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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2020

Open Access 01-12-2020 | Metastasis | Research

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

Authors: Qiong Huang, Shaowei 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

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2020

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Abstract

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. Specifically, ATOH8 was upregulated via activation of VEGFR2/AKT signalling pathway mediated by LSS induced VEGF release. ATOH8 then transcriptionally activated HK2-mediated glycolysis, thus promoting the intravascular survival of colorectal cancer cells in the circulation.

Conclusions

This study elucidates a novel mechanism that an LSS triggered VEGF-VEGFR2-AKT-ATOH8 signal axis mediates m-CTCs survival, thus providing a potential target for the prevention and treatment of hematogenous metastasis in CRC.
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Metadata
Title
Shear stress activates ATOH8 via autocrine VEGF promoting glycolysis dependent-survival of colorectal cancer cells in the circulation
Authors
Qiong Huang
Shaowei 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
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2020
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-020-1533-0

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