Pancreatic ductal adenocarcinoma (PDA) is a highly aggressive and lethal disease with the highest 1 and 5 year mortalities of any cancer. PDA is notoriously difficult to detect and resistant to all current therapeutic modalities. Moreover, most patients present at diagnosis with locally advanced or frankly metastatic disease; median survival in this setting is approximately 6 months. For the few patients (<15%) for whom surgical resection is possible, median survival increases to 2 years but is not durable: survival at 5 years is only 20% and continues to decline to less than 2% at 10 years. Tellingly, the majority of these patients also eventually die of metastatic disease suggesting that clinical stage I tumors are, in fact, already micrometastatic stage IV. Thus, understanding the mechanisms underlying this unusual drive for metastasis is essential to developing therapies that meaningfully prolong survival in pancreas cancer patients. A dearth of tissue specimens from primary pancreas cancers and, especially, from metastatic lesions, has hindered scientific study of this disease. Nevertheless, knowledge gleaned from studies of these scarce resected tissues has generated testable hypotheses and guided recent successful efforts to faithfully model the disease in mice. We and others have systematically engineered key oncogene and tumor suppressor gene (TSG) mutations into endogenous murine loci revealing critical insights into disease pathogenesis. We now know, for example, that activating mutations in the Kras proto-oncogene initiate preinvasive disease and that the resultant pancreatic intraepithelial neoplasms (PanIN) progress spontaneously to invasive and metastatic PDA. Disease progression can be hastened in the context of concomitant mutation of Trp53 or p16/p19. Interestingly, heterozygous mutation of Smad4/Dpc4 in the context of oncogenic Kras alters the differentiation state of the precursor lesions to instead generate mucinous cystic neoplasms (MCN). These lesions progress more slowly, and with a lower metastatic burden, to invasive PDA through a combination of LOH of Dpc4 and mutation of either Trp53 or p16. Thus, the relative timing of mutations in these TSG contributes to determining the pathobiology and prognosis of the resulting disease. We have further explored the effects of Dpc4 mutation on disease behavior by generating KrasLSL-G12D/+;Trp53LSL-R172H/+;Dpc4flox/+;Cre (KPDC) animals. Somewhat surprisingly, these animals display the same median survival as KrasLSL-G12D/+;Trp53LSL-R172H/+;Cre (KPC) mice, albeit with a different spectrum of metastatic spread. Through a combination of in vivo and in vitro analyses, we have revealed critical pathways that serve to modulate the relative balance in PDA cells between proliferation, differentiation, invasion and metastasis. These studies identify specific targets to pursue therapeutically for distinct stages of disease.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1487. doi:10.1158/1538-7445.AM2011-1487