Shear stress activates ATOH8 via autocrine VEGF promoting glycolysis dependent-survival of colorectal cancer cells in the circulation

作者：Qiong Huang, Shao-wei Li, Xingbin Hu, Mengting Sun, Qijing Wu, Huiru Dai, Yujing Tan, Fei Sun, Chunlin Wang, Xiaoxiang Rong, Wangjun Liao, Jianjun Peng, Jianjun Xiao, Li Huang, Jiao Wang, Bishan Liang, Kelin Lin, Yajing Liu, Min Shi · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2020 · DOI：10.1186/s13046-020-1533-0 · 被引用次数：60 · 研究领域：Cancer Cells and Metastasis、Cancer, Hypoxia, and Metabolism、Erythrocyte Function and Pathophysiology

BACKGROUND: Metastasis and recurrence, wherein circulating tumour cells (CTCs) play an important role, are the leading causes of death in colorectal cancer (CRC). Metastasis-initiating CTCs manage to maintain intravascular survival under anoikis, immune attack, and importantly shear stress; however, the underlying mechanisms remain poorly understood. METHODS: In view of the scarcity of CTCs in the bloodstream, suspended colorectal cancer cells were flowed into the cyclic laminar shear stress (LSS) according to previous studies. Then, we detected these suspended cells with a CK8+/CD45-/DAPI+ phenotype and named them mimic circulating tumour cells (m-CTCs) for subsequent CTCs related researches. Quantitative polymerase chain reaction, western blotting, and immunofluorescence were utilised to analyse gene expression change of m-CTCs sensitive to LSS stimulation. Additionally, we examined atonal bHLH transcription factor 8 (ATOH8) expressions in CTCs among 156 CRC patients and mice by fluorescence in situ hybridisation and flow cytometry. The pro-metabolic and pro-survival functions of ATOH8 were determined by glycolysis assay, live/dead cell vitality assay, anoikis assay, and immunohistochemistry. Further, the concrete up-and-down mechanisms of m-CTC survival promotion by ATOH8 were explored. RESULTS: The m-CTCs actively responded to LSS by triggering the expression of ATOH8, a fluid mechanosensor, with executive roles in intravascular survival and metabolism plasticity. Specifi...