Shaping the Microenvironment by DPEP1 Facilitates Adenoma Progression

项目摘要/摘要 项目1：DPEP1塑造微环境促进腺瘤进展 项目1旨在研究DPEP1塑造微环境如何促进腺瘤进展。这 将是一个基本的项目。我们认为二肽酶-1(DPEP1)标记这些腺瘤具有潜在的 通过与中性粒细胞的积极双向交流进展到结直肠癌(CRC)。DPEP1 有两个功能：二肽酶活性和新近发现的中性粒细胞结合活性。我们的假设是 DPEP1主要通过其中性粒细胞结合活性，标志着腺瘤有进展的倾向。我们 已经发现在27%的结直肠腺瘤中检测到DPEP1免疫反应，但这一比例上升到72% 与DPEP1一致，标志着进展为结直肠癌的腺瘤的一小部分。利用人 标本，一种独特的Transwell腺瘤类器官和新鲜分离的中性粒细胞共培养系统 从健康志愿者和有信息的小鼠模型中，我们将测试DPEP1表达的腺瘤是否有更多 有效地与中性粒细胞沟通，创造中性粒细胞丰富的微环境，增加 这些腺瘤进展的可能性。外体作为一种富有的生物，最近引起了人们的极大关注。 可作为癌症生物标记物的货物来源。我们已经发现DPEP1是在外体中释放的 它高度富含含有已知的CRC生物标志物CEA的外体的子集 和EpCAM。有趣的是，中性粒细胞也会释放含有中性粒细胞的细胞外小泡(SEV)。 弹性酶是一种不能被弹性酶抑制剂抑制的形式，因此它在降解 细胞外基质，癌症侵袭的关键步骤。我们还将使用一种独特的中性粒细胞报告鼠标来监测 中性粒细胞浸润的开始和持续时间，以及这些中性粒细胞的特性，在可诱导的， 干细胞驱动的小鼠结肠腺瘤模型。 。

PROJECT SUMMARY/ABSTRACT Project 1: Shaping the Microenvironment by DPEP1 Facilitates Adenoma Progression Project 1 aims to examine how shaping the microenvironment by DPEP1 facilitates adenoma progression. This will be a basic project. We propose that dipeptidase-1 (DPEP1) marks those adenomas with the potential to progress to colorectal cancer (CRC) through an active bi-directional communication with neutrophils. DPEP1 has two functions: dipeptidase activity and recently identified neutrophil-binding activity. Our hypothesis is that DPEP1, largely through its neutrophil-binding activity, marks adenomas with a predilection for progression. We have found that DPEP1 immunoreactivity is detected in 27% of colorectal adenomas but this increases to 72% of CRCs, consistent with DPEP1 marking the small subset of adenomas that progress to CRC. Utilizing human specimens, a unique Transwell co-culture system of adenoma organoids and freshly isolated neutrophils isolated from healthy volunteers, and an informative mouse model, we will test if DPEP1-expressing adenomas more effectively communicate with neutrophils and create a neutrophil-enriched microenvironment, increasing the likelihood that these adenomas will progress. Exosomes have attracted a great deal of recent attention as a rich source of cargo that may serve as cancer biomarkers. We have found that DPEP1 is released in exosomes from CRC cell lines and that it highly enriched in a subset of exosomes that contain known CRC biomarkers, CEA and EPCAM. Of interest, neutrophils also release small extracellular vesicles (sEVs) that contain neutrophil elastase in a form that cannot be inhibited by elastase inhibitors, and thus it is especially potent in degrading the extracellular matrix, a key step in cancer invasion. We will also use a unique neutrophil reporter mouse to monitor onset and perdurance of neutrophil infiltration, along with the properties of these neutrophils, in an inducible, stem cell-driven mouse model of colonic adenomas. .