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 - 抽象胰腺导管腺癌（PDAC）是癌症相关死亡率的第三个最常见原因美国，绝大多数患者出现晚期疾病。侵入性胰腺中的肿瘤代表了多步进的顶点，该进展始于非侵入性前体病变，仍然是未开发的“机会之窗”，用于早期检测和癌症拦截。识别前体病变的两个主要组织学亚型 - 更常见的非囊性途径，以胰腺内皮肿瘤或泛胞病变为代表，估计在PDAC的〜90％之前，并且囊性途径最常见于导管内乳头状粘液肿瘤或IPMNS表示剩下的10％。虽然该团队的成员在描述了 Panins和IPMN的组织学和遗传学，许多分子尚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提示重新编程“前体微环境”（PME），包括“与前体相关的成纤维细胞”（PAFS）。我们的三态胰腺腺癌TBEL（TRI-PACT）中心的目标癌症中心（UTMDACC），密歇根大学（Umich）和约翰·霍普金斯大学（JHU） - 是要创建一个合作和综合的U54中心，用于进行早期胰腺肿瘤的基础研究。 Tri-Pact中心将由Anirban Maitra博士（UTMDACC）和Co-Pi Marina Pasca di Magliano博士领导（Umich）。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在胰腺癌中”，我们提出了三个项目（两个基本，一个翻译），每个项目都将是得到多尺度计算肿瘤研究核心（M核）和行政核心（AC）的支持。项目1（基本）将研究关键细胞因子白细胞因子IL-33的功能需求，该因子在 PANIN和IPMN的PAF和上皮室响应KRAS和GNA突变，在PME的疾病进展和重编程中。项目2（基本）将研究独特的代谢“合成本质”以囊性前体产生的线粒体质量控制为中心 RNF43的港口损失，E3泛素连接酶在IPMN的约50％中损失。值得注意的是，三处条约调查人员有开发了胰腺癌的一般工程模型（GEMS），这些模型概括了同源人体病变，将在两个基本项目中广泛利用，并在跨物种验证中验证患者衍生的临床前模型。项目3（翻译）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以绘制个体的进化轨迹前体以空前的分辨率和高维分析相关联的分辨率 PME中的免疫和PAF组成的。累积地，这些项目将增强我们的了解早期胰腺肿瘤的驱动因素，以及用于早期检测方法的苗床。