Legend: patient-derived glioblastoma cells (in red) invading the mouse brain (in blue) using the blood vessel capillaries (in green). Photography credit: V. Le Joncour
High grade brain tumors (glioblastoma) are astrocytes-derived tumors that massively invade the brain. This unique property allow the cells to "hide" from the surgical resection in addition to be highly resistant to chemotherapies. Moreover, the brain is an isolated organ, surrounded by a "blood-brain-barrier" blocking the diffusion of circulating molecules from the periphery.
We recently discovered that invasive glioma cells are vulnerable to the lysosomal stress. When the lysosome's membrane is ruptured, its content is released in the tumor cell cytoplasm, leading to cell death. Interestingly, the fragile lysosomes of glioma cells are challenged by "old" drugs like anti-histamines. We discovered that it is possible to eliminate invasive glioblastoma cells by giving anti-histamines to mice bearing tumors and prolong their survival.
Currently, we are investigating the reason for the higher fragility of cancer cells lysosomes compared to normal cells. We are also searching for a genetic and molecular signature of invasive glioma cells.
Legend: breast cancer cells (in red) disseminating in the mouse brain (white). Brain metastasis cells notably extravasate from the blood vessels (in green) located in the meninges to infiltrate the central nervous system. Photography credit: V. Le Joncour.
A focus is made on screening for novel tumor targeting peptides that specifically home to the brain from breast cancer metastases using the phage display technology.
Chemistry driven approaches are being utilized in the binding studies of the homing peptides (delivery vector), their interacting receptors and the payload (drug) to selectively target brain metastases of breast cancer. We are using both in vitro and in vivo model for the brain metastasis formation and the drug delivery/uptake studies.
For this project is regularly used phage display technique, cell culture, animal experiment, whole brain isolation and ex vivo culture, microscopy imaging, protein production and purification, lentivirus production and transfection, western blotting, qPCR, flow cytometry, etc.
Legend: engineered extracellular vesicles called exosomes (in orange) can interact with cancer cells (in green) to deliver various payloads. Photography credit: H. Monzo
Gliomas constitute approximately 30% of all brain and central nervous system tumors and 80% of all malignant brain tumors. Glioblastoma Multiforme (GBM) tumors harbor dense, abnormal vasculature, large hypoxic and necrotic areas, and extensively proliferating tumor cells with the intrinsic ability to disseminate and colonize the organ far beyond the principal tumor mass.
Current therapeutic approaches of GBM face a number of challenges including (I) the GBM highly infiltrative nature, rendering impossible its complete surgical resection; (II) its intratumoral heterogeneity, including the presence of large dormant glioma cells with strong multidrug resistance which are associated with glioma recurrence; and (III) the blood-brain tumor barrier sheltering, which substantially impairs molecule drugs from accessing the tumor mass.
One of our research project focuses on the development of cancer-therapeutic delivery systems into the GBM tumor mass, with particular interest in the potential for engineered-exosomes (cell-derived nanovesicles) loaded with siRNA and drug molecules to cross the blood brain barrier and target glioma cells.
In order to achieve this we use the recently discovered interaction between MDGI (also known as fatty acid binding protein 3) and CooP peptide. CooP-MDGI binding occurs specifically in GBM cells and associated vasculature, thereby enabling the specific targeting of these cells. Exosomes are present in most body fluids and their specific contents constitute a fingerprint of the releasing cell type and its metabolic status; our research interest also focuses on the potential use of exosomes as a biomarker discovery tool for the diagnosis and prognosis of malignant tumors.