Modeling glioblastoma invasion using human brain organoids and single-cell transcriptomics
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PROVIDER: EGAS00001003852 | EGA |
REPOSITORIES: EGA
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Project description:Glioblastoma (GBM) is an aggressive tumor that frequently exhibits gain of chromosome 7, loss of chromosome 10 and aberrantly activated RTK signaling pathways. Here, we identify mesenchymal homeobox 2 (MEOX2) as a salient oncogenic transcription factor candidate with increased expression in GBMs. Our results suggest that MEOX2 can enhance ERK signaling through a feed-forward mechanism. We show that MEOX2 overexpression can lead to increased growth in bona fide GBM implantation models and cooperates with loss of p53 and PTEN in cerebral organoid models of human malignant gliomas to induce cell proliferation. Furthermore, using high-throughput genomics, we identify transcriptional target genes of MEOX2 in patient-derived GBM tumorsphere models and a fresh frozen GBM tumor.
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Project description:The infiltrative nature of Glioblastoma (GBM), the most aggressive primary brain tumor, critically prevents complete surgical resection and masks tumor cells behind the blood brain barrier reducing the efficacy of systemic treatment. New insight in molecular pathways underlying invasion to identify novel invasion-specific molecular targets are likely to improve treatment success and patient outcome. In the present study, we used a genome-wide interference screen to determine invasion-essential genes and identified the AN1/A20 zing finger domain containing protein 3 (ZFAND3) as a crucial driver of invasion in GBM. Using patient-derived cellular GBM models, we validated that loss of ZFAND3 dampens the invasive capacity of GBM, whereas ZFAND3 overexpression increases motility in GBM cells that were initially not invasive. At the mechanistic level, we demonstrate that ZFAND3 activity requires nuclear localization and integral zinc-finger domains. Using integrated transcriptomic and proteomic approaches coupled with reporter assays, we identify ZFAND3 as a novel functional member of a protein complex encompassing PUF60 to activate transcription and GBM cell invasion. Our findings indicate that ZFAND3 regulates the promoter of invasion-related genes such as COL6, FN1 and NRCAM through direct binding to GC rich regions. To harness the therapeutic potential of this transcriptional complex, further investigation in ZFAND3 function in GBM and related invasive cancer types is warranted.
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Project description:Glioblastomas (GBMs) are highly invasive brain tumors replete with brain- and blood-derived macrophages, collectively known as tumor-associated macrophages (TAMs). Targeting TAMs has been proposed as a therapeutic strategy but has thus far yielded limited clinical success in slowing GBM progression, due in part to an incomplete understanding of TAM function in GBM. Here, by using an engineered hyaluronic acid-based 3D invasion platform, patient-derived GBM cells, and multi-omics analysis of GBM tumor microenvironments, we show that M2-polarized macrophages stimulate GBM stem cell (GSC) mesenchymal transition and invasion. We identify TAM-derived transforming growth factor beta induced (TGFβI/BIGH3) as a pro-tumorigenic factor in the GBM microenvironment. In GBM patients, BIGH3 mRNA expression correlates with poor patient prognosis and is highest in the most aggressive GBM molecular subtype. Inhibiting TAM-derived BIGH3 signaling with a blocking antibody or small molecule inhibitor suppresses GSC invasion. Our work highlights the utility of 3D in vitro tumor microenvironment platforms to investigate TAM-cancer cell crosstalk and offers new insights into TAM function to guide novel TAM-targeting therapies.
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