Khauv, Davitte

Abstract Pancreatic ductal adenocarcinoma (PDA) arises at the convergence of genetic alterations in KRAS with a fostering microenvironment shaped by immune cell influx and fibrotic changes; identification of the earliest tumorigenic molecular mediators evokes the proverbial chicken and egg problem. Matrix metalloproteinases (MMP) are key drivers of tumor progression that originate primarily from stromal cells activated by the developing tumor. Here, MMP3, known to be expressed in PDA, was found to be associated with expression of Rac1b, a tumorigenic splice isoform of Rac1, in all stages of pancreatic cancer. Using a large cohort of human PDA tissue biopsies specimens, both MMP3 and Rac1b are expressed in PDA cells, that the expression levels of the two markers are highly correlated, and that the subcellular distribution of Rac1b in PDA is significantly associated with patient outcome. Using transgenic mouse models, coexpression of MMP3 with activated KRAS in pancreatic acinar cells stimulates metaplasia and immune cell infiltration, priming the stromal microenvironment for early tumor development. Finally, exposure of cultured pancreatic cancer cells to recombinant MMP3 stimulates expression of Rac1b, increases cellular invasiveness, and activation of tumorigenic transcriptional profiles. Implications: MMP3 acts as a coconspirator of oncogenic KRAS in pancreatic cancer tumorigenesis and progression, both through Rac1b-mediated phenotypic control of pancreatic cancer cells themselves, and by giving rise to the tumorigenic microenvironment; these findings also point to inhibition of this pathway as a potential therapeutic strategy for pancreatic cancer. Mol Cancer Res; 12(10); 1430–9. ©2014 AACR.

Abstract Epimorphin is a stromally produced factor that plays a role in normal mammary branching morphogenesis, but deregulated expression of epimorphin can have oncogenic consequences, although the oncogenic processes activated by epimorphin have not been elucidated. We had previously found that treatment of cultured mammary epithelial cells with epimorphin blocked activation of cell death pathways by a variety of apoptotic stimuli. These results implicated a potential role for epimorphin for inhibition of cellular apoptosis, a critical stage of tumor development. To identify potential mediators by which epimorphin could be affecting cell death pathways, we used a transcriptional profiling approach comparing mammary epithelial cells treated with epimorphin versus untreated cells. We found that epimorphin treatment led to significantly increased expression of IKBKE, which inhibits apoptosis through activation of NF-kappaB and which has recently been characterized as a key breast cancer oncogene. We found that epimorphin specifically blocks induction of apoptosis and activation of caspase-3 in cells treated with tumor necrosis factor-alpha, and that this activity was linked to epimorphin-mediated activation of IKBKE. We also found that knockdown of IKBKE blocked epimorphin-mediated induction of branching morphogenesis, implicating activation of IKBKE by epimorphin as a critical function for its normal morphogenic activities as well. These studies provide insight into an additional and unexpected linkage between mammary gland developmental processes and breast cancer progression. 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 4774. doi:10.1158/1538-7445.AM2011-4774