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.
