ABSTRACT
PanINs and IPMNs are the two most common precursor lesions that can progress to invasive pancreatic ductal adenocarcinoma (PDA). DCLK1 has been identified as a biomarker of progenitor cells in PDA progressed from PanINs. To explore the potential role of DCLK1-expressing cells in the genesis of IPMNs, we compared the incidence of DCLK1-positive cells in pancreatic tissue samples from genetically-engineered mouse models (GEMMs) for IPMNs, PanINs, and acinar to ductal metaplasia by immunohistochemistry and immunofluorescence. Mouse lineage tracing experiments in the IPMN GEMM showed that DCLK1+ cells originated from a cell lineage distinct from PDX1+ progenitors. The DCLK1+ cells shared the features of tuft cells but were devoid of IPMN tumor biomarkers. The DCLK1+ cells were detected in the earliest proliferative acinar clusters prior to the formation of metaplastic ductal cells, and were enriched in the "IPMN niches". In summary, DCLK1 labels a unique pancreatic cellular lineage in the IPMN GEMM. The clustering of DCLK1+ cells is an early event in Kras-induced pancreatic tumorigenesis and may contribute to IPMN initiation.
Subject(s)
Homeodomain Proteins/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Pancreatic Intraductal Neoplasms/genetics , Pancreatic Neoplasms/genetics , Protein Serine-Threonine Kinases/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Trans-Activators/metabolism , Animals , Carcinogenesis/genetics , Carcinogenesis/metabolism , Cell Lineage , Cell Proliferation , Doublecortin-Like Kinases , Female , Genetic Engineering , Homeodomain Proteins/genetics , Humans , Kruppel-Like Factor 4 , Male , Mice , Neoplasm Invasiveness , Neoplasm Transplantation , Pancreatic Intraductal Neoplasms/metabolism , Pancreatic Neoplasms/metabolism , Trans-Activators/geneticsABSTRACT
BACKGROUND: Photographic stimuli are commonly used to assess cue reactivity in the research and treatment of alcohol use disorder. The stimuli used are often non-standardized, not properly validated, and poorly controlled. There are no previously published, validated, American-relevant sets of alcohol images created in a standardized fashion. OBJECTIVES: We aimed to: 1) make available a standardized, matched set of photographic alcohol and non-alcohol beverage stimuli, 2) establish face validity, the extent to which the stimuli are subjectively viewed as what they are purported to be, and 3) establish construct validity, the degree to which a test measures what it claims to be measuring. METHODS: We produced a standardized set of 36 images consisting of American alcohol and non-alcohol beverages matched for basic color, form, and complexity. A total of 178 participants (95 male, 82 female, 1 genderqueer) rated each image for appetitiveness. An arrow-probe task, in which matched pairs were categorized after being presented for 200 ms, assessed face validity. Criteria for construct validity were met if variation in AUDIT scores were associated with variation in performance on tasks during alcohol image presentation. RESULTS: Overall, images were categorized with >90% accuracy. Participants' AUDIT scores correlated significantly with alcohol "want" and "like" ratings [r(176) = 0.27, p = <0.001; r(176) = 0.36, p = <0.001] and arrow-probe latency [r(176) = -0.22, p = 0.004], but not with non-alcohol outcomes. Furthermore, appetitive ratings and arrow-probe latency for alcohol, but not non-alcohol, differed significantly for heavy versus light drinkers. CONCLUSION: Our image set provides valid and reliable alcohol stimuli for both explicit and implicit tests of cue reactivity. The use of standardized, validated, reliable image sets may improve consistency across research and treatment paradigms.
