Pancreatic ductal adenocarcinoma ranks among the most lethal of human malignancies. Here, we assess the cooperative interactions of two signature mutations in mice engineered to sustain pancreas-specific Cre-mediated activation of a mutant Kras allele (Kras G12D) and deletion of a conditional Ink4a/Arf tumor suppressor allele. The phenotypic impact of Kras G12D alone was limited primarily to the development of focal premalignant ductal lesions, termed pancreatic intraepithelial neoplasias (PanINs), whereas the sole inactivation of Ink4a/Arf failed to produce any neoplastic lesions in the pancreas. In combination, Kras Pancreatic ductal adenocarcinoma has a median survival of 6 months and a 5-year survival of <5%, making it one of the most lethal human cancers (Warshaw and Fernandez-del Castillo 1992). This poor prognosis relates to the uniformly advanced disease stage at the time of diagnosis and to its profound resistance to existing therapies. A number of key challenges must be addressed to permit improvements in patient outcome, including the need to understand more definitively the cellular origins of this disease, to elucidate the biological interactions of the tumor cell and stromal components, to determine the role of specific genetic lesions and their signaling surrogates in the initiation and progression of the tumor, and to uncover the basis for the intense therapeutic resistance of these cancers ).This malignancy is thought to arise from the pancreatic ducts on the basis of its histological and immunohistochemical relationship to this cell type (Solcia et al. 1995). Consistent with a ductal origin, premalignant lesions, known as pancreatic intraepithelial neoplasms (PanINs)-which are thought to arise from the smaller pancreatic ducts-are found in close physical contiguity with advanced malignant tumors (Cubilla and Fitzgerald 1976;Hruban et al. 2001). PanINs appear to progress toward increasingly atypical histological stages and display the accumulation of clonal genetic changes, suggesting that they are precursors of ductal adenocarcinoma

Germline mutations in LKB1, TSC2, or PTEN tumor suppressor genes result in hamartomatous syndromes with shared tumor biological features. The recent observations of LKB1-mediated activation of AMP-activated protein kinase (AMPK) and AMPK inhibition of mTOR through TSC2 prompted us to examine the biochemical and biological relationship between LKB1 and mTOR regulation. Here, we report that LKB1 is required for repression of mTOR under low ATP conditions in cultured cells in an AMPK- and TSC2-dependent manner, and that Lkb1 null MEFs and the hamartomatous gastrointestinal polyps from Lkb1 mutant mice show elevated signaling downstream of mTOR. These findings position aberrant mTOR activation at the nexus of these germline neoplastic conditions and suggest the use of mTOR inhibitors in the treatment of Peutz-Jeghers syndrome.

Activating KRAS mutations and p16 Ink4a inactivation are near universal events in human pancreatic ductal adenocarcinoma (PDAC). In mouse models, Kras G12D initiates formation of premalignant pancreatic ductal lesions, and loss of either Ink4a͞Arf (p16 Ink4a ͞p19 Arf ) or p53 enables their malignant progression. As recent mouse modeling studies have suggested a less prominent role for p16 Ink4a in constraining malignant progression, we sought to assess the pathological and genomic impact of inactivation of p16 Ink4a , p19 Arf , and͞or p53 in the Kras G12D model. Rapidly progressive PDAC was observed in the setting of homozygous deletion of either p53 or p16 Ink4a , the latter with intact germ-line p53 and p19 Arf sequences. Additionally, Kras G12D in the context of heterozygosity either for p53 plus p16 Ink4a or for p16 Ink4a ͞p19 Arf produced PDAC with longer latency and greater propensity for distant metastases relative to mice with homozygous deletion of p53 or p16 Ink4a ͞p19 Arf . Tumors from the double-heterozygous cohorts showed frequent p16 Ink4a inactivation and loss of either p53 or p19 Arf . Different genotypes were associated with specific histopathologic characteristics, most notably a trend toward less differentiated features in the homozygous p16 Ink4a ͞p19 Arf mutant model. High-resolution genomic analysis revealed that the tumor suppressor genotype influenced the specific genomic patterns of these tumors and showed overlap in regional chromosomal alterations between murine and human PDAC. Collectively, our results establish that disruptions of p16 Ink4a and the p19 ARF -p53 circuit play critical and cooperative roles in PDAC progression, with specific tumor suppressor genotypes provocatively influencing the tumor biological phenotypes and genomic profiles of the resultant tumors.array comparative genomic hybridization ͉ mouse models ͉ pancreatic cancer ͉ KRAS ͉ tumor suppressor P ancreatic ductal adenocarcinoma (PDAC) ranks as the fourth leading cause of cancer mortality in the United States and causes Ͼ200,000 deaths worldwide annually (1, 2). Histopathological analyses have identified precursor lesions, pancreatic intraepithelial neoplasias (PanIN), which appear to progress through increasingly severe stages of cellular atypia leading to invasive PDAC (3). These lesions show multistep molecular progression that includes early activating KRAS mutations and telomere attrition, and subsequent inactivation of p16 Ink4a , p14 ARF , p53, and͞or SMAD4 tumor suppressors in a high percentage of cases (4-6).The Ink4a͞Arf locus (hereafter denoted p16 Ink4a ͞p19 Arf ) encodes tumor suppressors p16 INK4A and p14 ARF (p19 Arf in the mouse). p16 INK4A is a G 1 cyclin-dependent kinase (CDK) inhibitor that binds to CDK4 and CDK6 and prevents their association with D-type cyclins (7), thereby facilitating CDK4͞6-cyclin D-mediated phosphorylation and inactivation of retinoblastoma protein (RB) and S-phase entry. p16 INK4A -mediated tumor suppression may relate to its induction by activated oncogenes and consequen...

Hedgehog signaling through the ciliary membrane protein Smoothened dissociates the Gli transcription factors from their inhibitor, Suppressor of Fused.