Title : NF1-associated gliomas: Antioxidant treatments and spastin inactivation as possible therapeutic approaches
Abstract:
Neurofibromatosis type 1 (NF1) is the most common tumor predisposition syndrome and glioma is one of the prevalent tumors associated with it. Gliomagenesis in NF1 patients results in a heterogeneous spectrum of neoplasms, ranging from low- to high-grade, that can occur throughout their entire lifespan.
The NF1 tumor suppressor gene encodes neurofibroimin, a GTPase-activating protein that acts as a negative regulator of the RAS oncoprotein. Loss of neurofibromin expression, as observed in NF1.associated tumors, is predicted to increase cell growth and survival through hyperactivation of RAS. Neurofibromin is also involved in regulating the cytoskeleton and cell motility. The ability of glioma cells to migrate long distances through the brain is a major obstacle to effective treatment of this tumor.
The microtubule (MT)-severing protein spastin is an AAA ATPase enzyme controlling MT dynamics and lipid droplet (LD) trafficking and functions. Spastin plays key role in processes requiring active rearrangement of the cytoskeleton and membrane remodeling, such as cell proliferation and motility. Our observations indicate that spastin silencing or its inhibition, induced by the ATP competitive inhibitor spastazoline, reduces colony-forming capacity, single cell speed and migration ability in glioma cell models. We identified the molecular players involved in spastin-dependent LD behavior by mass spectrometry analyses. Automated cell imaging-based pipelines were developed to measure the number, size and distribution of LDs, as well as MT cytoskeleton organization, to investigate LD behavior and its crosstalk with migration. Furthermore, recent evidence supports the beneficial effect of antioxidants on the prevention and treatment of NF-1 associated tumors. Thus, the effects of antioxidant compounds in combination with spastin inhibition will be also analysed, opening the way to develop new therapeutic strategies for NF1-associated gliomas.
Audience Take Away Notes:
Our work aims to expand knowledge on the relationship between energy reserves (LD) and cell migration in the context of gliomas. It provides a practical solution for automatic cell-imaging analysis, particularly for the number of LDs and MT cytoskeletal organization. Additionally, we propose new therapeutic strategies based on the use of natural compounds.
