RON Receptor in Pancreatic Cancer Biology and Therapy

胰腺癌每年死亡率的持续上升要求我们迫切努力更好地了解 对肿瘤进展和治疗抗性至关重要的分子机制。我们集团和其他 将罗恩酪氨酸激酶受体鉴定为过表达的蛋白质和潜在的新治疗靶点 在胰腺癌中。我们实验室的工作假设是罗恩受体信号传导是一种有效的 在人胰腺癌细胞中的侵袭性生长和存活的促进剂，其独特地还有助于形成 肿瘤微环境通过其对骨髓细胞功能的影响。我们最近的研究表明，罗恩 信号传导加速KRAS启动的胰管瘤形成和胰腺癌中的罗恩信号传导 细胞启动正反馈环驱动罗恩本身及其同源配体的表达， 巨噬细胞刺激蛋白我们相信，罗恩信号传导从而起到修饰上皮和 免疫细胞表型促进肿瘤生长、转移和治疗抗性。这个的目标 应用：1）了解自分泌/旁分泌罗恩信号传导如何影响原发性胰腺癌 生长，2）确定罗恩信号转导修饰原发性和转移性小生境的机制， 促进肿瘤扩散和转移性生长，和3）测试罗恩抑制作为免疫调节剂 胰腺癌临床前模型的研究策略。这些研究的结果将提高我们的 了解罗恩生物学，从而为罗恩的开发和进一步测试提供信息。 针对胰腺癌的治疗。

The continued rise in annual pancreatic cancer mortalities demands urgent efforts to better understand molecular mechanisms critical to tumor progression and therapeutic resistance. Our group and others identified the RON tyrosine kinase receptor as an overexpressed protein and potential novel therapeutic target in pancreatic cancer. The working hypothesis of our laboratory is that RON receptor signaling is a potent promoter of invasive growth and survival in human pancreatic cancer cells which uniquely also helps to shape the tumor microenvironment via its effects on myeloid cell function. Our recent studies demonstrate that RON signaling accelerates pancreatic duct neoplasia initiated by KRAS and that RON signaling in pancreatic cancer cells initiates a positive feedback loop driving expression of both RON itself and its cognate ligand, macrophage stimulating protein. We believe that RON signaling thereby serves to modify both epithelial and immune cell phenotypes to promote tumor growth, metastasis and therapeutic resistance. The goals of this application are; 1) to understand how autocrine/paracrine RON signaling influences primary pancreatic cancer growth, 2) determine the mechanisms by which RON signaling modifies the primary and metastatic niche to promote tumor dissemination and metastatic outgrowth, and 3) to test RON inhibition as an immunomodulatory strategy in preclinical models of pancreatic cancer. The findings from these studies will enhance our understanding of RON biology and thereby serve to inform the development and further testing of RON- directed therapies in pancreatic cancer.