Tumor-intrinsic and paracrine roles of endoglin in pancreatic cancer

摘要 胰腺导管腺癌（PDAC）是一种致命的恶性肿瘤，具有早期转移，晚期发病， 症状和对现有疗法的臭名昭著的抵抗。这种疾病的一个关键的难以捉摸的方面涉及到 相对于其他实体癌，肿瘤通常血管化不足，表现为灌注不良， 药物输送受损。在初步研究中，我们发现内皮糖蛋白，通常是内皮特异性的， 血管生成所需的TGF-β辅助受体，在胰腺癌细胞中表达为两种变体- 野生型，支持肿瘤内在生长和化学抗性;和一种新的剪接变异体，具有不同的 分泌抑制肿瘤血管形成的结构特征。为了了解它们在 肿瘤微环境，我们已经产生了各种细胞和药理学试剂来询问 潜在的机制及其治疗潜力。我们建议定义新的旁分泌 TGF-β信号传导抑制PDAC血管形成的机制（Aim 1）;并确定肿瘤内在的 内皮糖蛋白途径作为PDAC的关键治疗靶点（目标2）;并确定内皮糖蛋白变体， 疾病进展期间的不同时空靶点（目标3）。这些研究的结果将定义TGF-β 1。 基于β的机制对PDAC肿瘤生长和血管化至关重要，并提供临床相关的 改善基于患者的治疗方法的数据。

ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy featuring early metastasis, late onset of symptoms, and notorious resistance to existing therapies. A critically elusive aspect of this disease relates to the tumors which are often hypovascularized relative to other solid cancers, manifesting in poor perfusion and impaired drug delivery. In preliminary studies, we discovered that endoglin, normally an endothelial-specific TGF-beta coreceptor required for angiogenesis, is expressed as two variants in pancreatic cancer cells- the wildtype, which supports tumor-intrinsic growth and chemoresistance; and a novel splice variant with distinct structural features that gets secreted to inhibit tumor vascularization. To understand their interplay in the tumor microenvironment, we have generated a variety of cellular and pharmacologic reagents to interrogate the underlying mechanisms and their therapeutic potential. We propose to define novel paracrine mechanisms of TGF-beta signaling that suppress PDAC vascularization (Aim 1); and identify tumor-intrinsic endoglin pathways as critical therapeutic targets in PDAC (Aim 2); and determine the endoglin variants as distinct spatiotemporal targets during disease progression (Aim 3). Results from these studies will define TGF- beta-based mechanisms critical for PDAC tumor growth and vascularization and deliver clinically relevant data for improved patient-based therapeutics.