TBEL Project 3

项目 3 - 摘要 胰腺癌由非侵入性癌前病变引起，如果及早发现和治疗，这些病变是可以治愈的。 胰腺上皮内瘤变 (PanIN) 是这些前驱病变中最常见的，代表了一种 早期检测和癌症预防方法的关键目标。我们小组之前的研究有 强调了一些 PanIN 中驱动克隆扩张和肿瘤进展的关键基因组改变。 这些研究还表明，扩展和进展可以在没有积累的情况下发生 额外的驱动基因组改变，表明不同的 PanIN 中存在不同的驱动机制。 该提案的总体假设是向 HG PanIN 的转变可以由基因组或前体驱动 微环境（PME）改变，不同病变中具有不同的驱动因素。为了调查此事 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 人类 PanIN 样本中的进展。我们将采用一种新颖的方法，允许三维 人类 PanIN 样本的重建和分子分析。我们将进行多区域全外显子组 测序和进化重建，以便将基因组改变与扩展和 肿瘤细胞在三个维度上的进展。为了确定肿瘤的非遗传驱动因素 随着进展，我们将在相同的三维重建中分析免疫细胞和基质细胞亚群 使用成像质谱流式细胞仪进行 PanIN 样品，使我们能够确定关键成分的变异性 这些 PanIN 样本的多个区域的 PME。这种补充分析将使我们能够将 微环境特征与相关 PanIN 细胞的分子变化。我们还将整合 预测同一 PanIN 区域上的新抗原和 T 细胞受体测序，提供了多维 分析对 PanIN 的免疫反应。总而言之，这些方法将系统地评估 肿瘤细胞进展和相关免疫反应的潜在驱动因素，提供了至关重要的 生物学见解和新型早期检测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.