Chemoresistance-related RNAs in GBM

Glioblastoma (GBM) is the most frequent and deadly primary brain tumors.
Despite aggressive therapies, its bad prognosis is mainly due to rapid tumor
recurrence and chemotherapeutic resistance. There is an urgent need to
develop improved treatment strategies based on novel molecular targets.
The Norlux Neuro-Oncology laboratory has a great expertise in GBM
biology and in the development of clinically relevant animal models of GBM.
Contrary to classical adherent cell lines, patient-derived sphere cultures
reflect tumor heterogeneity, expression of oncogenic markers and
phenotype in vivo. So far, attempts to study the chemoresistance of GBM
has largely focused on mRNA profiling based on classical adherent cell
lines. During the last decade, advances in transcriptomics allowed the
identification new important regulatory non-coding RNAs in cancer such as
micro RNAs (miRNAs) and long non-coding RNAs (lncRNAs). LncRNAs are
thought to play an important role in cancer, by affecting both mRNAs and
miRNAs. Although lncRNAs have been shown to be highly deregulated in
GBM the functional significance thereof is currently unknown. In this project
we seek to identify the role of non-coding RNAs in GBM chemoresistance
and propose novel RNA targets for therapy. We will characterize the
response to chemotherapy (temozolomide) in relevant pre-clinical GBM
cellular models by a combination of confocal microscopy and flow
cytometry. We will then use next generation sequencing to identify RNAs of
different classes that are deregulated in response to temozolomide.
Integration of small RNA-seq and RNA seq data at a systems level will
define new regulatory circuits involved in GBM chemoresistance and
identify novel therapeutic candidates which will be further validated with
gain and loss of function experiments. Finally, we will impact on miRNA,
mRNAs, lncRNA expression and characterize GBM development and
chemosensitivity in vivo using orthotopic xenotransplants. The strength of
this project relies on the innovative analysis of non-coding RNAs in GBM
and on the use of patient derived pre-clinical models that reflect human
GBM biology. Altogether, this project will lead to the identification of novel
RNA targets of GBM chemoresistance.