Document text
Principal Investigator: DAVID A. BRENNER
Organization: UNIVERSITY OF CALIFORNIA, SAN DIEGO
Fiscal Year: 2024
Award: $725,478
Funding agency: National Cancer Institute
Project Summary
Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive desmoplasia, resulting in occupancy
of most of the tumor mass by a dense stroma consisting of fibroblasts, macrophages, and extracellular matrix
(ECM). Fibrillar collagens, such as type I collagen (Col I), are major ECM components and were reported to
exert poorly understood stimulatory and inhibitory effects on PDAC growth and malignancy. It was also observed
that patients whose stroma is fibrolytic, with a high content of cleaved collagen fragments generated by matrix
metalloproteases (MMP), show poor overall survival after resection, whereas patients with an inert stroma, rich
in intact collagen fibers, have considerably improved survival. The mechanisms underlying these clinical
observations and the tumor stimulatory or inhibitory effects of Col I were heretofore unknown. Using a unique
culture system, preclinical models, and clinical specimens, we discovered that intact (i) Col I fibers and MMP-
generated cleaved (c) Col I fragments have diametrically opposed effects on PDAC metabolism and growth due
to their differential interactions with the collagen receptor DDR1. Whereas cCol I (and other MMP-cleaved
collagens) activates DDR1 and its downstream effectors, which include transcription factors NF-kB and NRF2,
to stimulate PDAC metabolism, mitochondrial biogenesis, and respiration, iCol I does not activate DDR1 and
instead induces its ubiquitin-dependent proteasomal degradation, thereby inhibiting NRF2 activation and PDAC
metabolism. Our goal is to understand how MMP cleavage enables the binding of cCol I to DDR1 and determine
if binding to DDR1 is required for induction of its degradation by iCol I. To fully understand how cCol I and DDR1
signaling control PDAC metabolism and growth, and why Col I ablation is not as inhibitory as prevention of Col
I cleavage, we will test whether the differential effects of cCol I and iCol I on DDR1 expression and activation
apply to other fibrillary collagens (Col III) and define the underlying biochemical mechanisms that enable DDR1
binding. Next, we will investigate how iCol I triggers DDR1 ubiquitination and proteasomal degradation, and the
role of the newly uncovered DDR1 E3 ligase FBXW2 in this process. These studies will include identification of
the mechanism by which iCol I stimulates DDR1 ubiquitination by FBXW2 and development of ligase-recruiting
tool compounds that induce DDR1 degradation, whose biological effects will be evaluated in cultured cells and
mouse models. This will be followed by studying the role of individual MMP isozymes, expressed in PDAC cancer
cells, cancer-associated fibroblasts, and macrophages, in collagen remodeling and PDAC metabolism and
growth. We will determine the suitability of individual collagen cleaving MMPs as drug targets for the treatment
of cCol I enriched PDAC. We will also determine the mechanisms responsible for MMP induction in the PDAC
microenvironment, as they may provide additional therapeutic targets. The proposed studies will employ cutting-
edge technologies, innovative ECM based PDAC cultures, new genetically modified mouse strains that allow the
evaluation of both primary and liver metastatic PDAC and clinical specimens.
