Tumour microenvironment programming by an RNA-RNA-binding protein complex creates a druggable vulnerability in IDH-wild-type glioblastoma

  • Nat Cell Biol. 2024 Jun;26(6):1003-1018. doi: 10.1038/s41556-024-01428-5.
Lele Wu  #  1 ,  Zheng Zhao  #  2 ,  Yong Jae Shin  #  3 ,  Yiyun Yin  #  2 ,  Anandhkumar Raju  1 ,  Thamil Selvan Vaiyapuri  1 ,  Khaireen Idzham  1 ,  Miseol Son  3 ,  Yeri Lee  3 ,  Jason K Sa  4 ,  Joelle Yi Heng Chua  1 ,  Bilal Unal  1 ,  You Zhai  2 ,  Wenhua Fan  2  5 ,  Lijie Huang  2 ,  Huimin Hu  2 ,  Jayantha Gunaratne  6 ,  Do-Hyun Nam  3  7 ,  Tao Jiang  8  9 ,  Vinay Tergaonkar  10  11  12
Affiliations
  • 1. Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science Technology and Research (A*STAR), Singapore, Republic of Singapore.
  • 2. Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.
  • 3. Research Institute for Future Medicine, Samsung Medical Center, Seoul, Republic of Korea.
  • 4. Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea.
  • 5. Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
  • 6. Laboratory of Translational Biomedical Proteomics, Institute of Molecular and Cell Biology (IMCB), Agency for Science Technology and Research (A*STAR), Singapore, Republic of Singapore.
  • 7. Department of Neurosurgery, Samsung Medical Center, Seoul, Republic of Korea.
  • 8. Beijing Neurosurgical Institute, Capital Medical University, Beijing, China. [email protected].
  • 9. Beijing Tiantan Hospital, Capital Medical University, Beijing, China. [email protected].
  • 10. Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science Technology and Research (A*STAR), Singapore, Republic of Singapore. [email protected].
  • 11. Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Republic of Singapore. [email protected].
  • 12. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Republic of Singapore. [email protected].
  • # Contributed equally.
PMID: 38858501 DOI: 10.1038/s41556-024-01428-5
Abstract

Patients with IDH-wild-type glioblastomas have a poor five-year survival rate along with limited treatment efficacy due to immune cell (glioma-associated microglia and macrophages) infiltration promoting tumour growth and resistance. To enhance therapeutic options, our study investigated the unique RNA-RNA-binding protein complex LOC-DHX15. This complex plays a crucial role in driving immune cell infiltration and tumour growth by establishing a feedback loop between Cancer and immune cells, intensifying Cancer aggressiveness. Targeting this complex with blood-brain barrier-permeable small molecules improved treatment efficacy, disrupting cell communication and impeding Cancer cell survival and stem-like properties. Focusing on RNA-RNA-binding protein interactions emerges as a promising approach not only for glioblastomas without the IDH mutation but also for potential applications beyond Cancer, offering new avenues for developing therapies that address intricate cellular relationships in the body.

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