Hupp, Ted

Rajan, Ajitha

Fentor, Amanda Vanessza

Medical Research Council (MRC)

2026-05-27T13:29:03Z

2026-05-27

GBM is the most common and lethal primary brain tumour, characterized by rapid growth and a high propensity for recurrence. Despite advancements in surgical, chemotherapeutic, and radiotherapeutic interventions, the median survival time for GBM patients remains low, often less than 15 months post-diagnosis. This underscores the urgent need for innovative research to unravel the molecular underpinnings of GBM and identify novel therapeutic targets. Glioblastoma Stem Cells (GSCs) play a pivotal role in enhancing the stem-like state of tumour cells, promoting pro-migratory and pro-invasive factors that fortify the tumour’s immunosuppressive microenvironment. This immunosuppression facilitates tumour maintenance, progression, recurrence, and resistance to conventional therapies, posing substantial challenges for immunotherapy and novel drug development. GSCs are commonly used to model GBM due to their ability to reciprocate key features of the disease. However, in this study, which integrates both cell line and tissue transcript expression analyses, demonstrates that this approach might not fully capture the complexity of the disease. The discrepancies between cell line models and actual tissue samples highlight the need for more representative models in GBM research. Cell adaptation to external and internal stressors is fundamentally governed by modifications in gene expression, which can be quantitatively assessed at the transcriptomic level. Hypoxic stress, a hallmark of Glioblastoma (GBM) tumorigenesis, has profound effects on brain cells, contributing significantly to the disease's aggressiveness and poor prognosis. In my PhD research, I employed comprehensive transcriptomic analyses to uncover both novel hypoxia-induced RNA transcripts in both GSCs and primary GBM tissues with particular focus on those implicated in tumour recurrence. This study integrated bulk RNAseq data and bioinformatics pipelines to map hypoxia-associated transcriptomic alterations in GSC models and recurrent GBM samples. Strikingly, tissue-specific analyses revealed distinct molecular signatures that were not detect in the cell lines: collagens associated with tumour recurrence, and HOX family alleles linked to tumour grade progression. These findings underscore the limitations of cell line models and emphasize the need for systems that better recapitulate the spatial and molecular heterogeneity of GBM. Utilizing a pathological approach, I conducted tissue microarray (TMA) staining to validate the presence and spatial distribution of these identified transcripts within tumour samples. These validated genes were subsequently subjected to medicinal microRNA target prediction using miTAR, a deep learning algorithm, to identify microRNAs that potentially regulate these novel driver transcripts. Given that microRNAs exert post-transcriptional control by downregulating their target mRNAs, the identification of such regulatory interactions is crucial for understanding the mechanisms driving GBM pathology. Moreover, my research highlights the therapeutic potential of medicinal plant-derived microRNAs. MicroRNAs have the ability to remain stable, enabling them to traverse the harsh gut environment and exert cross-kingdom effects. This property positions them to potentially serve as natural adjuncts to patient diets in clinical settings, offering a complementary approach to traditional therapies. Specifically, medicinal plant microRNAs could be integrated as dietary supplements to enhance recovery and mitigate disease progression, providing a novel, non-invasive strategy to bolster patient health during treatment and recovery phases. In conclusion, my findings underscore the intricate relationship between hypoxic stress, gene expression, and GBM progression, while also illuminating the promising role of medicinal plant microRNAs in therapeutic interventions. These microRNAs not only represent a natural, easily integrable supplement to patient diets but also offer potential for novel therapeutic avenues aimed at combating GBM and improving patient outcomes. Given the poor prognosis and limited treatment options for GBM, advancing our understanding of its molecular mechanisms and exploring innovative treatments is of utmost importance.

https://era.ed.ac.uk/handle/1842/44755

https://doi.org/10.7488/era/7270

en

Glioblastoma (GBM)

GBM

MicroRNA

Hypoxic stress

Gene expression

Therapeutic potential

Natural therapeutics: cross-kingdom microRNA and its potential to target the RNA landscape of glioblastoma

Thesis

Doctoral

PhD Doctor of Philosophy