Tumor-intrinsic and paracrine roles of endoglin in pancreatic cancer

摘要 摘要胰腺导管腺癌(PDAC)是一种以早期转移、晚期发病为特征的致命性恶性肿瘤。 症状，以及对现有疗法的臭名昭著的抵抗力。这种疾病的一个严重的难以捉摸的方面与 相对于其他实体癌，肿瘤通常是少血供的，表现为血流灌注不良和 药物传递受阻。在初步研究中，我们发现endoglin，通常是一种内皮特异性的 血管生成所需的转化生长因子-β辅助受体在胰腺癌细胞中以两种变体的形式表达-- 野生型，支持肿瘤的内在生长和化疗耐药；以及一种新的剪接变异体，具有明显的 分泌以抑制肿瘤血管形成的结构特征。要了解它们在 肿瘤微环境，我们已经产生了各种细胞和药理试剂来询问 潜在的机制及其治疗潜力。我们建议定义新的旁分泌 抑制PDAC血管形成的转化生长因子-β信号机制(AIM 1)；并识别肿瘤内源性 作为PDAC关键治疗靶点的endoglin通路(Aim 2)；并确定endoglin变体为 疾病进展期间不同的时空目标(目标3)。这些研究的结果将定义转化生长因子- 基于β的机制对PDAC肿瘤的生长和血管形成至关重要，并提供临床相关的信息 改善以患者为基础的治疗方法的数据。

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.