The PI3K/PTEN/AKT Pathway In Epithelial Tumorigenesis
The central theme of my laboratory is the use of genetically engineered mouse models to identify and characterize the specific biological processes that are controlled by the PI3K/PTEN/AKT pathway, a signal transduction cascade altered in most cancers.
Our work revolves around two major, interconnected, areas:
- Deepening our understanding of the pathways regulated by the PI3K/PTEN/AKT axis in epithelial homeostasis, neoplastic transformation and progression, and of its role in controlling stem cell function during these processes;
- Identifying the mechanisms that allow and regulate the crosstalk between the PI3K/PTEN/AKT cascade and hormone-dependent signaling pathways.
Some examples of current projects include:
1- the identification of the specific cellular responses induced by PI3K activation in the very early stages of neoplastic transformation, using expression profiling and proteomics approaches;
2- the elucidation of the role of the crosstalk between PI3K and Estrogen Receptor (ERa) in epithelial homeostasis and in neoplastic transformation of hormone-sensitive tissues;
3- the dissection of the mechanisms through which the senescence response resulting from Ras activation is abrogated by PI3K activation, thus leading to more aggressive tumors;
4- testing the hypothesis that genetic alteration of thyroid stem/precursor cells leads to the development of more aggressive tumors.
Our work is expected to lead not only to a more detailed knowledge of the molecular network that is induced in vivo upon chronic PI3K activation, but also to the identification of essential signaling nodes that may be amenable to therapeutic intervention.
More information at Antonio Di Cristofano's
Bellacosa, A., Kumar, C., Di Cristofano, A. & Testa, J.R. Activation of AKT Kinases in Cancer: Implications for Therapeutic Targeting. Adv. Cancer Res 94, 29-86 (2005).
Di Cristofano, A. & Pandolfi, P.P. The multiple roles of PTEN in tumor suppression. Cell 100, 387-90 (2000).
Vilgelm, A. et al. Akt-mediated phosphorylation and activation of estrogen receptor alpha is required for endometrial neoplastic transformation in Pten+/- mice. Cancer Res 66, 3375-80 (2006).
Lian, Z., De Luca, P. & Di Cristofano, A. Gene expression analysis reveals a signature of estrogen receptor activation upon loss of Pten in a mouse model of endometrial cancer. J Cell Physiol 208, 255-66 (2006).
Yeager, N., Klein-Szanto, A., Kimura, S. & Di Cristofano, A. Pten loss in the mouse thyroid causes goiter and follicular adenomas: insights into thyroid function and Cowden disease pathogenesis. Cancer Res 67, 959-66 (2007).
Brewer, C., Yeager, N. & Di Cristofano, A. Thyroid-stimulating hormone initiated proliferative signals converge in vivo on the mTOR kinase without activating AKT. Cancer Res 67, 8002-6 (2007).
Yeager, N., Brewer, C., Cai, K.Q., Xu, X.X. & Di Cristofano, A. mTOR is the key effector of PI3K-initiated proliferative signals in the thyroid follicular epithelium. Cancer Res 68, 444-449 (2008).
Antonio Di Cristofano's Laboratory