Document text
Principal Investigator: Whitney Jean Bell
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2024
Award: $40,491
Funding agency: National Cancer Institute
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest adult cancers with a 5-year survival rate of
only 11% and is one of the top five leading causes of cancer-related deaths for men and women in the United
States. These dire statistics underscore the need for a better understanding of the mechanisms that promote
pancreatic cancer initiation and progression. Recent studies have begun to show that metaplastic epithelial
differentiation in pancreatic cancer can significantly impact disease progression. Our preliminary data from
ongoing studies investigating the role of cytokines IL-12/IL-23 in pancreatic cancer cell differentiation showed
that gain of aggressive epithelial to mesenchymal-like phenotype is associated with the concurrent loss of gastric
lineage genes, including Gastrokine 2 (Gkn2). Gkn2 is abundantly expressed by normal stomach epithelial cells,
plays an anti-inflammatory role in gastric epithelial homeostasis. Recently, Gkn2 and its family member Gkn1
have been shown to be de novo upregulated in metaplastic epithelial cells in pancreatic cancer. However, the
functional roles of gastrokines in pancreatic tumorigenesis remain unclear. The goals of this proposal are to
elucidate the kinetics, cellular source, and driver(s) of de novo Gkn2 expression in pancreatic neoplasia, as well
as determine the functional role of Gkn2 in pancreatic cancer development. To achieve these goals, in Aim 1,
we will determine the expression pattern and cellular identity of Gkn2-positive cells, as well as understand how
oncogenic Kras and/or Src signaling may contribute to the expression of Gkn2 in pancreatic epithelial cells. In
Aim 2, we will investigate the functional role of Gkn2 in pancreatic tumor growth, tumor cell differentiation, and
invasion. Specifically, we will utilize reversible Gkn2 knockdown systems to determine its contribution to the
growth and differentiation of Kras-transformed epithelial cells in pancreatic cancer. Our proposed research will
utilize state-of-the art models to provide an understanding of how a gastric identity gene program emerges early
in transformed pancreatic epithelium and acts as a potential impediment to the aggressive progression of cancer.
Terms: <21+ years old><Address><Adult><Adult Human><Affect><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antioncogene Protein p53><Assay><Autoregulation><BCEI><Bioassay><Biological Assay><Breast Cancer Estrogen-Inducible Sequence><Cancer Cause><Cancer Etiology><Cancers><Causality><Cell Body><Cell Communication and Signaling><Cell Differentiation><Cell Differentiation process><Cell Growth in Number><Cell Line><Cell Multiplication><Cell Proliferation><Cell Signaling><CellLine><Cells><Cellular Morphology><Cellular Proliferation><Cellular Tumor Antigen P53><Cessation of life><Color><Confocal Microscopy><Data><Death><Development><Diagnosis><Differentiation and Growth><Disease><Disease Progression><Disorder><Doxycycline><Duct><Duct (organ) structure><Edodekin Alfa><Epithelial Cells><Epithelium><Etiology><Event><Family member><Gastric Body Cancer><Gastric Cancer><Gastric Cardia Cancer><Gastric Fundus Cancer><Gastric Pit><Gastric Pylorus Cancer><Gastrointestinal Trefoil Protein PS2><Gene Expression><Genes><Genetic Markers><Goals><Histologic><Histologically><Homeostasis><Human><IL-12><IL-23><IL12><Immunoblotting><Immunofluorescence><Immunofluorescence Immunologic><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><In Vitro><Interleukin-12><Intracellular Communication and Signaling><Invaded><KRAS driven oncogenesis><KRAS oncogenesis><KRAS-driven tumorigenesis><KRAS-mediated tumorigenesis><Kinetics><Knowledge><Lesion><Lesion by Stage><Maintenance><Malignant Gastric Neoplasm><Malignant Gastric Tumor><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Mesenchymal><Metaplastic Cell><Metaplastic Epithelial Cell><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Modeling><Modern Man><Molecular Biology Techniques><Mucins><Mucosa><Mucosal Tissue><Mucous Membrane><Mucus Glycoprotein><Murine><Mus><NKSF><Natural Killer Cell Stimulatory Factor><Neoplasm Metastasis><Oncoprotein p53><Operative Procedures><Operative Surgical Procedures><Organoids><P53><Pancreas><Pancreas Cancer><Pancreas Ductal Adenocarcinoma><Pancreas Neoplasms><Pancreas Tumor><Pancreatic><Pancreatic Cancer><Pancreatic Diseases><Pancreatic Disorder><Pancreatic Ductal Adenocarcinoma><Pancreatic Tumor><Pathological Staging><Pattern><Phenotype><Phosphoprotein P53><Phosphoprotein pp53><Physiological Homeostasis><Play><Population><Protein TP53><Proteins><RNA Seq><RNA sequencing><RNAseq><Regulation><Reporting><Research><Research Proposals><Role><Secondary Neoplasm><Secondary Tumor><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Source><Specific qualifier value><Specified><Staging><Staining method><Stains><Stomach><Stomach Cancer><Strains Cell Lines><Surface><Surgical><Surgical Interventions><Surgical Procedure><Survival Rate><System><TFF1><TFF1 gene><TP53><TP53 gene><TRP53><Testing><Therapeutic Intervention><Training><Trefoil Factor 1><Tumor Cell><Tumor Protein p53><Tumor Protein p53 Gene><Tumor Subtype><Tumor Volume><Tumor Weights><United States><Up-Regulation><Upregulation><Vibramycin><Western Blotting><Western Immunoblotting><Woman><Work><adulthood><alpha-6-Deoxyoxytetracycline><axon growth cone guidance><axon guidance><biological signal transduction><biomarker development><cancer cell differentiation><cancer initiation><cancer metastasis><cancer progression><causation><cell morphology><cellular differentiation><cultured cell line><cytokine><developmental><differential expression><differentially expressed><disease causation><experiment><experimental research><experimental study><experiments><expression subtypes><gastric><gastric foveola><gastric malignancy><gene biomarker><gene expression biomarker><gene marker><gene signature biomarker><genetic biomarker><histologic stains><histological stains><immunocytochemistry><in vivo><inducible expression><inducible gene expression><inhibitor><insight><interleukin-23><intervention therapy><knock-down><knockdown><loss of function><malignancy><malignant stomach neoplasm><malignant stomach tumor><men><molecular sub-types><molecular subsets><molecular subtypes><mutant><neoplasm progression><neoplasm/cancer><neoplastic><neoplastic cell><neoplastic progression><oncogenic KRAS><p53 Antigen><p53 Genes><p53 Tumor Suppressor><pS2><pancreas disorder><pancreatic cancer cells><pancreatic carcinogenesis><pancreatic malignancy><pancreatic neoplasia><pancreatic neoplasm><pancreatic oncogenesis><pancreatic tumor cells><pancreatic tumorigenesis><patient prognosis><precancer><precancerous><premalignant><programs><protein blotting><protein expression><protein p53><response to therapy><response to treatment><scRNA-seq><shRNA><short hairpin RNA><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><small hairpin RNA><social role><statistics><stomach fundus cancer><stomach pylorus cancer><surgery><therapeutic response><therapy response><transcriptional differences><transcriptome sequencing><transcriptomic sequencing><treatment response><treatment responsiveness><tumor><tumor cell metastasis><tumor growth><tumor progression><tumorigenic>