Project Grant R01CA276347

DISSECTING ROLES OF LUNATIC FRINGE-DEPENDENT NOTCH SIGNALING IN PANCREATIC CANCER - DESPITE IMPROVEMENTS IN OVERALL SURVIVAL FOR MOST CANCERS, SURVIVAL FOR PATIENTS WITH PANCREATIC CANCER REMAINS DISMALLY LOW DUE TO THE LATE DIAGNOSIS AND RAPID SPREADING. UNDERSTANDING PANCREATIC CANCER INITIATION AND PROGRESSION IS OF GREAT IMPORTANCE FOR THE DEVELOPMENT OF EFFECTIVE INTERVENTION STRATEGY. MOUSE MODELS RECAPITULATING HUMAN PANCREATIC DUCTAL ADENOCARCINOMA (PDAC) HAVE BEEN GENERATED THROUGH ACTIVATION OF ONCOGENIC KRAS COMBINED WITH VARIOUS GENETIC MUTATIONS IN DIFFERENT PANCREATIC CELL TYPES, AND STUDIES USING MOUSE GENETICS SUGGEST THAT BOTH ACINAR AND DUCTAL CELLS CAN GIVE RISE TO PDAC, AND CELLULAR ORIGINS AND SPECIFIC GENE MUTATIONS MAY DETERMINE THE PRECURSOR LESION INITIATION, PROGRESSION, AS WELL AS MOLECULAR SUBTYPE OF PDAC. NOTCH SIGNALING PATHWAY IS A MASTER REGULATOR OF CELL FATE DECISION AND DIFFERENTIATION CRITICAL FOR PANCREATIC DEVELOPMENT AND IS DYSREGULATED IN PANCREATIC CANCER. WE RECENTLY DISCOVERED THAT EXPRESSION OF A NOTCH MODULATOR, LUNATIC FRINGE (LFNG), IS CONFINED TO A SUBSET OF CENTROACINAR CELLS IN THE NORMAL PANCREAS. LFNG-EXPRESSING CENTROACINAR CELLS ARE UNIQUELY SUSCEPTIBLE TO ONCOGENIC TRANSFORMATION AND DELETION OF LFNG BLOCKS TUMOR INITIATION FROM THESE CELLS. LFNG IS UPREGULATED IN ACINAR AND DUCTAL CELL-DERIVED PRECURSOR LESIONS, AND DELETION OF LFNG DECELERATES TUMOR DEVELOPMENT FROM THESE TWO CELL TYPES. THUS, LFNG EXERTS ONCOGENIC ROLES IN THE DEVELOPMENT OF PDAC FROM THREE DISTINCT CELLULAR ORIGINS: CENTROACINAR, ACINAR AND DUCTAL CELLS. AMPLIFICATION AND UPREGULATION OF LFNG ARE NOTED IN HUMAN PDAC AND ARE ASSOCIATED WITH POOR SURVIVAL. THEREFORE, WE PROPOSE TO DISSECT ROLES OF LFNG-DEPENDENT NOTCH SIGNALING IN PANCREATIC CANCER USING MULTIPLE APPROACHES INCLUDING ORGANOID CULTURE, LINEAGE TRACING, TEMPORAL AND LINEAGE-SPECIFIC GENETIC MANIPULATIONS, DIFFERENTIAL GENE EXPRESSION ANALYSIS, AS WELL AS FUNCTIONAL ANALYSIS OF CANDIDATE GENES IN HUMAN PDAC CELL LINES TO ADDRESS THE FOLLOWING SPECIFIC AIMS: 1) DETERMINE ROLES OF LFNG-DEPENDENT NOTCH SIGNALING IN PANCREATIC CANCER DEVELOPMENT FROM LFNG- EXPRESSING CENTROACINAR CELLS; 2) DETERMINE ROLES OF LFNG-DEPENDENT NOTCH SIGNALING IN ACINAR- AND DUCTAL-DERIVED PDAC PATHOGENESIS; AND 3) CHARACTERIZE LFNG-EXPRESSING PANCREATIC CANCER CELLS AND IDENTIFY GENES DIFFERENTIALLY EXPRESSED IN THESE CELLS AS POTENTIAL THERAPEUTIC TARGETS. WE HOPE TO DEMONSTRATE THAT LFNG IS CRITICAL FOR THE INITIATION AND PROGRESSION OF PANCREATIC CANCERS ARISING FROM DIFFERENT CELL TYPES OF THE PANCREAS, AND THAT LFNG MARKS PANCREATIC CANCER STEM CELLS THOUGHT TO BE RESPONSIBLE FOR DRUG RESISTANCE AND CANCER RELAPSE. IDENTIFICATION OF GENES DOWNSTREAM OF LFNG-DEPENDENT NOTCH SIGNALING MAY LEAD TO THE DEVELOPMENT OF BIOMARKERS FOR TARGETED THERAPY FOR THIS PARTICULARLY DEADLY DISEASE.