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Papa, Antonella

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Papa

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Antonella

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Papa, Antonella
Author's Publications: search.filters.isAuthorOfPublication.349f7711-aafc-48a3-a8ef-9f179c04d875

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    Role of aberrant PI3K pathway activation in gallbladder tumorigenesis
    (Impact Journals LLC, 2014) Lunardi, Andrea; Webster, Kaitlyn A.; Papa, Antonella; Padmani, Bhavik; Clohessy, John; Bronson, Roderick; Pandolfi, Pier Paolo
    The PI3K/AKT pathway governs a plethora of cellular processes, including cell growth, proliferation, and metabolism, in response to growth factors and cytokines. By acting as a unique lipid phosphatase converting phosphatidylinositol-3,4,5,-trisphosphate (PIP3) to phosphatidylinositol-4,5,-bisphosphate (PIP2), phosphatase and tensin homolog (PTEN) acts as the major cellular suppressor of PI3K signaling and AKT activation. Recently, PI3K mutations and loss/mutation of PTEN have been characterized in human gallbladder tumors; whether aberrant PTEN/PI3K pathway plays a causal role in gallbladder carcinogenesis, however, remains unknown. Herein we show that in mice, deregulation of PI3K/AKT signaling is sufficient to transform gallbladder epithelial cells and trigger fully penetrant, highly proliferative gallbladder tumors characterized by high levels of phospho-AKT. Histopathologically, these mouse tumors faithfully resemble human adenomatous gallbladder lesions. The identification of PI3K pathway deregulation as both an early event in the neoplastic transformation of the gallbladder epithelium and a main mechanism of tumor growth in Pten heterozygous and Pten mutant mouse models provides a new framework for studying in vivo the efficacy of target therapies directed against the PI3K pathway, as advanced metastatic tumors are often addicted to “trunkular” mutations.
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    Pml Represses Tumour Progression Through Inhibition of mTOR
    (Wiley-VCH Verlag Berlin, 2011) Bernardi, Rosa; Papa, Antonella; Egia, Ainara; Coltella, Nadia; Teruya-Feldstein, Julie; Signoretti, Sabina; Pandolfi, Pier Paolo
    The promyelocytic leukaemia gene PML is a pleiotropic tumour suppressor. We have recently demonstrated that PML opposes \(mTOR-HIF1\alpha -VEGF\) signalling in hypoxia. To determine the relevance of PML-mTOR antagonism in tumourigenesis, we have intercrossed Pml null mice with Tsc2 heterozygous mice, which develop kidney cysts and carcinomas exhibiting mTOR upregulation. We find that combined inactivation of Pml and Tsc2 results in aberrant TORC1 activity both in pre-tumoural kidneys as well as in kidney lesions. Such increase correlates with a marked acceleration in tumour progression, impacting on both the biology and histology of kidney carcinomas. Also, Pml inactivation decreases the rate of loss of heterozygosity (LOH) for the wt Tsc2 allele. Interestingly, however, aberrant TORC1 activity does not accelerate renal cystogenesis in Tsc2/Pml mutants. Our data demonstrate that activation of mTOR is critical for tumour progression, but not for tumour initiation in the kidney.