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Identifying Intestine Specific Homeobox gene ISX as a biomarker and therapeutic target for metastatic pancreatic cancer: developing spontaneous progression models displaying stage-specific genomic changes

ABSTRACT: Purpose: Majority of pancreatic cancer (PDAC) patient deaths are associated to the metastatic progression of disease. To identify novel targeted-therapies, a complete understanding of transformation in genetic landscape in tumors during disease progression is needed. Widely in use, the artificially immortalized PDAC cell lines do not rightly represent the progression because of multiple donors and disparate genetic characteristics. To identify key genes underlying the progression of PDAC from localized disease to a metastatic form, we performed whole transcriptome RNA-Sequencing analysis of cell models representing localised to metaststic stage through paired-end deep sequencing Method: Mouse expressing a Cre-activated KrasG12D allele inserted into the endogenous Kras locus, and these mice were crossed with mice expressing Cre recombinase in pancreatic tissue by virtue of a PDX-1 promoter-driven transgene. Next a cross between K-rasG12D Pdx-Cre and p16-/- mice, transgenic K-rasG12D Pdx-Cre p16-/- mice were generated harboring tissue specific mutant Kras and p16 deletion resulting in an earlier appearance of PanIN lesions followed by rapid progression into highly invasive and metastatic pancreatic cancers. Results: Transgenic K-rasG12D Pdx-Cre p16-/- mice developed spontaneous- localized, invasive and metastatic pancreatic tumors and transcriptome of these cell models representing localized, invasive and metastatic pancreatic tumors were sequenced. Conclusions: Based on genetic analysis of a same-lineage genetic background cell models, this study identifies a novel molecular pathway underlying the progression of pancreatic cancer disease. This study shows that Intestine Specific Homeobox (ISX) gene is a novel biomarker unique to pancreatic cancer progression.

ORGANISM(S): Mus musculus

PROVIDER: GSE116635 | GEO | 2019/06/20

REPOSITORIES: GEO

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Project description:Cyclooxygenase-2 (COX-2) is upregulated in pancreatic ductal adenocarcinomas (PDAC). However, how COX-2 promotes PDAC development is unclear. While previous studies have evaluated the efficacy of COX-2 inhibition via the use of non steroidal anti-inflammatory drugs (NSAIDs) or the COX-2 inhibitor celecoxib in PDAC models, none have addressed the cell intrinsic vs. microenvironment roles of COX-2 in modulating PDAC initiation and progression. We tested the cell intrinsic role of COX-2 in PDAC progression, using both loss-of-function and gain-of-function approaches. Cox-2 deletion in Pdx1+ pancreatic progenitor cells significantly delays the development of PDAC in mice with K-ras activation and Pten haploinsufficiency. Conversely, COX-2 over-expression promotes early onset and progression of PDAC in the K-ras mouse model. Loss of PTEN function is a critical factor in determining lethal PDAC onset and overall survival. Mechanistically, COX-2 over-expression increases P-AKT levels in the precursor lesions of Pdx1+;K-rasG12D/+;Ptenlox/+ mice in the absence of Pten LOH. In contrast, Cox-2 deletion in the same setting diminishes P-AKT levels and delays cancer progression. These data suggest an important cell intrinsic role for COX-2 in tumor initiation and progression through activation of the PI3K/AKT pathway. PDAC that is independent of intrinsic COX-2 expression eventually develops with decreased FKBP5 and increased GRP78 expression, two alternate pathways leading to AKT activation. Together, these results support a cell intrinsic role for COX-2 in PDAC development and suggest that, while anti-COX-2 therapy may delay the development and progression of PDAC, mechanisms known to increase chemoresistance through AKT activation must also be overcome. Murine mutants with pancreatic specific loss of Pten (Pten +/-) and K-ras activation (K-rasG12D) and either COX-2 over-expression (Cox-2 COE) or knockout (Cox-2 KO) under regulation of the Pdx-1 promoter developed pancreatic ductal adenocarcinoma. RNA was extracted from pancreatic tumors from individual mutants with pathology thought to closely mimic the human disease. Pancreatic tissue was subject to RNA extraction and hybridization on Affymetrix cDNA microarrays.

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Identifying Intestine Specific Homeobox gene ISX as a biomarker and therapeutic target for metastatic pancreatic cancer: developing spontaneous progression models displaying stage-specific genomic changes

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