Studies on the role of PTEN in tumorigenesis and development of chemoresistance in a miR30-based transgene murine model of conditional PTEN inactivation

• Applicant: Dr. Cornelius Miething
• Subject Area: Hematology, Oncology
• Term: from 2006 to 2011
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 35265781

The tumor suppressor gene PTEN is mutated in a significant fraction of human cancers and is believed to play an important role in the pathogenesis and also in the resistance towards chemotherapy of these tumors. Functional inactivation of the PTEN gene has been shown to hyperactivate the Akt/mTOR pathway, which can be targeted by the mTOR inhibitor rapamycin and similar novel compounds. Several aspects of the role of PTEN in cancer development are currently unresolved, though. The pattern of PTEN inactivation in tumors does not follow the classical ´Two-Hit´ hypothesis (Knudson), and murine models of PTEN inactivation have implicated a haploinsufficent function of PTEN at least in some tumors. Also, it is currently unclear, if PTEN is required only for cancer initiation, or also for maintaining the disease. Furthermore, functions of PTEN independent of the mTOR pathway have been described. Therefore, we aim to establish a murine model, where we can conditionally switch on and off PTEN expression in vivo by utilizing a novel approach entailing the tetracycline regulatable transgenic expression of a short interfering RNA (siRNA) incorporated into a microRNA structure (miR30) targeting the PTEN mRNA. By crossing these mice into murine tumor models of AML, B-cell lymphoma and hepatocellular carcinoma, we want to look at the impact of PTEN deficiency on tumor development and maintenance. By switching PTEN expression back on in tumors which have developed in PTEN suppressed cells, we hope to clarify if e.g. targeting the mTOR pathway can fully counter the effects of PTEN inactivation. Furthermore, we aim to analyze the effects of PTEN deficiency on tumor responses to conventional chemotherapy as well as to novel compounds targeting a specific pathway.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Scott Lowe, Ph.D.