title: Amplified centrosomes may underlie aggressive disease course in pancreatic ductal adenocarcinoma.
abstract: Centrosome amplification (CA), the presence of centrosomes that are abnormally numerous or enlarged, is a well-established driver of tumor initiation and progression associated with poor prognosis across a diversity of malignancies. Pancreatic ductal adenocarcinoma (PDAC) carries one of the most dismal prognoses of all cancer types. A majority of these tumors are characterized by numerical and structural centrosomal aberrations, but it is unknown how CA contributes to the disease and patient outcomes. In this study, we sought to determine whether CA was associated with worse clinical outcomes, poor prognostic indicators, markers of epithelial-mesenchymal transition (EMT), and ethnicity in PDAC. We also evaluated whether CA could precipitate more aggressive phenotypes in a panel of cultured PDAC cell lines. Using publicly available microarray data, we found that increased expression of genes whose dysregulation promotes CA was associated with worse overall survival and increased EMT marker expression in PDAC. Quantitative analysis of centrosomal profiles in PDAC cell lines and tissue sections uncovered varying levels of CA, and the expression of CA markers was associated with the expression of EMT markers. We induced CA in PDAC cells and found that CA empowered them with enhanced invasive and migratory capabilities. In addition, we discovered that PDACs from African American (AA) patients exhibited a greater extent of both numerical and structural CA than PDACs from European American (EA) patients. Taken together, these findings suggest that CA may fuel a more aggressive disease course in PDAC patients.
authors.affiliation: a Department of Biology ; Georgia State University ; Atlanta , GA USA.
authors.forename: Karuna
authors.initials: K
authors.lastname: Mittal
authors.forename: Angela
authors.initials: A
authors.lastname: Ogden
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Reid
authors.forename: Padmashree C G
authors.initials: PC
authors.lastname: Rida
authors.forename: Sooryanarayana
authors.initials: S
authors.lastname: Varambally
authors.forename: Ritu
authors.initials: R
authors.lastname: Aneja
mesh_terms: D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D018385:Centrosome / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
keywords: centrosome amplification; epithelial-mesenchymal transition; ethnic health disparity; pancreatic cancer; pancreatic ductal adenocarcinoma