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FRIMEDBIO-Fri prosj.st. med.,helse,biol

The role of exosomes in brain tumor heterogeneity and plasticity

Alternative title: Rollen til eksosomer i hjernesvulstens heterogenitet og plastisitet

Awarded: NOK 3.9 mill.

Glioblastoma, a highly lethal malignant brain tumor known for its invasive nature into the surrounding brain parenchyma, has been subjected to comprehensive analysis of exosomal content through transcriptomics and proteomics. This approach aims to elucidate the oncogenic potential of exosomes within the tumor microenvironment. Although the analysis of omics data is currently ongoing, the anticipated outcome is the generation of novel insights into extracellular vesicle content, encompassing nucleic acids and proteins, which play a crucial role in the glioma tumor microenvironment. Furthermore, during my research tenure in the United States, this work has yielded a review paper published online and a manuscript currently under revision. The focus of these publications revolves around advocating for an immunotherapy strategy targeting glioblastoma in preclinical mouse models.In summary, this project introduces an innovative approach as an alternative to unsuccessful clinical trials involving immune checkpoint inhibitors in glioblastoma. It not only highlights the promising outcomes within the context of glioblastoma but also suggests broader implications, indicating potential efficacy in addressing immunotherapy-resistant cancers beyond glioblastoma.

Cellular heterogeneity at the genomic level has been well established within numerous cancer types, including malignant brain tumors (glioblastomas). Another less explored layer of heterogeneity relates to phenotypic plasticity of tumor cells induced by microenvironmental changes. It is now highly recognized that exosomes represent an important factor involved in intercellular communication. To what extent such communication (between stromal cells and tumor cells) can induce changes in cellular heterogeneity, plasticity and tumor progression is currently not known. Knowing that genetic information can be exchanged through exosomes, our hypothesis is that a major route of molecular cross-talk between tumor cell and brain tissue is mediated by exosome transfer. The presented application aims at identifying key genes and pathways involved in exosome mediated tumor/host reciprocal cross-talk. For this purpose, we will use advanced model systems and technologies to analyze the influence of exosomes on the induction of tumor cell adaptability/plasticity with special emphasis on tumor cell invasion. We have isolated and characterized exosomes from a high number of human GBM models as well as from brain organoids. Both tumor cells and brain tissue will be exposed to defined exosomal preparations using 3D tumor/brain organoid co-culture systems ex vivo as well as in patient derived orthotopic xenografts models in vivo. Functional perturbation of putative target genes involved in brain/tumor exosomal cross talk using CRISPR technology will be further evaluated to determine the mechanism involved in tumor cell invasion. The results obtained will be validated in co-culture model and PDOX models as well as in clinical samples. This project will thus collectively provide a better understanding of oncogenic signatures present in exosomes that are functionally important in modulating the tumor/host microenvironment thus providing new therapeutic strategies for GBM patients.

Funding scheme:

FRIMEDBIO-Fri prosj.st. med.,helse,biol

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