The role of exosomes in brain tumor heterogeneity and plasticity

Glioblastoma, en svært dødelig ondartet hjernesvulst kjent for sin invasive natur inn i det omkringliggende hjerneparenkymet, har blitt gjenstand for grundig analyse av innholdet i eksosomer gjennom transkriptomikk og proteomikk. Denne tilnærmingen har som mål å belyse det onkogene potensialet til eksosomer i tumormikromiljøet. Selv om analysen av omics-data pågår, forventes det at resultatet vil gi ny innsikt i ekstracellulære vesiklers innhold, som omfatter nukleinsyrer og proteiner, og som spiller en avgjørende rolle i gliomtumor-mikromiljøet. Videre, i løpet av min forskningsperiode i USA, har dette arbeidet resultert i en oversiktsartikkel publisert på nettet og et manuskript som for øyeblikket er under revisjon. Fokuset for disse publikasjonene dreier seg om å fremme en immunterapistrategi rettet mot glioblastom i prekliniske musemodeller. Oppsummert introduserer dette prosjektet en innovativ tilnærming som et alternativ til mislykkede kliniske studier som involverer immunkontrollpunkthemmere i glioblastom. Det fremhever ikke bare de lovende resultatene i sammenheng med glioblastom, men antyder også bredere implikasjoner, noe som indikerer potensiell effekt i å adressere immunterapi-resistente kreftformer utover glioblastom.

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.