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Abstract
Ionizing radiation is widely used for patient with glioblastoma (GBM). However, the effect of radiation on patient survival is marginal and upon recurrence tumors frequently shift toward mesenchymal subtype adopting invasiveness. Here, we show that ionizing radiation affects biomechanical tension in GBM microenvironment and provides proinvasive extracellular signaling cue, hyaluronic acid (HA)-rich condition. In response to radiation, HA production was increased in GBM cells by HA synthase-2 (HAS2) that was transcriptionally upregulated by NF-ĸB. Notably, NF-ĸB was persistently activated by IL-1α-feedback loop, making HA abundance in tumor microenvironment after radiation. Radiation-induced HA abundance causally has been linked to invasiveness of GBM cells by generating movement track as an extracellular matrix, and by acting as a signaling ligand for CD44 receptor, leading to SRC activation, which is sufficient for mesenchymal shift of GBM cells. Collectively, our findings provide an explanation for the frequent brain tumor relapse after radiotherapy, and potential therapeutic targets to block mesenchymal shift upon relapse.

Author information

Yoo KC1, Suh Y1, An Y1, Lee HJ2, Jeong YJ2, Uddin N1, Cui YH1, Roh TH3, Shim JK3, Chang JH3, Park JB4, Kim MJ5, Kim IG6, Kang SG7, Lee SJ8.
1
Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, 04763, Korea.
2
Division of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul, 01812, Korea.
3
Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, 03722, Korea.
4
Specific Organs Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang, 10408, Korea.
5
Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Sciences, Seoul, 01812, Korea.
6
Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, Daejeon, 34057, Korea.
7
Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, 03722, Korea. seokgu9@gmail.com.
8
Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, 04763, Korea. sj0420@hanyang.ac.kr.

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