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

in Nature cell biology by Lele Wu, Zheng Zhao, Yong Jae Shin, Yiyun Yin, Anandhkumar Raju, Thamil Selvan Vaiyapuri, Khaireen Idzham, Miseol Son, Yeri Lee, Jason K Sa, Joelle Yi Heng Chua, Bilal Unal, You Zhai, Wenhua Fan, Lijie Huang, Huimin Hu, Jayantha Gunaratne, Do-Hyun Nam, Tao Jiang, Vinay Tergaonkar

TLDR

  • The study found that a protein called LOC-DHX15 helps cancer cells grow by letting immune cells infiltrate and help the cancer cells grow. The study found that targeting this protein with a special kind of medicine called a small molecule can stop the cancer cells from growing and make the immune cells stop helping the cancer cells. The study also found that this protein is important for many other diseases and conditions in the body, so it could be used to treat those too.

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.

Overview

  • The study investigates the role of the RNA-RNA-binding protein complex LOC-DHX15 in promoting immune cell infiltration and tumor growth in IDH-wild-type glioblastomas. The study aims to identify potential therapeutic targets to improve treatment efficacy and disrupt cell communication. The methodology used includes in vitro and in vivo experiments with human glioblastoma cells and mouse models, as well as analysis of gene expression and protein-protein interaction data. The primary objective of the study is to understand the mechanisms underlying immune cell infiltration and tumor growth in IDH-wild-type glioblastomas and to identify potential therapeutic targets to improve treatment efficacy.

Comparative Analysis & Findings

  • The study found that LOC-DHX15 plays a crucial role in driving immune cell infiltration and tumor growth in IDH-wild-type glioblastomas. The complex establishes 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. The study also identified potential therapeutic targets for other cancers and diseases beyond cancer, highlighting the importance of RNA-RNA-binding protein interactions in addressing intricate cellular relationships in the body.

Implications and Future Directions

  • The study's findings have significant implications for the treatment of IDH-wild-type glioblastomas, as targeting LOC-DHX15 and its interactions with other RNA-RNA-binding proteins could improve treatment efficacy and disrupt cell communication. The study also highlights the importance of RNA-RNA-binding protein interactions in addressing intricate cellular relationships in the body, offering new avenues for developing therapies that target these interactions. Future research directions could include further investigation of the role of LOC-DHX15 and other RNA-RNA-binding proteins in cancer and other diseases, as well as development of novel therapies that target these interactions.
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