Solid-pseudopapillary neoplasms are a rare human neoplasm that account for approximately 1% of pancreatic tumors 41
. Various groups have reported that over 90% of these tumors contain mutations that are predicted to interfere with the serine/threonine phosphorylation that is necessary to properly target β-catenin for degradation 18, 42
. Similar loss of this phosphorylation in β-catactive
mice, through Cre-mediated loss of the third exon, results in large tumors that appear closely related to human SPN. Thus, this study demonstrates for the first time that these human mutations in β-catenin are likely the proximate cause of SPN. Moreover, the Ptf1a-Cre; β-catactive
mouse is the first published murine model of this enigmatic tumor and proves that β-catenin stabilization, alone, is sufficient to induce SPN tumorigenesis within the appropriate cellular context. Interestingly, human SPNs most often occur in young females 41
. However, tumor frequency was equivalent in male and female mice and increased with age in the Ptf1a-Cre; β-catactive
mouse. This suggests that there might be different modifiers which alter human susceptibility to this pancreatic tumor.
Lineage tracing experiments are necessary to conclusively demonstrate that pancreatic ducts are the cells of origin in the SPN-like tumors we describe in the Ptf1a-Cre; β-catactive
mice. Unfortunately, efforts to create a mouse strain in which Cre-recombinase activity is restricted to the pancreatic ductal compartment have been unsuccessful so far. However, comparing the phenotype we observe in the Ptf1a-Cre; β-catactive
with that of the Pdx-Crelate; β-catactive 28
provides compelling, although not definitive, evidence of a ductal origin for SPN. Pdx-Crelate
mice have Cre-recombinase activity in acinar cells and pancreatic islets, but not within pancreatic ducts. The pancreas of Pdx-Crelate; β-catactive
mice grows to nearly 5 times the size of control littermates due to expansion of the exocrine compartment, a phenotype similar to that seen in Ptf1a-Cre; β-catactive
mice. In contrast, tumors did not develop in Pdx-Crelate; β-catactive
mice or in another model of pancreatomegaly that is based on the conditional elimination of APC43
. Conversely, Ptf1a-Cre; β-catactive
mice successfully activate β-catenin within pancreatic ducts, in addition to the islet and acinar compartments, resulting in a high frequency of SPN like tumors. While one cannot rule out the existence of a previously unappreciated cell population that is being selectively targeted by the Ptf1a-Cre
and not the PdxCrelate
mouse strain, it is likely that cells residing within the ductal compartment are responsible for the tumors observed. A schematic of the expression domains of the various mouse Cre
strains we have used to stabilize β-catenin and their resultant phenotype is provided in .
Comparison of Cre expression domains of Pdx-Creearly, Pdx-Crelate, and Ptf1a-Cre
Our finding that concurrent activation of β-catenin in the KrasG12D
mouse diverts the cellular fate of neoplasms from PanIN’s to novel ductal and cribriform tumor isoforms was particularly surprising. The Ptf1a-Cre; KrasG12D
mouse model has proven to be especially permissive to the formation of PDA in mice. The introduction of a variety of oncogenic mutations, such as the loss of the tumor suppressors p53 or Ink4a/Arf 44,34
into this model results in the formation of tumors with differing degrees of malignancy. More recently it has been shown that the introduction of other mutations in the Ptf1a Cre; KrasG12D
mouse model can shift the formation of PanIN lesions towards the formation of cystic neoplasms. The combination of a Kras mutation and Dpc4/Smad4 mutations in the mice results in the formation of mucinous cystic neoplasms (MCN) and intraductal papillary mucinous neoplasms (IPMN), respectively 45,46
. These recently recognized entities are also thought to give rise to PDAC. In contrast to the Kras/DPC4 induced aberrations, the lesions we observed in Ptf1aCre; β-catactive
are not mucinous. Therefore, the activation of β-catenin in the context of a Kras activating mutation prevents the formation of PanIN lesions while resulting in other neoplastic alterations. The exact nature of these tumors remains to be established, but their ductal properties display similarities to recently defined intraductal tubular tumors (ITTs)35–37
, a subgroup of intraductal neoplasms possibly related to intraductal papillary-mucinous neoplasms (IPMN). However, because these ITTs have only recently been described, a direct comparison between Ptf1a-Cre; β-catactive; KrasG12D
mouse and human tumors will need to be addressed in future studies. A discriminating feature of the tumors observed in the Ptf1a-Cre; β-catactive; KrasG12D
mice is the absence of Hh signaling that is seen in PanIN lesions. It will be interesting to investigate the status of Hh signaling in human ITTs.
In conclusion, our study demonstrates that the context and sequence in which oncogenic mutations are acquired in the pancreas have a profound impact on tumor initiation and outcome. Moreover, our results suggest that the Wnt signaling pathway may act as a key determinant of tumor fate within the pancreas. Human pancreatic ductal adenocarcinoma is the 4th leading cause of cancer death in the United States. Current therapies are ineffective in treating this malignancy, resulting in a 5 year survival rate that is less than 5%. Our observation that stabilization of β-catenin dramatically alters the tumor phenotype in a mouse model of early PDA provides another window into the complex molecular circuitry involved in tumorigenesis. Further dissection of how β-catenin activation alters the downstream consequences of Kras activation might lead to novel therapeutic opportunities.