MAtChinG · Mechanically Activated Channels in Glioma: the role of mechanoreceptor Piezo1 and hnRNP K in cancer as novel oncoregulators
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2021-09-01 → 2023-08-31
- EU contribution
- €160,932
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Mechanically Activated Channels in Glioma: the role of mechanoreceptor Piezo1 and hnRNP K in cancer as novel oncoregulators
Glioma is a broad category of brain tumours from glial cell. Amongst them, glioblastoma multiforme (GBM) is the most malignant and aggressive subtype in adults, having an incidence of 2-3 per 100,000 adults per year and affecting more males than females up to a ratio 3:1. This subtype is a grade 4 tumour, with fast growth rate, and sometimes spread to other parts of the brain. Current treatments include surgery, radiotherapy and chemotherapy; however, prognosis of most glioma is not optimistic, with survival rate normally ranging 14-18 months, with only around 10% of the patients living up to 5 years after diagnosis. This is partly due to the existence of glioma ‘cancer stem cells’ (CSCs), a subtype of tumour-initiating cells found in glioma with stem cell-like properties and resistant to conventional therapeutic treatments, being the cause of most relapses after treatment. Its aggressiveness is due to the complexity and the lack of full understanding of the biochemical nature and mechanisms of these type of tumours. Recently, the importance of the mechanical properties of tissues in health and disease has become evident and has opened a new research field in biology. It is known that the mechanical environment of tumours is very hard, and that tumour cells overexpress proteins that respond to these changes in the mechanical properties, named mechanoreceptors. Stretch-activated cation channels (SACs) are a broad family of mechanosensitive channels that when activated by stretch, allows the influx of cations. Piezo1 –also known as FAM38A-, belongs to this subtype of mechanoreceptors. This project is focused on understanding the importance of the mechanical properties of brain tumour environment and investigating new therapies tackling these changes. It has been observed that tumour cells contribute to the stiffening of their surroundings, and we have studied that when tumour cells sense these mechanical changes, it contributes to the progression of the cancer. Thus, our main objective is to fully understand why it happens and to develop new therapeutic strategies that could help combat gliomas, so that later on they could be translated into the clinic for the patients to benefit from them.
Data: CORDIS, © European Union
Project objective
Glioblastoma multiforme (GBM) is one of the most common and aggressive forms of brain tumour, affecting 2-3 per 100,000 adults per year, and with a usual survival time of 14-18 months after diagnosis with only a 10% of the patients living up to 5 years after it. Because of its location, early detection of the tumour and surgical removal may be complicated. Furthermore, its fast growth rate and migration capacity makes it extremely aggressive. Aditionally the presence of glioma cancer stem cells contribute to radio- and chemioresistance of GBM. Because of all this, a deeper understanding about its genetical, biochemical and microenviromental nature is needed. In order to gain more insight into the formation and development of glioma, in this proposed project we hypothesize that the heterogeneous nuclear ribonucleoprotein K (hnRNPK) and the mechanically activated ion channel Piezo1 constitute an axis that promotes the onset and progression of glioma. HnRNPK is a multifunctional protein that influences transcription, translation and RNA stability amongst other function, and it exerts its function depending on its phosphorylation state, which is modulated by kinases such as ERK, JNK or PKC. Piezo1 is a stretch-activated cation channel, that activated upon mechanical cues allowing the influx of calcium in the cell and activation of multiple cascades, such as ERK or PKC pathways, as well as in apoptosis and migration. Both hnRNPK and Piezo1 are upregulated in gliomas and preliminary data suggests a relation in their regulation. Here, we proposed that there is a regulation between Piezo1 and hnRNPK, and that this axis promotes the onset of gliomas cancer stem cells and contributes to its aggressiveness. With this project, we aim to investigate how this axis could contribute to the formation and aggressiveness of gliomas, and how its modulation can contribute to its control, therefore turning Piezo1 and hnRNPK into a new promising target for glioma treatment.
Original text from CORDIS.
Participants
- FUNDACION SECTOR PUBLICO ESTATAL CENTRO NACIONAL INVESTIGACIONES ONCOLOGICAS CARLOS III · MadridCoordinatorSpain
Links
Data: CORDIS, © European Union