Terms: <20S Catalytic Proteasome><20S Core Proteasome><20S Proteasome><20S Proteosome><APF-1><ATP-Dependent Proteolysis Factor 1><Ablation><Abscission><Athymic Mice><Athymic Nude Mouse><Autophagocytosis><Binding><Biochemical><Biogenesis><Biological><Biology><Bypass><CAK gene><COL1A1><COL1A1 gene><Cancers><Cell Adhesion Kinase><Cell Communication and Signaling><Cell Signaling><Cell model><Cell-Extracellular Matrix><Cellular model><Clinical><Clostridiopeptidase A><Clostridium histolyticum Collagenase><Collagen><Collagen Fiber><Collagen Receptors><Collagen Type I><Collalysine><Compensation><Complex><Cultured Cells><DDR gene><DDR1><DDR1 gene><Deposit><Deposition><Desmoplastic><Desmoplastic Reaction><Development><Discoidin Domain Receptor Family Member 1><Down-Regulation><E3 Ligase><E3 Ubiquitin Ligase><ECM><EDDR1><Epithelial Discoidin Domain Receptor 1><Epithelial-Specific Receptor Kinase><Evaluation><Excision><Extirpation><Extracellular Matrix><Fiber><Fibrillar Collagen><Fibroblasts><Fibrosis><Fucus><Future><Gene Modified><Generalized Growth><Genetic Alteration><Genetic Change><Genetic defect><Goals><Growth><HMG-20><Hepatic><High Mobility Protein 20><Human><Immunoglobulin Enhancer-Binding Protein><In Vitro><Individual><Inflammation><Intermediary Metabolism><Intracellular Communication and Signaling><Isoenzymes><Isozymes><Ligase><Ligase Gene><Liver><MMPs><Macropain><Macrophage><Macroxyproteinase><Malignant><Malignant - descriptor><Malignant Cell><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Matrix Metalloproteinases><Mediating><Metabolic Processes><Metabolic stress><Metabolism><Metallopeptidases><Metalloproteases><Metalloproteinases><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Microbial Collagenase><Mitochondria><Modern Man><Molecular Interaction><Mouse Homolog of PTK3><Mouse Strains><Multicatalytic Proteinase><Murine><Mus><Mutant Strains Mice><Mutation><Myeloid Cells><Myofibroblast><Mφ><NEP gene><NF-kB><NF-kappa B><NF-kappaB><NFKB><NTRK4><Neoplasm Metastasis><Neuroepithelial Tyrosine Kinase><Neurotrophic Tyrosine Kinase Receptor Type 4><Nuclear Factor kappa B><Nuclear Transcription Factor NF-kB><Nucleolysin><Nude Mice><Nutrient availability><Nutritional><Origin of Life><PDAC cancer cell><PDAC cell><PTK Receptors><PTK3 Homolog><Pancreas><Pancreas Cancer><Pancreas Ductal Adenocarcinoma><Pancreas Grafting><Pancreas Transplantation><Pancreatic><Pancreatic Cancer><Pancreatic Ductal Adenocarcinoma><Patients><Play><Pre-Clinical Model><Preclinical Models><Prevention><Process><Prosome><Proteasome><Proteasome Endopeptidase Complex><Proteosome><RTK6><Receptor Protein-Tyrosine Kinases><Receptor Tyrosine Kinase 6><Receptor Tyrosine Kinase Gene><Removal><Reporting><Research Specimen><Resistance><Respiration><Role><Secondary Neoplasm><Secondary Tumor><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Site-Directed Mutagenesis><Site-Specific Mutagenesis><Specimen><Stress><Surgical Removal><Synthetases><System><TRKE><Targeted DNA Modification><Targeted Modification><Technology><Testing><Time><Tissue Growth><Transcription Factor NF-kB><Transmembrane Receptor Protein Tyrosine Kinase><Type 1 Collagen><Tyrosine Kinase Linked Receptors><Tyrosine Kinase Receptor E><Tyrosine Kinase Receptors><Ubiquitilation><Ubiquitin><Ubiquitin Ligase Component Gene><Ubiquitin Ligase Gene><Ubiquitin Protein Ligase><Ubiquitin-Protein Ligase Complexes><Ubiquitin-Protein Ligase E3><Ubiquitination><Ubiquitinoylation><autophagy><biologic><biological signal transduction><cancer cell><cancer cell metabolism><cancer metabolism><cancer metastasis><collagenase I><developmental><experiment><experimental research><experimental study><experiments><gene modification><genetically modified><genome mutation><hepatic body system><hepatic organ system><improved><innovate><innovation><innovative><intrahepatic><kappa B Enhancer Binding Protein><malignancy><mitochondrial><mouse model><mouse mutant><multicatalytic endopeptidase complex><murine model><neoplasm blood supply><neoplasm vascular supply><neoplasm/cancer><nuclear factor kappa beta><nutritious><ontogeny><pancreatic ductal adenocarcinoma cell><pancreatic malignancy><pharmacologic><recruit><resection><resistant><respiratory mechanism><small molecule><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><tool><trait><tumor><tumor blood supply><tumor cell metabolism><tumor cell metastasis><tumor metabolism><tumor vascular supply><ubiquination><ubiquitin conjugation><ubiquitin ligase><ubiquitin-protein ligase>