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 胰腺中有两种不同的侵入性肿瘤的途径 - 更常见的非囊肿 （胰腺内肿瘤或潘宁）和囊性（主要是导管内乳头状粘液 肿瘤或IPMN）。 Panin和IPMN的人口的发生率显着高于入侵 癌症，重申只有一小部分前体病变发展为胰腺导管腺癌 （PDAC），但是确定目前无法进行哪个患者进展。 Panins和IPMN都是 以致癌性KRAS突变的常见发生为特征，而后者也内置 2/3病例中伴随的“热点” GNA突变。这些早期的上皮变化及其串扰如何 随着肿瘤微环境（TME）影响到癌症的发展。形成 早期的胰腺前体是通过扩大异质成纤维细胞种群来实现的。在 晚期疾病，成纤维细胞成为癌症相关的成纤维细胞（CAF）。关于前体知之甚少 病变相关的成纤维细胞（PAF），包括两个前体亚型之间的普遍差异。我们的 初步数据表明，成纤维细胞重编程发生在早期胰腺病变中，并导致表达 IL6和IL33。虽然IL6分泌并已知用于调节免疫微环境，但IL33普遍存在 成纤维细胞中的核。有趣的是，IPMN的上皮核IL33也极高。 IL33包含a DNA结合结构域，已知可以调节转录。基于这些观察结果，我们建议研究 成纤维细胞重编程和比较Panins和IPMN中成纤维细胞基因表达的机制 （目标1）。此外，我们将研究成纤维细胞IL33在病变进展和建立前体的作用 Panin和IPMN中的病变微环境（PME）（AIM 2）。最后，我们将确定上皮的IL33 IPMN调节PME以及对恶性肿瘤的发展（AIM 3）。我们将整合鼠标模型，并 木材实验室中产生的原代人体组织和类器官的体外研究（请参见项目3）。 总之，这些研究将阐明PAF在不同的预示威病变中的组成和作用 胰腺。