TBEL Project 3

项目3 -摘要 胰腺癌起源于非侵入性的前驱病变，如果早期发现和治疗，这些病变是可以治愈的。 胰腺上皮内瘤变（PanIN）是这些前体病变中最常见的，代表了一种 早期发现和癌症预防方法的关键目标。我们小组以前的研究表明， 强调了在一些PanIN中驱动克隆扩增和肿瘤进展的关键基因组改变。 这些研究还表明，扩张和进展可以发生，而不积累 额外的驱动基因组改变，表明不同的驱动机制在不同的PanIN中起作用。 该提议的总体假设是，向HG PanIN的转变可以由基因组或前体驱动。 微环境（PME）改变，不同的驱动因素在不同的病变中占主导地位。调查这一 假设，拟议的研究将评估肿瘤的细胞内在和细胞外在驱动因素。 在人类PanIN样品中的进展。我们将采用一种新颖的方法， 人PanIN样品的重建和分子分析。我们将进行多区域的全外显子组 测序和进化重建，以便将基因组改变与扩增相关联， 肿瘤细胞在三维中的进展。为了确定肿瘤的非遗传驱动因素， 进展，我们将分析免疫和基质细胞亚群在同一个三维重建 PanIN样本使用成像质谱细胞术，使我们能够确定的关键组成部分的变异性， 这些PanIN样本的多个区域的PME。这种互补分析将使我们能够将 微环境特征与相关PanIN细胞中的分子改变有关。我们还将整合 预测的新抗原和T细胞受体测序在相同的PanIN区域，提供了一个多维的 分析对PanIN的免疫应答。总而言之，这些方法将系统地评估 肿瘤细胞进展的潜在驱动因素和相关的免疫反应， 生物学见解和新的早期发现和预防方法的合理基础。

PROJECT 3 - ABSTRACT Pancreatic cancer arises from non-invasive precursor lesions that are curable if detected and treated early. Pancreatic intraepithelial neoplasia (PanIN) is the most common of these precursor lesions and represents a critical target of early detection and cancer prevention approaches. Previous studies from our group have highlighted critical genomic alterations that drive clonal expansion and neoplastic progression in some PanINs. These studies have also demonstrated that expansion and progression can occur without the accumulation of additional driver genomic alterations, suggesting that diverse driver mechanisms operate in different PanINs. The overall hypothesis of this proposal is that the transition to HG PanIN can be driven by genomic or precursor microenvironment (PME) alterations, with distinct drivers dominating in different lesions. To investigate this hypothesis, the proposed studies will evaluate both cell intrinsic and cell extrinsic drivers of neoplastic progression in human PanIN samples. We will employ a novel approach that allows both three-dimensional reconstruction and molecular analysis of human PanIN samples. We will perform multi-region whole exome sequencing and evolutionary reconstruction in order to correlate genomic alterations with expansion and progression of neoplastic cells in three dimensions. In order to identify non-genetic drivers of neoplastic progression, we will analyze immune and stromal cell subsets in the same three-dimensionally reconstructed PanIN samples using imaging mass cytometry, allowing us to determine the variability of key components of the PME across multiple regions of these PanIN samples. This complementary analysis will allow us to correlate the microenvironmental features with the molecular alterations in associated PanIN cells. We will also integrate predicted neoantigens and T-cell receptor sequencing on the same PanIN regions, providing a multi-dimensional analysis of the immune response to PanINs. Taken together, these approaches will systematically evaluate potential drivers of progression in the neoplastic cells and associated immune response, providing crucial biological insights and a rational foundation for novel early detection and prevention approaches.