U54CA274371

Tumor Microenvironment Crosstalk Drives Early Lesions in Pancreatic Cancer - Overall - Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the 3rd most common cause of cancer-related mortality in the United States, with the overwhelming 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 intraductal 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 provide a seedbed for early detection approaches.

New York University

TO PROVIDE AN ORGANIZATIONAL FOCUS AND STIMULUS FOR THE HIGHEST QUALITY CANCER RESEARCH THAT EFFECTIVELY PROMOTES INTERDISCIPLINARY CANCER RESEARCH AIMED TOWARD THE ULTIMATE GOAL OF REDUCING CANCER INCIDENCE, MORTALITY AND MORBIDITY. THE CANCER CENTER SUPPORT GRANT (CCSG) PROVIDES THE RESOURCES AND INFRASTRUCTURE TO FACILITATE THE COORDINATION OF INTERDISCIPLINARY PROGRAMS ACROSS A BROAD SPECTRUM OF RESEARCH FROM BASIC LABORATORY RESEARCH TO CLINICAL INVESTIGATION TO POPULATION SCIENCE. THE CCSG SUPPORTS SALARIES FOR SCIENTIFIC LEADERSHIP OF THE CENTER, SHARED RESOURCES FOR FUNDED CENTER INVESTIGATORS, CERTAIN ADMINISTRATIVE COSTS, PLANNING AND EVALUATION, AND DEVELOPMENTAL FUNDS FOR NEW RECRUITMENTS AND FEASIBILITY STUDIES.

93.397 - Cancer Centers Support Grants

National Cancer Institute (NCI) [HHS - NIH]

New York, New York 100165818 United States

Single Zip Code

Translational and Basic Science Research in Early Lesions (TBEL) (U54 Clinical Trial Not Allowed) (RFA-CA-21-054)

Amendment Since initial award the total obligations have increased 268% from $1,558,076 to $5,735,872.