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High-Resolution Structural Genomics Reveals New Therapeutic Vulnerabilities in Glioblastoma

Abstract

SUMMARY

We investigated the role of 3D genome architecture in instructing functional properties of glioblastoma stem cells (GSCs) by generating the highest-resolution 3D genome maps to-date for this cancer. Integration of DNA contact maps with chromatin and transcriptional profiles identified specific mechanisms of gene regulation, including individual physical interactions between regulatory regions and their target genes. Residing in structurally conserved regions in GSCs was CD276, a gene known to play a role in immuno-modulation. We show that, unexpectedly, CD276 is part of a stemness network in GSCs and can be targeted with an antibody-drug conjugate to curb self-renewal, a key stemness property. Our results demonstrate that integrated structural genomics datasets can be employed to rationally identify therapeutic vulnerabilities in self-renewing cells.

SIGNIFICANCE 

In adult GBM, GSCs act as therapy-resistant reservoirs to nucleate tumour recurrence. New therapeutic approaches that target these cell populations hold the potential of significantly improving patient care and overall prognosis for this always-lethal cancer. Our work describes new links between 3D genome architecture and stemness properties in GSCs. In particular, through integration of multiple genomics and structural genomics datasets, we found an unexpected connection between immune-related genes and self-renewal programs in GBM. Among these, we show that targeting CD276 with knockdown strategies or specific antibody-drug conjugates achieve suppression of self-renewal. Strategies to target CD276+ cells are currently in clinical trials for solid tumours. Our results indicate that CD276-targeting agents could be deployed in GBM to specifically target GSC populations.

HIGHLIGHTS

  • We generated high (sub-5 kb) resolution Hi-C maps for stem-like cells from GBM patients.
  • Integration of Hi-C and genomics datasets dissects mechanisms of gene regulation.
  • 3D genomes poise immune-related genes, including CD276, for expression.
  • Targeting CD276 curbs self-renewal properties of GBM cells.

bioRχiv doi: https://doi.org/10.1101/442277

Keywords: N/A

Copyright 

The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.