The in vitro incorporation of [32P]orthophosphate into chicken-erythrocyte phospholipids has been studied by means of one-and two-dimensional thin-layer chromatography as a timerelated function: from 10 min to 6 h.Labelled phosphatidic acid appears after 10 min and represents about 90°/, of the total labelled phospholipids. Sphingomyelin turnover is as low as in mammal erythrocytes whereas glycerophospholipids' turnover is high. The specific activity of phosphatidylserine is ten times higher than that of phosphatidylethanolamine ; phosphstidylserine decarboxylase seems to he absent. In contrast with the metabolism of non-nucleated erythrocytes, the [32P]orthophosphate is incorporated into phosphatidylglycerol, the turnover of which is important.These data should agree with a de novo biosynthesis of phospholipids in nucleated erythrocytes, but many studies on mammal erythrocytes have demonstrated that there are essentially exchange reactions of phospholipids with plasma phospholipids and eventual acylation of plasma lysophospholipids. Par contre les phospholipides des hematies nucl66es ont 6th Btudihs seulement sur le plan analytique [8,9]; leur turnover n'a jamais BtB envisag6. L'absence de travaux dans ce domaine et les d86rences de composition phospholipidique entre les h6maties de mammifhres et les hematies nuclebes des oiseaux, nous ont incites Q entreprendre 1'Btude de l'incorporation in vitro de [32P]orthophosphate dans les globules rouges de poulet. MATfCRIEL ET MkTHODES Isolement et incubation des hkmatiesLe sang est pr6lev6 sur hhparine 8, des poulets de race White Leghorn, Bges de 2 Q 3 mois, Q la veine alaire.Aprks centrifugation Q 2500 tourslmin pendant 15 min, le plasma est rejet6 et les globules rouges laves A trois reprises au s6rum physiologique.

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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