Epigenomic heterogeneity as a source of tumour evolution

Nuclear Factor I/B: Duality in Action in Cancer Pathophysiology

Brain tumours and Gliomas, in particular, are among the primary causes of cancer mortality worldwide. Glioma diagnosis and therapy have not significantly improved despite decades of efforts. Autocrine TGF-β signalling promotes glioma proliferation, invasion, epithelial-to-mesenchymal transition (EMT), and drug resistance. Non-coding RNAs such as miRNA, lncRNA, and circRNAs have emerged as critical transcriptional and post-transcriptional regulators of TGF-β pathway components in glioma. Here, we summarize the complex regulatory network among regulatory ncRNAs and TGF-β pathway during Glioma pathogenesis and discuss their role as potential therapeutic targets for Gliomas.

Role of Non-Coding RNAs in TGF-β Signalling in Glioma

Novel tissue-agnostic therapeutics targeting driver mutations in tumor cells have been recently approved by FDA, driven by basket trials that have demonstrated their efficacy and safety across diverse tumor histology. However, the relative rarity of primary brain tumors (PBTs) has limited their representation in early trials of tissue-agnostic medications. Thus, consensus continues to evolve regarding utility of tissue-agnostic medications in routine practice for PBTs, a diverse group of neoplasms characterized by limited treatment options and unfavorable prognoses. We describe current and potential impact of tissue-agnostic approvals on management of PBTs. We discuss data from clinical trials for PBTs regarding tissue-agnostic targets, including BRAFV600E, neurotrophic tyrosine receptor kinase (NTRK) fusions, microsatellite instability-high (MSI-High), mismatch repair deficiency (dMMR), and high tumor mutational burden (TMB-H), in context of challenges in managing PBTs. Described are additional tissue-agnostic targets that hold promise for benefiting patients with PBTs, including RET fusion, fibroblast growth factor receptor (FGFR), ERBB2/HER2, and KRASG12C, and TP53Y220C. 

Impact of tissue-agnostic approvals on management of primary brain tumors.

The epigenome harbors diverse sets of DNA elements that can be revealed with distinct sequencing technologies. Epigenomic sequencing studies identify chromatin states to partition the genome into DNA elements and find alterations between healthy and disease settings, known as chromatin variants, to identify the genetic basis of disease. These disease-associated chromatin variants serve as biomarkers and define vulnerabilities for epigenetic therapy. Epigenomic sequencing technologies are constantly evolving and their adoption for clinical uptake should be considered to improve therapeutic applicability. 

Epigenomic Sequencing Technologies

In 2021, the World Health Organization reclassified glioblastoma, the most common form of adult brain cancer, into isocitrate dehydrogenase (IDH)-wild-type glioblastomas and grade IV IDH mutant (G4 IDHm) astrocytomas. For both tumor types, intratumoral heterogeneity is a key contributor to therapeutic failure. To better define this heterogeneity, genome-wide chromatin accessibility and transcription profiles of clinical samples of glioblastomas and G4 IDHm astrocytomas were analyzed at single-cell resolution. These profiles afforded resolution of intratumoral genetic heterogeneity, including delineation of cell-to-cell variations in distinct cell states, focal gene amplifications, as well as extrachromosomal circular DNAs. Despite differences in IDH mutation status and significant intratumoral heterogeneity, the profiled tumor cells shared a common chromatin structure defined by open regions enriched for nuclear factor 1 transcription factors (NFIA and NFIB). Silencing of NFIA or NFIB suppressed in vitro and in vivo growths of patient-derived glioblastomas and G4 IDHm astrocytoma models. These findings suggest that despite distinct genotypes and cell states, glioblastoma/G4 astrocytoma cells share dependency on core transcriptional programs, yielding an attractive platform for addressing therapeutic challenges associated with intratumoral heterogeneity.

Integrated analysis of single-cell chromatin state and transcriptome identified common vulnerability despite glioblastoma heterogeneity.


 
 
 In 2021, the World Health Organization (WHO) reclassified glioblastoma, the most common form of adult brain cancer, into isocitrate dehydrogenase (IDH) wild-type glioblastomas and grade IV IDH mutant (G4 IDHm) astrocytomas. For both tumor types, intra-tumoral heterogeneity is a key contributor to therapeutic failure.
 
 
 
 we applied integrated genome-wide chromatin accessibility (snATACseq) and transcription (snRNAseq) profiles to clinical specimens derived IDHwt glioblastomas and G4 IDHm) astrocytomas, with goal of therapeutic target discovery.
 
 
 
 The integrated analysis achieved resolution of intra-tumoral heterogeneity not previously possible, providing a molecular landscape of extensive regional and cellular variability. snATACseq delineated focal amplification down to an ~40 KB resolution. The snRNA analysis elucidated distinct cell types and cell states (neural progenitor/oligodendrocyte cell-like or astrocyte/mesenchymal cell-like) that were superimposable onto the snATACseq landscape. Paired-seq (parallel snATACseq and snRNAseq using the same clinical sample) provided high resolution delineation of extrachromosomal circular DNA (ecDNA), harboring oncogenes including CCND1 and EGFR. Importantly, the copy number of ecDNA genes correlated closely with the level of RNA expression. Integrated analysis across all specimens profiled suggests that IDHm grade 4 astrocytoma and IDHwt glioblastoma cells shared a common chromatin structure defined by open regions enriched for Nuclear Factor 1 transcription factors (NFIA and NFIB). Silencing of NF1A or NF1B suppressed in vitro and in vivo growth of patient-derived IDHwt glioblastomas and G4 IDHm astrocytoma models that mimic distinct glioblastoma cell states.
 
 
 
 Our findings suggest despite distinct genotypes and cell states, glablastoma/G4 astrocytoma cells share dependency on core transcriptional programs, yielding an attractive platform for addressing therapeutic challenges associated with intra-tumoral heterogeneity.


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Dddr-24. integrated analysis of single cell chromatin accessibility and rna expression identified common vulnerability despite glioblastoma heterogeneity

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Integrated analysis of single-cell chromatin state and transcriptome identified common vulnerability despite glioblastoma heterogeneity.

Dddr-24. integrated analysis of single cell chromatin accessibility and rna expression identified common vulnerability despite glioblastoma heterogeneity