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These PDX1 Cre/RASG12D animals develop typically, but develop harmless precursor lesions termed pancreatic intraepithelial neoplasms that will, with long latency, progress to form PDAC. These enzalutamide neoplastic lesions stain absolutely for markers of senescence, including expression of p53 and p21CIP1 and SA W lady, as shown previously. Conversely, they typically lack markers of proliferation, particularly Ki67, MCM2 expression and incorporation of BrdU. To test the impact of PIK3CA/AKT pathway activation with this activated RAS induced in vivo senescence like state, the PDX1 Cre/RASG12D animals were crossed to animals that have one or both PTEN alleles flanked by Cre recombination sites, to drive simultaneous activation of RAS and partial or biallelic inactivation of PTEN in the pancreas. Notably, total inactivation of PTEN in the mouse pancreas does not stimulate senescence. Comparing PanINs in the pancreata of 6 week-old PDX1 Cre/RASG12D and PDX1 Cre/RASG12D/PTEN animals, we found Lymph node that inactivation of PTEN mainly abolished expression of p21, p53, senescence markers and SA B gal. In keeping with the idea that inactivation of PTEN facilitates the senescence to a whole bypass like state, we found the PanINs of the PDX1 Cre/RASG12D/PTEN animals to become very proliferative, as measured by an increase in immunohistochemical staining of MCM2, Ki67 and incoporation of BrdU. Senescence by-pass was associated with phosphorylation of GSK3 on serine 9, like the in vitro model. In keeping with this senescence like state being a potent tumor suppression mechanism in this in vivo model, expression of activated RAS and concurrent inactivation of PTEN triggered Evacetrapib rapid development of PanINs into PDAC, as reported recently. Previously, we've noted that inactivation of p21CIP1 boosts tumorigenesis in this model, likely although inactivation of senescence. Significantly, scarcity of p21CIP1 didn't further accelerate tumorigenesis in PDX1 Cre/RASG12D/ PTENfl/ animals, indicating that loss of p21CIP1 and PTEN accelerate PDAC via the same pathway, further implicating loss of PTEN in abrogation of senescence in this model. IHC analysis of PTEN indicated that tumors arising from PDX1 Cre/RASG12D/PTENfl/ mice had lost the second allele of PTEN. Also, the effects of PTEN trouble were more marked when both, rather than one, alleles of PTEN were engineered for inactivation within the pancreas. Loss of two alleles of PTEN led to a remarkably dangerous speed of tumorigenesis, leading often to rapid death and a mean survival of 15 days. In these mice, almost the complete pancreas was changed by neoplastic tissue, with hardly any normal tissue remaining. Neoplastic muscle included popular mitoses, including some aberrant results. In areas, there is lack of the normal pancreatic architecture with angulated glands, indicating invasive carcinoma.