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’s role in tumor progression had yet to be determined. I decided to investigate this and found that concomitant loss of Pten with expression of a constitutively active KrasG12D 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.
Hill R, Hargan J, Kim C, Wang Y, Dawson D, Donahue T, Dry S, and Wu H. PTEN Loss Accelerates KrasG12D-Induced Pancreatic Cancer Development. Cancer Research. 2010 Sep 15;70(18):7114-24.
Hill R and Wu H. PTEN, Stem Cells, and Cancer Stem Cells. Journal of Biological Chemistry. 2009 May 1;284(18):11755-9.
- KrasG12D;Pten+/-;Cox-2 OE
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.
Hill R, 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 Cox-2. Molecular Cancer Therapeutics 2012 Oct11(10):2127-2137. (Cover)