Role of the PP2A Regulatory Subunit B55alpha in Development, Organ Homeostasis, and Cancer

• Applicant: Dr. Manuel Ehling
• Subject Area: Cell Biology ; Evolutionary Cell and Developmental Biology (Zoology)
• Term: from 2014 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 263020616

Although great achievements in the treatment of cancer were made in recent years, many tumor histotypes are still associated with a poor prognosis. This underlines the importance to identify novel and complementary approaches for the treatment of cancer.Our proposed study aims to analyze the role of the regulatory protein phosphatase 2A (PP2A) subunit B55alpha in different in vivo conditions, with a special emphasis on the validation of this pathway as a potential target in tumor therapy.The PP2A heterotrimeric holoenzyme is one of the most important serine/threonine protein phosphatase controlling a plethora of different signaling pathways. In this context, the regulatory subunits are responsible for targeting the PP2A holoenzyme to specific protein substrates. Unpublished data from the host lab strongly showed that the regulatory subunit B55alpha plays an important role in the regulation of the cancer cell cycle. As a consequence, silencing of B55alpha in colorectal cancer cells abates tumor progression. However, when conceiving a novel therapeutic strategy, it is highly important to also understand the role of the targeted protein in tissue development, homeostasis, and in tumor-associated stromal cells to minimize the risk of potential side effects during therapy and to understand all the possible effects on the tumor.To study the physiological relevance of B55alpha, we will use conditional knockout mice recently generated by the host lab to ubiquitously inactivate B55alpha in pups and adult mice. Subsequently, we will then analyze differences in organ development and homeostasis in control and mutant mice. In the case defects occur after genetic inactivation of B55alpha, it willunderline the importance of PP2A/B55alpha signaling for organ homeostasis and function. We will thus continue to analyze the pathways and mechanisms involved, to understand and identify other, safer targets for therapy.If no obvious organ defects occur in adult mutant mice, it will validate B55alpha as a safe target for therapy. In this case we will proceed to analyze the effects of B55alpha targeting on tumor progression. Besides the proliferative behavior of cancer cells, also stromal cells play a crucial role in tumor progression. Assuming a potential effect of B55alpha targeting on immature tumor blood vessels as well as on tumor associated macrophages (TAMs), we will especially focus on the characterization of phenotypic changes in these cells. To further analyze the specific contribution of certain cells on the observed phenotypes, we will use cell-specific conditional knockout mice to target B55alpha exclusively in TAMs, cancer, or endothelial cells (ECs). These final experiments might result in the identification of novel and cell specific B55alpha-mediated pathways, thus paving the way towards more specific targeted therapies.

• DFG Programme: Research Fellowships
• International Connection: Belgium
• Host: Professor Massimiliano Mazzone, Ph.D.