Daniel De Carvalho: Inhibiting EZH2 in Atypical Teratoid Rhabdoid Tumor
Daniel De Carvalho, Co-founder and Chief Scientific Officer at Adela, shared on LinkedIn about a recent paper by Shengrui Feng et al. published in Nature Communications:
“Our latest research paper is now published: ‘Inhibiting EZH2 targets atypical teratoid rhabdoid tumor by triggering viral mimicry via both RNA and DNA sensing pathways.’
Key findings:
- SMARCB1 and Viral Mimicry: Loss of SMARCB1 triggers a viral mimicry state, increasing double-stranded RNA (dsRNA). When EZH2 is inhibited, this viral mimicry effect is intensified, making SMARCB1-deficient cells particularly vulnerable to EZH2 inhibitors.
- Dual Pathway Activation: EZH2 inhibition activates both RNA sensing (MDA5/MAVS) and DNA sensing (cGAS/STING) pathways in SMARCB1-deficient cells. Blocking both pathways is essential to completely prevent this effect.
- RNA Sensing via IR-Alus: Intronic IR-Alus, forming dsRNAs in interferon-stimulated genes, create a feedback loop that enhances viral mimicry through RNA sensing.
- DNA Sensing and LINE1: Loss of H3K27me3 reactivates young LINE1 elements, causing reverse transcription and DNA damage. The resulting cGAS/STING activation can be mitigated by RT inhibitors or LINE1 depletion.
These findings highlight the critical role of viral mimicry in targeting SMARCB1-deficient cells with EZH2 inhibition and show how RNA and DNA sensing pathways cooperate to drive this response.”
Authors: Shengrui Feng, Sajid Marhon, Dustin Sokolowski, Jared Simpson, Daniel De Carvalho et al.
More posts featuring Daniel De Carvalho.
Daniel De Carvalho, PhD, is the Co-Founder and Chief Scientific Officer of Adela. He is a scientist, entrepreneur, and executive with expertise in cancer epigenetics, liquid biopsy, and cancer therapy. Professor Carvalho and his research group has pioneered DNA methylation profiling for early cancer detection and monitoring.
As a Canada Research Chair and senior scientist at Princess Margaret Cancer Centre, he also serves as an Associate Professor at the University of Toronto and on the senior advisory board of the Research Institute.
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