The Brain Microenvironment Induces DNMT1 Suppression and Indolence of Metastatic Cancer Cells

Eishu Hirata; Kojiro Ishibashi; Shinji Kohsaka; Keiko Shinjo; Shinya Kojima; Yutaka Kondo; Hiroyuki Mano; Seiji Yano; Etsuko Kiyokawa; Erik Sahai

doi:10.1016/j.isci.2020.101480

The Brain Microenvironment Induces DNMT1 Suppression and Indolence of Metastatic Cancer Cells

iScience. 2020 Aug 20;23(9):101480. doi: 10.1016/j.isci.2020.101480. eCollection 2020 Sep 25.

Authors

Eishu Hirata^{1

2}, Kojiro Ishibashi¹, Shinji Kohsaka³, Keiko Shinjo⁴, Shinya Kojima³, Yutaka Kondo⁴, Hiroyuki Mano³, Seiji Yano^{2

5}, Etsuko Kiyokawa⁶, Erik Sahai⁷

Affiliations

¹ Division of Tumor Cell Biology and Bioimaging, Cancer Research Institute of Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
² Nano Life Science Institute, Kanazawa University, Kanazawa 920-1192, Japan.
³ Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
⁴ Division of Cancer Biology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
⁵ Division of Medical Oncology, Cancer Research Institute of Kanazawa University, Kanazawa 920-0934, Japan.
⁶ Department of Oncologic Pathology, Kanazawa Medical University, Uchinada 920-0293, Japan.
⁷ Tumour Cell Biology Laboratory, Francis Crick Institute, London NW1 1AT, UK.

Abstract

Brain metastasis is an ineffective process, and many cancer cells enter into an indolent state following extravasation in the brain. Single cell RNA sequencing of melanoma brain metastases reveals that non-proliferating brain metastatic melanoma cells exhibit a pattern of gene expression associated with inhibition of DNA methyltransferase 1 (DNMT1). The brain microenvironment, specifically the combination of reactive astrocytes and mechanically soft surroundings, suppressed DNMT1 expression in various cancer types and caused cell cycle delay. Somewhat unexpectedly, we find that DNMT1 suppression not only induces cell cycle delay but also activates pro-survival signals in brain metastatic cancer cells, including L1CAM and CRYAB. Our results demonstrate that transcriptional changes triggered by DNMT1 suppression is a key step for cancer cells to survive in the brain microenvironment and that they also restrict cancer cell proliferation. The dual consequences of DNMT1 suppression can explain the persistence of indolent cancer cells in the brain microenvironment.

Keywords: Biological Sciences; Cancer; Cell Biology; Transcriptomics.