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

• Final Report Year: 2017

Final Report Abstract

The PP2A heterotrimeric holoenzyme is one of the most important serine/threonine protein phosphatases and reported to regulate a plethora of different signaling pathways. Differential assembly of the holoenzyme, but also cell type, microenvironment, cell context, and developmental state of a given cell might play a role in this differential readout of PP2A activity. 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 Unpublished data from the host lab strongly showed that the regulatory B55α subunit plays an important role in the regulation of the cancer cell cycle. As a consequence, silencing of B55α 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. In this research project, we have now analyzed the role of B55α in different cell types and at different stages of development. Hereby we especially focused on potential clinical applications in the context of cancer progression. Having used several different mouse lines and complementary in vitro approaches, we found that B55α is highly important for embryonic development and hereby especially for the formation and stability of immature blood vessels. In contrast to this, B55α was dispensable for tissue homeostasis and organ functions in adult mice. In the context of cancer, deletion of B55α had a very strong anti-angiogenic effect, drastically limiting tumor growth without affecting metastatic formation. Taken together, my data provides the very first proof of concept that B55α is a safe and very powerful target for novel cancer therapies, not only limiting cancer cell growth directly, but also modulate tumor stromal cells in way as to inhibit cancer progression.

Publications

• (2016) Vessel Normalization in the Spot-LIGHT of Cancer Treatment. Trends in molecular medicine 22 (2) 85–87
  Ehling, Manuel; Mazzone, Massimiliano
  
• (2017) Loss of Caveolin-1 in Metastasis-Associated Macrophages Drives Lung Metastatic Growth through Increased Angiogenesis. Cell reports 21 (10) 2842–2854
  Celus, Ward; Di Conza, Giusy; Oliveira, Ana Isabel; Ehling, Manuel; Costa, Bruno M.; Wenes, Mathias; Mazzone, Massimiliano
  
• (2017) Retinoid X receptor suppresses a metastasis-promoting transcriptional program in myeloid cells via a ligand-insensitive mechanism. Proceedings of the National Academy of Sciences of the United States of America 114 (40) 10725–10730
  Kiss, Mate; Czimmerer, Zsolt; Nagy, Gergely; Bieniasz-Krzywiec, Pawel; Ehling, Manuel; Pap, Attila; Poliska, Szilard; Boto, Pal; Tzerpos, Petros; Horvath, Attila; Kolostyak, Zsuzsanna; Daniel, Bence; Szatmari, Istvan; Mazzone, Massimiliano; Nagy, Laszlo
  
• (2017) The mTOR and PP2A Pathways Regulate PHD2 Phosphorylation to Fine-Tune HIF1α Levels and Colorectal Cancer Cell Survival under Hypoxia. Cell reports 18 (7) 1699–1712
  Di Conza, Giusy; Trusso Cafarello, Sarah; Loroch, Stefan; Mennerich, Daniela; Deschoemaeker, Sofie; Di Matteo, Mario; Ehling, Manuel; Gevaert, Kris; Prenen, Hans; Zahedi, Rene Peiman; Sickmann, Albert; Kietzmann, Thomas; Moretti, Fabiola; Mazzone, Massimi