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

• 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
• 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

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