TBEL Project 1

TBEL项目1

• 批准号: 10708201
• 负责人: Marina Pasca Di Magliano
• 金额: $ 28.04万
• 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/10708201
• 关键词: CXCL1 gene; Cell Death; Cell Line; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; DNA Binding Domain; Data; Disease; Epithelial Cells; Epithelium; Family; Fibroblasts; Gene Expression; Genes; Genetic Transcription; Goals; Human; IL6 gene; In Vitro; Inflammatory; KRAS oncogenesis; KRAS2 gene; Laboratories; Lead; Lesion; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mediator; 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; 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 胰腺浸润性肿瘤有两种不同的途径， （胰腺上皮内瘤变或PanIN）和囊性（大部分为导管内乳头状粘液性） 肿瘤或IPMN）。PanIN和IPMN在人群中的发生率均显著高于侵袭性 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展。PanIN和IPMN都是 其特征在于致癌KRAS突变的常见发生，而后者也含有 在2/3的病例中存在伴随的“热点”GNAS突变。这些早期上皮细胞的改变和它们之间的相互影响 肿瘤微环境（TME）对癌症进展的影响仍未得到充分研究。的形成 早期胰腺前体伴随着异质成纤维细胞群的扩增。在 在晚期疾病中，成纤维细胞变成癌相关成纤维细胞（CAF）。对前体知之甚少 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 初步数据显示，成纤维细胞重编程发生在早期胰腺病变中， IL 6和IL 33。虽然IL 6是分泌的并且已知调节免疫微环境，但IL 33是优选的。 成纤维细胞有核。有趣的是，IPMN也具有极高的上皮细胞核IL 33。IL 33含有 DNA结合结构域，并且已知调节转录。根据这些观察，我们建议研究 成纤维细胞重编程的机制以及PanIN和IPMNs中成纤维细胞基因表达的比较 (Aim 1）。此外，我们将研究成纤维细胞IL 33在病变进展和前体细胞的建立中的作用。 PanIN和IPMN的病变微环境（PME）（目的2）。最后，我们将确定上皮细胞IL 33在 IPMN调节PME以及恶性进展（目的3）。我们将整合小鼠模型， 在Wood实验室中生成的原代人体组织和类器官的体外研究（见项目3）。 总之，这些研究将阐明PAF在不同的癌前病变中的组成和作用。 胰腺