Glioblastoma metabolism and microenvironment putting tumor back in context
Glioblastomas are brain tumors that are derived from astrocytes or oligodendrocytes. These tumors have a heterogeneous structure composed of a necrotic and vascularized center and an invasive periphery. The rapid development of glioblastoma and its ability to invade surrounding tissues makes it a complex pathology to treat. Tumor cell invasion is the central element in tumor recurrence. It is therefore important to understand the mechanisms of tumor invasion and understand the interactions between tumor cells and their microenvironment.
We performed total RNA sequencing of the angiogenic and infiltrative areas of glioblastoma derived from patient xenografts. Data analysis in bioinformatics allowed us to identify molecules that may represent markers of tumor invasion.
A/ We first identified Thrombospondin-1 (THBS1), which is one of the most up-regulated genes in the infiltrative areas with the highest connectivity. Mechanistically, we showed that the TGFb canonical pathway transcriptionally regulates THBS1, through binding of SMAD3 to the TBHS1 gene promoter. THBS1 silencing inhibited cell invasion in vitro and in vivo, also in combination with anti-angiogenic therapy. Specific inhibition of THBS1/CD47 interaction using an antagonist peptide decreased cell in vivo invasion when combined with anti-angiogenic therapy. These data show that TGFb-induced THBS1 expression contributes to the invasive behavior of GBM cells and promotes resistance to anti-angiogenic therapy partially through interaction with CD47 (Daubon et al, Nat Comm 2019).
B/ The acquired data sets also contained transcripts related to tumor cell metabolism, such as lactate dehydrogenase (LDH). My current project aims to understand the role of energy metabolism in glioblastoma development. A systematic analysis is performed not only on LDHA, but also on LDHB. We analyzed their impact on tumor development and invasion as well as on the tumor microenvironment. This study will lead to a better understanding of the role of LDHs in tumor cell invasion and in the brain tumor microenvironment.
U1029 INSERM-Angiogenesis and cancer Lab; University of Bordeaux
Domain 1 - UMR 3347 / U1021 - Normal and pathological signaling