IL4-Regulated Metabolic Changes Contribute to Metastatic Capability

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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 IL4Rα, a component of the IL4 receptor, promotes the growth of colon cancer metastases, yet how IL4Rα 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 IL4Rα-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 IL4Rα 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/IL4Rα-induced alterations in glucose metabolism dependent upon Stat6; and 3) What is the contribution of IL4Rα-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.