Tumor Microenvironment Crosstalk Drives Early Lesions in Pancreatic Cancer

肿瘤微环境串扰导致胰腺癌早期病变

基本信息

批准号：
10708199
负责人：
ANIRBAN MAITRA
金额：
$ 160.05万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
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/10708199
关键词：
3-Dimensional Accounting Animal Model Architecture Basic Science Biology Cancer Biology Cancer Center Cancer Etiology Cessation of life Collaborations Communication Computational Biology Credentialing Cues Data Analyses Data Science Dependence Disease Disease Progression Distant Early Diagnosis Epithelium Event Excision Fibroblasts Genetic Genetic Engineering Genome Goals Heterogeneity Histologic Histology Human Immune Individual Institution Interleukins KRAS2 gene Lesion Malignant Neoplasms Malignant neoplasm of pancreas Maps Mediator Metabolic Michigan Mitochondria Modeling Molecular Mucinous Neoplasm Mus Mutation Neoplasms Oncology Operative Surgical Procedures Pancreas Pancreatic Adenocarcinoma Pancreatic Ductal Adenocarcinoma Pancreatic Intraepithelial Neoplasia Pancreatic cystic neoplasia Papillary Pathogenesis Pathway interactions Patients Play Pre-Clinical Model Process Quality Control Research Research Personnel Resolution Resource Sharing Role Seminal Signal Transduction Site Specificity Survival Rate Testing Translational Research United States Universities Validation cancer genomics cytokine data analysis pipeline data harmonization data sharing dimensional analysis endoplasmic reticulum stress high dimensionality improved improved outcome member molecular pathology mortality pancreatic neoplasm paracrine premalignant programs prototype reconstruction response tool translational study tumor heterogeneity tumor metabolism tumor microenvironment tumor progression ubiquitin-protein ligase

项目摘要

OVERALL - ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is the 3rd most common cause of cancer-related mortality in the United States, with the overhwhelming majority of patients presenting advanced stage disease. Invasive neoplasia in the pancreas represents the culmination of a multistep progression that begins with non-invasive precursor lesions, which remain an untapped “window of opportunity” for early detection and cancer interception. Two major histological subtypes of precursor lesions are recognized - the more common non-cystic pathway, represented by pancreatic intarepithelial neoplasia or PanIN lesions, estimated to precede ~90% of PDAC, and the cystic pathway, most commonly represented by intraductal papillary mucinous neoplasms or IPMNs, accounting for the remaining 10%. While members of this team have played a seminal role in characterizing the histology and genetics of PanINs and IPMNs, much remains to be elucidated in terms of the molecular dependencies that sustain early pancreatic neoplasia, and how signaling cues from these early lesions reprogram the “precursor microenvironment” (PME), including “precursor-associated fibroblasts” (PAFs). The goal of our Tri-state Pancreatic Adenocarcinoma TBEL (Tri-PACT) Center - incorporating UT MD Anderson Cancer Center (UTMDACC), University of Michigan (UMich) and Johns Hopkins University (JHU) - is to create a collaborative and integrated U54 center to conduct basic and translational studies in early pancreatic neoplasia. The Tri-PACT Center will be led by Dr. Anirban Maitra (UTMDACC) and Co-PI Dr. Marina Pasca di Magliano (UMich). The title of our Tri-PACT Center proposal is “Tumor Microenvironment Crosstalk Drives Early Lesions in Pancreatic Cancer”, and we are proposing three projects (two basic, one translational), each of which will be supported by a Multiscale Computational Oncology Research Core (M-CORE) and an Administrative Core (AC). Project 1 (basic) will study the functional requirement of a pivotal cytokine, interleukin IL-33, which is induced in the PAF and epithelial compartments of PanINs and IPMNs in response to KRAS and GNAS mutations, respectively, in disease progression and reprogramming of the PME. Project 2 (basic) will study a unique metabolic “synthetic essentiality” centered on mitochondrial quality control created in cystic precursors that harbor loss of RNF43, a E3 ubiquitin ligase lost in ~50% of IPMNs. Notably, the Tri-PACT investigators have developed genetically engineered models (GEMs) of pancreatic preneoplasia that recapitulate the cognate human lesions, and will be extensively leveraged in the two basic projects, with cross-species validation in patient-derived preclinical models. Project 3 (translational) will deploy a unique 3D reconstruction tool (CODA) paired with multi-region sequencing of human precursor lesions to map the evolutionary trajectory of individual precursors at an unprecedented resolution, and correlate subclonal architecture with high dimensional analysis of the immune and PAF composition within the PME. Cumulatively, these projects will enhance our understanding of the drivers of early pancreatic neoplasia, and a seedbed for early detection approaches.

总体 - 摘要胰腺导管腺癌 (PDAC) 是癌症相关死亡的第三大常见原因美国，绝大多数患者出现晚期侵袭性疾病。胰腺肿瘤代表着从非侵入性开始的多步骤进展的顶峰前体病变，这仍然是早期检测和癌症拦截的未开发的“机会之窗”。已知前体病变的两种主要组织学亚型 - 更常见的非囊性途径，以胰腺上皮内瘤变或 PanIN 病变为代表，估计先于约 90% 的 PDAC，以及囊性途径，最常见的是导管内乳头状粘液性肿瘤或 IPMN，占剩余的 10%，而该团队的成员在表征方面发挥了重要作用。 PanIN 和 IPMN 的组织学和遗传学，在分子机制方面仍有许多待阐明。维持早期胰腺肿瘤的依赖性，以及这些早期病变的信号传导机制重新编程“前体微环境”（PME），包括“前体相关成纤维细胞”（PAF）。我们三州胰腺癌 TBEL (Tri-PACT) 中心的目标 - 合并 UT MD 安德森癌症中心 (UTMDACC)、密歇根大学 (UMich) 和约翰霍普金斯大学 (JHU) - 旨在创建一个协作和综合的 U54 中心，致力于早期胰腺肿瘤的基础和转化研究。 Tri-PACT 中心将由 Anirban Maitra 博士 (UTMDACC) 和联合 PI 博士 Marina Pasca di Magliano 领导（密歇根大学）我们的 Tri-PACT 中心提案的标题是“肿瘤微环境串扰驱动早期病变”。胰腺癌”，我们提出了三个项目（两个基础项目，一个转化项目），每个项目都将是由多尺度计算肿瘤学研究核心（M-CORE）和管理核心（AC）支持。项目 1（基础）将研究关键细胞因子白细胞介素 IL-33 的功能需求，该细胞因子在 PAF 以及 PanIN 和 IPMN 的上皮区室响应 KRAS 和 GNAS 突变，项目 2（基础）将分别在疾病进展和重编程方面研究独特的方法。代谢“合成必需性”以囊性前体中产生的线粒体质量控制为中心 RNF43 缺失，这是一种 E3 泛素连接酶，约 50% 的 IPMN 中缺失。值得注意的是，Tri-PACT 研究人员发现。开发了胰腺癌前病变的基因工程模型（GEM），概括了同源人类病变，并将在两个基本项目中得到广泛利用，并进行跨物种验证源自患者的临床前模型项目 3（转化）将部署独特的 3D 重建工具 (CODA)。与人类前体病变的多区域测序配对，绘制个体的进化轨迹以前所未有的分辨率分析前体，并将亚克隆结构与高维分析相关联总的来说，这些项目将增强我们的 PME 中的免疫和 PAF 组成。了解早期胰腺肿瘤的驱动因素，并为早期检测方法奠定基础。