TBEL Project 1

TBEL项目1

• 批准号: 10518937
• 负责人: Marina Pasca Di Magliano
• 金额: $ 37万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10518937
• 关键词: CXCL1 gene; Cell Death; Cell Line; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; DNA Binding Domain; Data; Disease; Epithelial; Epithelial Cells; Family; Fibroblasts; Gene Expression; Genes; Genetic Transcription; Goals; Human; IL6 gene; In Vitro; Inflammatory; KRAS oncogenesis; KRAS2 gene; Laboratories; Lead; Lesion; Light; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mediator of activation protein; Metabolic; Modeling; Molecular; Mucinous Neoplasm; Mus; Mutation; Natural History; Neoplasms; Nuclear; Organoids; Outcome; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Papillary; Pathway interactions; Patients; Pattern; Population; Process; Role; Signal Pathway; Signal Transduction; Testing; Tissue Microarray; Wood material; advanced disease; base; cancer invasiveness; carcinogenesis; cytokine; disease natural history; homeodomain; human tissue; in vivo; insight; member; mouse model; mutant; neoplastic cell; pancreatic neoplasm; paracrine; premalignant; receptor; response; tumor microenvironment; tumor-immune system interactions

PROJECT 1 - ABSTRACT There are two distinct pathways to invasive neoplasia in the pancreas – the more common non-cystic (pancreatic intraepithelial neoplasia or PanIN) and cystic (mostly, intraductal papillary mucinous neoplasm or IPMN). Both PanIN and IPMNs occur at significantly higher rates in the population than invasive cancer, reiterating that only a fraction of precursor lesions progress to pancreatic ductal adenocarcinoma (PDAC), but determining which patient will progress is currently not possible. PanINs and IPMNs are both characterized by the common occurrence of oncogenic KRAS mutations, while the latter also harbors concomitant “hotspot” GNAS mutations in 2/3rd of cases. How these early epithelial alterations and their crosstalk with the tumor microenvironment (TME) impacts progression to cancer remains understudied. The formation of early pancreatic precursors is accompanied by the expansion of a heterogeneous fibroblast population. In advanced disease, fibroblasts become cancer associated fibroblasts (CAFs). Little is known about precursor lesion associated fibroblasts (PAFs), including prevalent differences between the two precursor subtypes. Our preliminary data show that fibroblast reprogramming occurs in early pancreatic lesions, and leads to expression of IL6, and IL33. While IL6 is secreted and known to regulate the immune microenvironment, IL33 is prevalently nuclear in fibroblasts. Interestingly, IPMNs also have extremely elevated epithelial nuclear IL33. IL33 contains a DNA binding domain and is known to regulate transcription. Based on these observations, we propose to study the mechanisms of fibroblast reprogramming and comparing fibroblast gene expression in PanINs and IPMNs (Aim 1). Further, we will study the role of fibroblast IL33 in lesion progression and establishment of the precursor lesion microenvironment (PME) in PanIN and IPMN (Aim 2). Lastly, we will determine how epithelial IL33 in IPMNs regulates the PME as well as progression to malignancy (Aim 3). We will integrate the mouse model and in vitro studies with primary human tissue and organoids generated in the Wood laboratory (see Project 3). Together, these studies will shed light on the composition and role of PAFs in different premalignant lesions of the pancreas.

项目1--摘要 胰腺侵袭性肿瘤有两种不同的途径--更常见的是非囊性病变。 (胰腺上皮内瘤变或Panin)和囊性(主要是导管内乳头状粘液 肿瘤或IPMN)。PANIN和IPMN在人群中的发生率明显高于侵袭性 癌症，重申只有一小部分前驱病变进展为胰腺导管腺癌 (PDAC)，但目前无法确定哪个患者会进步。PAINS和IPMN都是 以常见的致癌KRAS突变为特征，而后者也 伴随的“热点”GNAS突变在2/3的病例中。这些早期的上皮改变和它们的串扰 肿瘤微环境(TME)对肿瘤进展的影响尚不清楚。形成了一种 早期胰腺前体细胞伴随着异质成纤维细胞群体的扩张。在……里面 晚期疾病时，成纤维细胞成为癌症相关成纤维细胞(CAF)。人们对前兆知之甚少 病变相关成纤维细胞(PAF)，包括两种前体亚型之间的普遍差异。我们的 初步数据显示，成纤维细胞重编程发生在早期胰腺病变中，并导致表达 白介素6和白介素33。虽然IL6是分泌的，并且已知可以调节免疫微环境，但IL33普遍存在 成纤维细胞中的核。有趣的是，IPMN也有极高的上皮核IL33。IL33包含一个 DNA结合域，并被认为是调节转录。基于这些观察，我们建议研究 PAINS和IPMNS中成纤维细胞重编程机制及成纤维细胞基因表达的比较 (目标1)。进一步，我们将研究成纤维细胞IL33在病变进展中的作用和前体的建立 Panin和IPMN的病变微环境(PME)(目标2)。最后，我们将确定上皮性IL33是如何在 IPMns调节PME以及向恶性肿瘤的进展(目标3)。我们将把鼠标模型和 对伍德实验室产生的原生人体组织和有机类化合物进行体外研究(见项目3)。 总之，这些研究将阐明PAF在不同癌前病变中的组成和作用。 胰腺。