Abstract 5017: Prox1-happloinsuficiency contributes to the transforming effects of Kras in the pancreas.
Authors: Drosos Yiannis , Ye Jianming , Kuliyev Emin , Rehg Jerold , Maitra Anirban , Means Anna , Klein-Geltink Ramon , Grosveld Gerard , Sosa-Pineda Beatriz 
Published: August 2014

Invasive pancreatic adenocarcinoma (PDAC) is one of the most lethal solid malignancies. PDAC arises from distinctive forms of neoplasia, with pancreatic intraepithelial neoplasia (PanIN) being the most common lesion. Mutational activation of Kras is nearly universal in PanINs and PDAC.

We previously reported expression of the homeodomain transcription factor Prox1 in multipotent progenitors and in specific cell lineages of the mouse embryonic pancreas. We also uncovered that Prox1 controls growth and morphogenesis in the early developing pancreas (Wang et al., Dev.Dyn. 2005), and showed that the lack of its activity results in congenital ductal malformations, prominent loss of acinar cells, and gradual deterioration of the exocrine parenchyma (Westmoreland et al, Gastroenterology 2012).

Prox1 expression persists in centroacinar and ductal cells in the adult mouse pancreas. In contrast, in mature pancreatic acinar cells Prox1 expression is never observed, except when these cells undergo acinar-to-ductal metaplastic conversion. Interestingly, different from other ductal transcription factors (e.g., Sox9, Pdx1, Hnf1β), Prox1 expression rapidly decays in developing PanINs whereas PDAC specimens from mice or humans completely lack Prox1 expression. This dynamic expression of Prox1 in the adult exocrine pancreas raised the possibility that Prox1 down-regulation could be necessary for pancreatic neoplastic transformation.

We generated mice expressing both oncogenic Kras (KrasG12D) and normal Prox1 levels in the pancreas (KrasG12DPanc), and mice expressing KrasG12D which are also Prox1-happloinsufficient (Prox1ΔPanc/+;KrasG12DPanc), to investigate the effects of reducing the Prox1 dosage in PDAC formation. We found that Prox1-happloinsufficiency significantly increases the formation of both, PanINs and PDAC, in pancreatic tissues carrying oncogenic Kras. In addition, pancreatic tissues with combined Prox1-happloinsufficiency and KrasG12D expression also exhibited more prominent fibrosis, higher infiltration of inflammatory cells, and increased proliferation, in comparison to KrasG12DPanc mice. In line with these results, expression of Prox1 in Capan1 cells (which are Prox1-negative) using retroviruses significantly reduced CyclinD1 transcript levels and induced growth arrest.

We are currently undertaking a combination of in vivo and in vitro approaches to uncover how Prox1 function counteracts Kras-driven transformation in pancreatic epithelial cells.

Citation Format: Yiannis Drosos, Jianming Ye, Emin Kuliyev, Jerold Rehg, Anirban Maitra, Anna Means, Ramon Klein-Geltink, Gerard Grosveld, Beatriz Sosa-Pineda. Prox1-happloinsuficiency contributes to the transforming effects of Kras in the pancreas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5017. doi:10.1158/1538-7445.AM2013-5017