Abstract
Bidirectional communication between tumours and neurons has emerged as a key facet of the tumour microenvironment that drives malignancy. Another hallmark feature of cancer is epigenomic dysregulation, in which alterations in gene expression influence cell states and interactions with the tumour microenvironment. Ependymoma (EPN) is a paediatric brain tumour that relies on epigenomic remodelling to engender malignancy; however, how these epigenetic mechanisms intersect with extrinsic neuronal signalling during EPN tumour progression is unknown. Here we show that the activity of serotonergic neurons regulates EPN tumorigenesis, and that serotonin itself also serves as an activating modification on histones. We found that inhibiting histone serotonylation blocks EPN tumorigenesis and regulates the expression of a core set of developmental transcription factors. High-throughput, in vivo screening of these transcription factors revealed that ETV5 promotes EPN tumorigenesis and functions by enhancing repressive chromatin states. Neuropeptide Y (NPY) is one of the genes repressed by ETV5, and its overexpression suppresses EPN tumour progression and tumour-associated network hyperactivity through synaptic remodelling. Collectively, this study identifies histone serotonylation as a key driver of EPN tumorigenesis, and also reveals how neuronal signalling, neuro-epigenomics and developmental programs are intertwined to drive malignancy in brain cancer.
Overview
- The study investigates the intersection of epigenomic dysregulation and extrinsic neuronal signalling in ependymoma (EPN) tumour progression. The study aims to understand how these mechanisms contribute to EPN malignancy and identify potential therapeutic targets. The methodology used includes in vivo experiments with EPN tumour models, histone serotonylation inhibition, and high-throughput screening of developmental transcription factors. The primary objective is to identify key drivers of EPN tumorigenesis and their roles in tumour progression and network hyperactivity.
Comparative Analysis & Findings
- The study found that inhibiting histone serotonylation blocks EPN tumorigenesis and regulates the expression of a core set of developmental transcription factors. Neuropeptide Y (NPY) was identified as one of the genes repressed by ETV5, and its overexpression suppresses EPN tumour progression and tumour-associated network hyperactivity through synaptic remodelling. The study also revealed that serotonergic neurons regulate EPN tumorigenesis, and that serotonin itself serves as an activating modification on histones. These findings suggest that histone serotonylation is a key driver of EPN tumorigenesis and that neuronal signalling, neuro-epigenomics and developmental programs are intertwined to drive malignancy in brain cancer.
Implications and Future Directions
- The study's findings have significant implications for the field of research and clinical practice. The identification of histone serotonylation as a key driver of EPN tumorigenesis opens up new avenues for therapeutic intervention. The study also highlights the importance of understanding the interplay between epigenomic dysregulation and neuronal signalling in brain cancer. Future research directions could include further investigation of the role of histone serotonylation in other brain tumours, as well as exploration of the potential therapeutic benefits of targeting histone serotonylation in EPN. Additionally, the study suggests that synaptic remodelling may play a role in EPN tumour progression, and future research could explore this area in more detail.