Novel xenograft and cell line derived from an invasive intraductal papillary mucinous neoplasm of the pancreas give new insights into molecular mechanisms.
OBJECTIVE
Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are a unique entity with malignant potential. Histologically, pancreatic ductal adenocarcinoma (PDAC) arising in IPMN (intraductal papillary mucinous carcinoma [IPMC]) appears similar to sporadic PDAC; biologically, however, IPMC seems to have a less aggressive clinical course. Little is known about the genetic signature of IPMC. In this study, we describe a novel xenograft model and cell culture created to biologically and genetically characterize these tumors.


METHODS
Xenograft mice and cell lines were created from IPMC. Global genomic changes were evaluated by cytogenetic analysis and array comparative genomic hybridization. Specific mutations and sonic hedgehog (Shh) pathway activity were examined and xenografts evaluated for sensitivity to anti-Shh therapy.


RESULTS
Cytogenetic analysis showed a tetraploid karyotype with multiple aberrations. KRAS and p53 mutations and overexpression of the Shh pathway were identified. Array comparative genomic hybridization revealed multiple chromosomal aberrations comparable with previously published data in IPMNs. Murine xenograft tumors were sensitive to anti-Shh treatment.


CONCLUSIONS
Characterization of IPMC cell lines and xenografts reveals similarities to previously published data on IPMN. In comparison to PDAC, moreover, these data reveal shared aberrations and distinct genomic changes. Thus, these xenograft model and cell lines may be useful for future preclinical investigations.
Fritz
Stefan
S
Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Fernández-del Castillo
Carlos
C
Iafrate
A John
AJ
Mino-Kenudson
Mari
M
Neyhard
Nancy
N
LaFemina
Jennifer
J
Stirman
Amy
A
Warshaw
Andrew L
AL
Thayer
Sarah P
SP
D002288:Adenocarcinoma, Mucinous / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000231:Adenocarcinoma, Papillary / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D016147:Genes, Tumor Suppressor; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors / Q000235:genetics; D014704:Veratrum Alkaloids / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
D053823:Hedgehog Proteins; D014704:Veratrum Alkaloids; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); C000541:cyclopamine