Cecilia Sahlgren becomes Finnish professor and receives 1 million euros in grants
The two large funds Cecilia Sahlgren received for her research in Finland and at the TU/e are related to her specialization in cell biology. As a professor in Finland she will focus on the cells and biology, where the part-time appointment in Eindhoven will bring technology and computational input into her projects. She has some years of experience with a combinational appointment, however the professorship and new funding bring new opportunities.
Since October she works 80% as a professor at the Turku Centre for Biotechnology in Finland, for 20% she will have a satellite group at the TU/e focusing on education and research. The opportunity to become a professor offered itself and it was not easy to say no. In Finland there is no tenure track, you have to fund yourself from the very beginning. Her ambition has stayed the same: she wants the opportunity to do science. This professorship and funding gives her this opportunity.
She will keep working on the research she started at the TU/e some years ago in the research group Soft Tissue Biomechanics of prof. Carlijn Bouten. The work they started on understanding the biomechanics of cells for tissue engineering is now starting to pay off so it’s important to keep involved.
The first funding (A) is aimed at discovering how a vessel wall is build. The architecture of a vessel wall is different in different vessels, depending on mechanical properties like blood flow and pressure and depending on cell-cell-signaling. The questions raised are about how mechanical properties and cell-cell-signaling influence each other and how this relates to the architecture of the vessel. To answer these questions, research is done in vitro (in the lab), in vivo (in e.g. animal models) and computationally. Especially the computational work will be done in close collaboration with the TU/e (part of the grant will be spend on a postdoc in the field of computational modelling at the TU/e), but also for the in vitro work the TU/e provides the engineering by building models, for example vessels on a chip.
The second funding (B) aims at gaining more knowledge on breast cancer. In aggressive metastatic breast cancer, cell-cell-signaling is overactive. With fundamental research, Cecilia Sahlgren wants to gain knowledge on the differences between healthy and cancerous tissue in the specific case of aggressive metastatic breast cancer. There is no collaboration with the TU/e yet however this fundamental knowledge is essential for applied research done at our university, so collaboration in the future is a valid possibility.
(A) Mechanoregulation of jagged in vascular tissue homeostasis
The main hypothesis of this project is that the hemodynamic environment critically influences vascular tissue physiology and pathology through interaction with the Notch signaling pathway. We envision that detailed and mechanistic understanding of the interrelationship between Notch signaling and mechanics will open up new therapeutic possibilities and help us predict therapeutic outcomes in vascular medicine and engineering. We will use an interdisciplinary research approach and novel model systems to address our objectives. By integrating molecular cell biology and in vivo model systems with microtissue engineering and computational modelling we aim to gain mechanistic insight of how cell signalling and hemodynamic forces integrate in vascular tissue.
- Project duration 2017-2020
- Funded by Academy of Finland
- Funding 460 950 euros
- Key collaborators Eindhoven University of Technology
(B) Regulation of notch3 by Pim Kinases – novel possibilities for notch targeted therapy in breast cancer
The Notch family of transmembrane receptors encompasses a central pathway of cell-cell contact-dependent signaling in cells both in development and cancer. In breast cancer hyperactivity of Notch is linked to aggressive therapy-resistant forms. Human clinical trials of Notch pathway inhibitors are ongoing and several approaches to intervene with the pathway are under preclinical evaluation. To date there is no approved Notch targeted therapy in the clinic. The challenges are prominent side effects, lack of specificity and poor knowledge of the underlying mechanisms behind deregulated Notch activity. However, the study of post-translational modifications of the Notch receptors has the potential to unravel as of yet unknown regulatory pathways of high importance to Notch signaling outcomes, and open up for novel cancer therapies. We are applying for a research grant from the Jane & Aatos Erkko Foundation to study Pim kinase-mediated regulation of the Notch3 paralog in breast cancer utilizing the CRISPR technology, a novel gene editing tool which allows us to introduce specific regulatory mutations in the Notch3 gene. We have shown that the intracellular domains of Notch1 (NICD1) and Notch3 (NICD3) are phosphorylated by oncogenic Pim kinases. Here we wish to study the physiological importance of the phosphorylation of NICD3. Notch3 activation in breast cancer is known to be linked to inflammatory breast cancer and brain metastases of breast cancer. We have established that the phosphorylation site resides within the important RAM-domain, which is necessary for binding of NICD3 to CSL, the Notch transcriptional regulator. Furthermore, phosphorylation perturbs the binding of NICD3 to CSL, affecting p21 levels with the potential to fine-tune the observed tumor promoting or tumor suppressing effect of Notch3. The knowledge acquired from this research could shed new light on the regulation of Notch signaling in cancer and aid the development of novel therapeutic regimes and combinatorial treatment tactics.
Funding 478 000 euro