IL4-Regulated Metabolic Changes Contribute to Metastatic Capability

描述(申请人提供)：结直肠癌是美国男性和女性癌症相关死亡的第二大原因，它既致命又普遍。有转移性疾病的结直肠癌患者的5年存活率是令人沮丧的12%。FDA批准了针对血管内皮生长因子或EGFR的靶向治疗，仅能将患者的生存期提高6个月或更短。此外，这些疗法中的一些对肿瘤具有K-RAS等蛋白质特定突变的患者无效。结肠癌患者迫切需要新的靶向治疗，特别是那些患有转移性疾病的患者。白介素4(IL4)是一种Th2细胞因子，与IL4/IL4受体(IL4R)具有良好的相互作用 在免疫系统中定义的角色。然而，IL4Rs在包括结肠癌在内的许多上皮性癌症中过表达，可能成为抗肿瘤治疗的一个有前途的靶点。我们已经证明，IL4R？，IL4受体的一种成分，促进结肠癌转移瘤的生长，但IL4R？如何促进转移瘤的生长尚不清楚。通过加强葡萄糖代谢的代谢重新编程可能支持增加转移定植(存活和增殖)。我们已经证明信号转导和转录激活因子6(Stat6)在结肠癌细胞对IL4的反应中被激活，并且可能在介导控制IL4R增强代谢的基因的转录中起关键作用。我们假设IL4R激活的Stat6信号有助于增加结肠癌细胞对葡萄糖的摄取和利用，从而促进肝转移瘤的定植。除了之前产生的IL4R基因敲除克隆外，我们还将使用表达显性阴性或结构性活性Stat6的结肠癌克隆来检验这一假说。IL4/IL4R诱导的葡萄糖代谢和结肠癌生长之间的因果关系将通过靶向糖酵解酶在IL4存在或不存在的情况下得到证实。利用这些工具，我们将回答三个主要问题：1)IL4对STAT6介导的促进葡萄糖代谢的基因转录的变化；2)IL4/IL4R？诱导的葡萄糖代谢的改变是否依赖于STAT6；以及3)IL4R？诱导的葡萄糖代谢对转移定植的贡献是什么？在这些研究完成后，我们将首次确定免疫细胞因子(IL4)是否可以为特定的目标(转移性肿瘤生长)重新编程上皮细胞的新陈代谢。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.