Proteomic Characterization of Pancreatic Neuroendocrine Tumors and Metastatic Progression

项目摘要/摘要 看似相同的胰腺神经内分泌肿瘤(PanNETs)患者的临床结果往往不同。 (转移的出现、治疗反应、存活率等)，表明这些恶性肿瘤实际上可能是不同的 目前未知且无法通过标准诊断(例如组织学或基因组学)区分的亚型。PanNETs 仅靠传统的基因组或转录学方法很难进一步分类或风险分层。目前， 手术切除后的随访监测主要是基于单纯的放射成像。目前还没有根治方法 一旦发生转移，没有早期发现和转移风险的蛋白质标记物，也没有确定的分子手段 监视系统。我们假设，根据蛋白质组特征可以更好地对PanNETs进行分类。我们建议 通过深入的蛋白质组学分析发现新的基于蛋白质组的亚型，更好地定义这些肿瘤。 在初步研究中，我们已经表明，蛋白质组图谱可以区分和细分不同的肿瘤并识别 原发灶或转移灶的蛋白质特征。在这个提案中，我们将首先阐明深层蛋白质组 组织学分级从G1到G3的分化良好的PanNETs。我们将研究两种临床结果的组织 队列，“低风险”组(肿瘤在手术后至少5年内没有转移)和“高风险”组 (肿瘤随后发生转移，但用目前的诊断方法无法区分)。通过检查 无论是原发灶还是转移灶，我们都将确定区分这两种结果和信号的蛋白质标记物。 来区分原发灶和转移灶。肿瘤内和肿瘤间的空间异质性、新肽/新蛋白 标记物和磷酸蛋白质组信号通路也将被研究。广泛的蛋白质组学和整合性 将进行蛋白质基因组分析，以确定PanNETs内以及初级和初级之间基于蛋白质组的亚型 转移的病变。我们将通过免疫组织化学验证独立队列中的标记板，并与 临床结果。基于蛋白质组签名，我们将能够开发风险分层模型，以预测 PanNETs的转移性倾向。 我们的研究将对了解胰腺神经内分泌肿瘤产生重大影响。成功的可能性 这一建议很高，因为我们已经在初步研究中发现了新的癌症亚型。该项目将受益 来自项目团队强大的科学和临床专业知识以及大量罕见的胰腺肿瘤的治疗 在MSKCC。我们设想的基于蛋白质组的风险分层可以解释为什么患者患有 目前看似相似的PanNet表现出显著不同的转移倾向、治疗反应和持续时间。 生死存亡。新的蛋白质组亚型可能通过提供亚型特异性和转移- 特定的蛋白质靶标。来自该项目的最有希望的候选蛋白质标记可能会迅速转化为 临床诊断和未来治疗，使癌症患者直接受益。

Project Summary/Abstract Patients with seemingly identical pancreatic neuroendocrine tumors (PanNETs) often differ in their clinical outcomes (emergence of metastases, treatment response, survival, etc.), suggesting that these malignancies may in fact be of different subtypes that are currently unknown and indistinguishable by standard diagnostics (e.g., histology or genomics). PanNETs have been difficult to further classify or risk-stratify by traditional genomic or transcriptomic methods alone. Currently, follow-up monitoring after surgical resection is mostly based on radiographic imaging alone. There are no curative therapies once metastases occur, no protein markers of early detection and metastatic risk, and no established molecular means of surveillance. We hypothesize that PanNETs can be better classified according to proteome signatures. We propose to uncover new proteome-based subtypes by deep proteomic analysis that better define these tumors. In preliminary studies, we have shown that proteomic profiling can distinguish and sub-classify various tumors and identify protein signatures characteristic of primary or metastatic lesions. In this proposal, we will first elucidate the deep proteomes of well differentiated PanNETs of histologic grades ranging from G1 to G3. We will study tissues from two clinical outcome cohorts, a “low risk” group (tumors did not show metastases for at least 5 years after surgery) and a “high risk” group (tumors developed subsequent metastases, but are otherwise indistinguishable by current diagnostic means). By examining both primary and metastatic lesions, we will identify protein markers that differentiate these two outcomes and signatures that distinguish primary from metastatic lesions. Spatial heterogeneity within and between tumors, neopeptide/neoprotein markers, and phosphoproteomic signaling pathways will also be examined. Extensive proteomic and integrated proteogenomic analyses will be performed to define proteome-based subtypes within PanNETs and between primary and metastatic lesions. We will validate marker panels in independent cohorts by immunohistochemistry and correlate with clinical outcomes. Based on the protein-panel signatures, we will be able to develop risk stratification models that predict metastatic propensity of PanNETs. Our study will have significant impact on understanding pancreatic neuroendocrine tumors. The likelihood of success of this proposal is high, as we have already discovered new cancer subtypes in our preliminary studies. The project will benefit from the strong scientific and clinical expertise of the project team and the high volume of rare pancreatic neoplasms treated at MSKCC. Our envisioned proteome-based risk stratification may explain the clinical conundrum of why patients with currently seemingly similar PanNETs exhibit strikingly different metastatic propensity, treatment response, and length of survival. New proteomic subtyping may inform future therapy development by providing subtype-specific and metastasis- specific protein targets. The most promising candidate protein markers from this project may be rapidly translated into clinical diagnostics and future therapies for the direct benefit of cancer patients.