Umeå University's logo

Alterations in 3D chromatin organization and epigenetic regulation drivecancer progression. Here I use glioblastoma (GB) as a model to understandthe broad impact of epigenetic changes on tumour biology. By mapping the promoter-enhancer interactome and chromatin states in GB, we uncovered extensive rewiring of chromatin architecture that leads to the activation of gene networks associated with synaptic communication, axonogenesis, axon guidance, and chromatin remodelling. Central to these networks are transcription factors (TFs) such as SMAD3 and PITX1, identified as keyplayers in gene regulatory networks (GRNs) mediating neuron-to-gliomasynaptic communication. Moreover, we showed that tumour growth can be affected by modulating the activity of TFs, such as SMAD3, which mediates neuron-to-glioma synapses. These findings highlight how epigenetic changes and reorganization of 3D genome topology enable GB cells to integrate neural signals and translate them into a proliferative response.

Through epigenetic perturbation of novel EGFR (Epidermal Growth Factor Receptor) enhancers, we observed a reduction in GB cell proliferation and invasion, alongside increased sensitivity to the chemotherapeutic agent temozolomide (TMZ). Therefore, targeting specific regulatory regions canalso influence tumour cell behaviour, though to a lower extent than targeting complete GRNs via TF modulation.

Additionally, using Multi-Omics Binary Integration via Lasso Ensembles (MOBILE), a Machine Learning (ML)-based tool, we identified novel GRNs impacted by the rewiring of GB’s epigenetic landscape and critical for GB pathogenesis. Among them, GABA signalling emerged as a previously unrecognized driver of GB tumour progression. 

In summary, this work advances our understanding of how epigenetic regulation and 3D chromatin architecture shape the gene expression landscape of glioblastoma tumours. It paves the way for novel therapeutic strategies targeting chromatin regulators and GRNs to tackle difficult-to-treat cancers, such as glioblastoma.

Förändringar i 3D-kromatinorganisation och epigenetisk reglering driver cancerprogression. Här använder vi glioblastom (GB) som en modell för att förstå den bredare effekten av epigenetiska förändringar på tumörbiologi. Genom att kartlägga promotor-enhancerinteraktomet och kromatintillstånd i GB, upptäckte vi omfattande omkoppling av kromatinarkitektur. Detta leder till aktivering av gennätverk associerade med synaptisk kommunikation, axonogenes, axonvägledning och kromatinstrukturering. Centrala i dessa nätverk är transkriptionsfaktorer (TF) som SMAD3 och PITX1, identifierade som nyckelspelare i genreglerande nätverk (GRN) som förmedlar neuron-till-gliom synaptisk kommunikation. Dessa fynd belyser hur neuronal aktivitet främjar gliomcellproliferation via epigenetiskt drivna förändringar i 3D-genomtopologi. Dessutom visade vi att tumörtillväxt kan påverkas genom att modulera aktiviteten hos TF:er, som SMAD3, som förmedlar neuron-till-gliom synaptisk kommunikation.

Genom epigenetisk störning av nya EGFR (Epidermal Growth Factor Receptor)-enhancers observerade vi en minskning av GB-cellproliferation och invasion, samt ökad känslighet för det kemoterapeutiska medlet temozolomid (TMZ). Därför kan inriktning på specifika regulatoriska regioner också påverka tumörcellsbeteende, även om det sker i mindre utsträckning än genom att rikta in sig på kompletta GRN via TF-modulering.

Dessutom, med hjälp av Multi-Omics binär integration via Lasso Ensembles (MOBILE), ett maskininlärningsbaserat verktyg (ML), identifierade vi nya GRN:er som påverkas av omkopplingen av GB epigenetiska landskap ochsom är kritiska för GB patogenes. Bland dessa framträdde GABA-signaleringsom en tidigare okänd drivkraft för GB-tumörprogression.

Sammanfattningsvis främjar detta arbete vår förståelse av hur epigenetisk reglering och 3D-kromatinarkitektur formar genuttryckslandskapet i glioblastomtumörer. Det banar väg för nya terapeutiska strategier som rikta rsig mot kromatinregulatorer och GRNs för att tackla svårbehandlade cancerformer, såsom glioblastom.

Neural-cancer interactions involve the complex interplay between the nervous system and cancer cells, influencing tumour initiation, progression, and metastasis. In gliomas, these interactions mostly entail the secretion of paracrine growth factors, and electrochemical communication mediated by synapses between neurons and glioma cells. Understanding such interactions is vital for developing new therapeutic strategies against cancer aimed at modulating neuron-to-tumour communication. For this purpose, we have used in vivo mouse models of glioblastoma (GB) and established in vitro assays to study neural-cancer interactions, including the co-culture of cancer cells with either hiPSC-derived glutamatergic neurons or GABAergic interneurons, as well as 3D cultures of tumour spheres and fetal spheroids. The co-culture of hiPSC-derived neurons and cancer cells, including GB cells, was established both as a contact and non-contact assay, allowing to study the relevance of neural-cancer interactions for cancer cell proliferation and migration. While 3D spheroids generally replicate the organization and complexity of tissues effectively, our 3D invasion assay between organ spheroids and tumour spheres enabled us to specifically examine tumour invasion. This is exemplified by GB tumour spheres that exhibit reduced invasiveness of 3D brain spheroids upon repression of EGFR regulatory sequences.

Additionally, the co-culture systems enabled us to profile the transcriptome and chromatin accessibility of GB cells upon neural activity stimulation. GB cells in contact with either glutamatergic neurons or GABAergic interneurons exhibit differential gene expression and chromatin accessibility profiles. This provides new insights into the regulatory networks mediating neuron-to-glioma communication and highlights the relevance of GABAergic signalling in GB pathogenesis. This integrated approach holds promise for furthering our understanding of neural-cancer interactions, offering potential candidates to target neural pathways involved in tumour progression.