have shown that signal transducer and activator of transcription six (Stat6) is activated in colon cancer cells in response to IL4, and may be a key player in mediating the transcription of genes controlling IL4R-enhanced metabolism in colon cancer cells. We hypothesize that IL4R¿-activated Stat6 signaling serves to enhance increased glucose uptake and utilization in colon cancer cells to promote the colonization of liver metastases. In addition to previously generated IL4R¿ knockdown clones, we will test this hypothesis using colon cancer clones expressing either a dominant-negative or constitutively active Stat6. The causal relationship between IL4/IL4R-induced glucose metabolism and colon cancer growth will be confirmed by targeting glycolytic enzymes in the presence or absence of IL4. Utilizing these tools we will answer three main questions: 1) What are the Stat6 mediated changes in gene transcription that promote glucose metabolism in response to IL4; 2) Are IL4/IL4R?-induced alterations in glucose metabolism dependent upon Stat6; and 3) What is the contribution of IL4R?-induced glucose metabolism to metastatic colonization? At the completion of these studies, we will have determined for the first time if an immune cytokine (IL4) can re-program the metabolism of an epithelial cell for a specific goal (metastatic tumor growth). Ultimately, these results will aid in the identification of novel targets for therapy for patients ith metastatic colon cancer.