{"id":519,"date":"2016-02-11T18:45:02","date_gmt":"2016-02-11T23:45:02","guid":{"rendered":"http:\/\/blogs.nd.edu\/hilllab\/?page_id=519"},"modified":"2016-02-25T11:26:33","modified_gmt":"2016-02-25T16:26:33","slug":"mouse-models-of-pdac","status":"publish","type":"page","link":"https:\/\/sites.nd.edu\/hilllab\/research\/mouse-models-of-pdac\/","title":{"rendered":"Mouse Models of PDAC"},"content":{"rendered":"<ul>\n<li><em><strong>KrasG12D;Pten+\/-<\/strong> <\/em><\/li>\n<\/ul>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignleft wp-image-523 size-thumbnail\" src=\"http:\/\/sites.nd.edu\/hilllab\/files\/2016\/02\/Webpage-mouse-models-figure-1-150x150.jpg\" alt=\"Webpage mouse models figure 1\" width=\"150\" height=\"150\" \/>The most commonly observed genetic alterations in PDAC are constitutively activating mutations in <em>Kras<\/em>. Aberrant activation of the PI3K\/AKT pathway by either PTEN loss or other mechanisms had been observed in a significant subset of human PDACs, yet PTEN\u2019s role in tumor progression had yet to be determined. I decided to investigate this and found that concomitant loss of <em>Pten<\/em> with expression of a constitutively active <em>Kras<sup>G12D<\/sup><\/em> mutant allele drastically accelerated tumor development, and increased the number of cells possessing the hallmarks of cancer stem\/therapy resistant cells. This indicated that PI3K\/AKT and KRAS signaling pathways act synergistically to promote pancreatic initiation and progression and moreover, established PTEN as the gatekeeper to tumorigenesis in the pancreas.<\/p>\n<p><strong>Related Publications<\/strong><\/p>\n<p><strong>Hill R<\/strong>, Hargan J, Kim C, Wang Y, Dawson D, Donahue T, Dry S, and Wu H. PTEN Loss Accelerates KrasG12D-Induced Pancreatic Cancer Development. <em>Cancer Research<\/em>. 2010 Sep 15;70(<em>18<\/em>):7114-24.<\/p>\n<p><strong>Hill R<\/strong> and Wu H. PTEN, Stem Cells, and Cancer Stem Cells.\u00a0 <em>Journal of Biological Chemistry<\/em>. 2009 May 1;284(<em>18<\/em>):11755-9.<\/p>\n<ul>\n<li><em><strong>KrasG12D;Pten+\/-<\/strong>;<strong>Cox-2 OE<\/strong><\/em><\/li>\n<\/ul>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignleft wp-image-524 size-thumbnail\" src=\"http:\/\/sites.nd.edu\/hilllab\/files\/2016\/02\/Webpage-mouse-models-figure-2-150x150.jpg\" alt=\"Webpage mouse models figure 2\" width=\"150\" height=\"150\" srcset=\"https:\/\/sites.nd.edu\/hilllab\/files\/2016\/02\/Webpage-mouse-models-figure-2-150x150.jpg 150w, https:\/\/sites.nd.edu\/hilllab\/files\/2016\/02\/Webpage-mouse-models-figure-2-298x300.jpg 298w, https:\/\/sites.nd.edu\/hilllab\/files\/2016\/02\/Webpage-mouse-models-figure-2.jpg 621w\" sizes=\"auto, (max-width: 150px) 100vw, 150px\" \/>Recognizing that inflammation is a predisposing risk for cancer development, I next chose to directly test the role inflammation plays in pancreatic tumorigenesis. COX-2, a key mediator of inflammation, is up-regulated in all stages of PDAC development and portends a poor prognosis for patients. However, its role in tumor development has yet to be fully investigated. I developed a novel mouse model of PDAC, based on COX-2 over-expression, which fully recapitulates the severe inflammatory response observed in the human disease, an important feature missing in previously developed models. I identified cell intrinsic mechanisms through which COX-2 expression can lead to accelerated tumor progression and most importantly, resistance to current treatment regimens by activation of signaling pathways linked to cell survival.<\/p>\n<p><strong>Related Publications<\/strong><\/p>\n<p><strong>Hill R<\/strong>, Li Y, Tran L, Garcia A, Hargan J, Kim C, Wang Y, Dry S, Donahue T, Herschman H, and Wu H. Delayed progression of pancreatic cancer development through cell-intrinsic activity of <em>Cox-2<\/em>.\u00a0 <em>Molecular Cancer Therapeutics<\/em> 2012 Oct11(10):2127-2137. (<strong>Cover<\/strong>)<\/p>\n<p>&nbsp;<\/p>\n","protected":false},"excerpt":{"rendered":"<p>KrasG12D;Pten+\/- The most commonly observed genetic alterations in PDAC are constitutively activating mutations in Kras. Aberrant activation of the PI3K\/AKT pathway by either PTEN loss or other mechanisms had been observed in a significant subset of human PDACs, yet PTEN\u2019s &hellip; <a href=\"https:\/\/sites.nd.edu\/hilllab\/research\/mouse-models-of-pdac\/\">Continue reading <span class=\"meta-nav\">&rarr;<\/span><\/a><\/p>\n","protected":false},"author":932,"featured_media":0,"parent":2,"menu_order":1,"comment_status":"closed","ping_status":"closed","template":"","meta":{"footnotes":""},"class_list":["post-519","page","type-page","status-publish","hentry"],"_links":{"self":[{"href":"https:\/\/sites.nd.edu\/hilllab\/wp-json\/wp\/v2\/pages\/519","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/sites.nd.edu\/hilllab\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/sites.nd.edu\/hilllab\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/sites.nd.edu\/hilllab\/wp-json\/wp\/v2\/users\/932"}],"replies":[{"embeddable":true,"href":"https:\/\/sites.nd.edu\/hilllab\/wp-json\/wp\/v2\/comments?post=519"}],"version-history":[{"count":6,"href":"https:\/\/sites.nd.edu\/hilllab\/wp-json\/wp\/v2\/pages\/519\/revisions"}],"predecessor-version":[{"id":541,"href":"https:\/\/sites.nd.edu\/hilllab\/wp-json\/wp\/v2\/pages\/519\/revisions\/541"}],"up":[{"embeddable":true,"href":"https:\/\/sites.nd.edu\/hilllab\/wp-json\/wp\/v2\/pages\/2"}],"wp:attachment":[{"href":"https:\/\/sites.nd.edu\/hilllab\/wp-json\/wp\/v2\/media?parent=519"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}