Kunal Rai, Scientific Director, MDACC Epigenomics Therapy Initiative (METI) at MD Anderson Cancer Center, shared on LinkedIn:
“Excited to share our latest preprint, where we present a comprehensive chromatin atlas that redefines how we classify solid tumors.
Title: Chromatin Landscape of Cancer Cell Lines Identifies Enhancer Subtypes
Authors: Mahinur Mattohti, Emre Arslan, Ayush T. Raman, Christopher Terranova, Zhiyi Liu, Elias Orouji, Sanjana Srinivasan, Veena Kochat, Ming Tang, Samirkumar B. Amin, Jonathan Schulz, Neha S. Samant, Anand K. Singh, Emmanuel Martinez-Ledesma, Sharmistha Sarkar, Marcus Coyle, Christopher Bristow, Faye M. Johnson, Curtis R. Pickering, Keila E. Torres, Jeffery N. Myers, Kunal Rai
In this major effort, we generated 800+ chromatin profiles across 142 widely used cancer cell lines and 100+ primary tumors spanning multiple cancer types to ask fundamental questions:
What does the chromatin landscape of cancer cells look like? How does it drive tumor biology? And can epigenomic states reveal new clinically actionable strategies?
A few findings I’m especially excited about:
- Discovery of EpiC4 – a new pan-cancer epigenetic subtype.
We identify EpiC4, a previously unrecognized cancer subgroup defined entirely by its enhancer landscape, independent of tissue or histologic origin. These tumors are characterized by activation of the FN1-CAV1-SRC-PI3K-AKT signaling axis, pointing to extracellular matrix remodeling and mechanical stress as potential drivers of this epigenetic state. - Epigenetic memory shapes tumor identity. The enhancer-based organization of cancers into EpiC1-3 reflects both developmental lineage and the acquisition of epigenetic plasticity, offering new insight into how tumors maintain adaptability and resist therapy.
- Master transcription factors define each EpiC subtype. Each of the five EpiC states appears to be established by coordinated networks of lineage-defining transcription factors. Importantly, advances in targeted protein degradation, including molecular glues and PROTACs, are making these previously ՛undruggable՛ factors increasingly tractable therapeutic targets.
- Epigenomic states predict therapeutic vulnerabilities. By integrating large-scale drug response datasets, we uncover distinct drug dependencies for each EpiC subtype, supporting an epigenome-informed framework for precision oncology.
Beyond serving as a valuable community resource, this work provides a new framework for understanding epigenomic dysregulation across cancers and opens exciting opportunities for biomarker discovery and targeted therapeutic development.
Congratulations to everyone who contributed to this tremendous effort.
A special shout-out to Mahinur Mattohti for leading this ambitious project, and to Ayush Raman, Emre Arslan, Ph.D., and the many talented members of the lab whose dedication made this work possible.
I look forward to hearing your thoughts and discussions from the community!”
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