Tumour-derived substrate-adherent cells promote neuroblastoma survival through secreted trophic factors
Publication in refereed journal
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香港中文大學研究人員
替代計量分析
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其它資訊
摘要Neuroblastoma (NB) is the most common extracranial solid tumour in children. NB is highly heterogeneous and is comprised of a mixture of neuroblastic cancer cells and stromal cells. We previously reported that N-type cells (neuroblastic cells) and S-type cells (substrate-adherent cells) in the SK-N-SH cell line shared almost identical genetic backgrounds. Sublines of N- and S-type cells were isolated from an early passage (P35) of SK-N-SH. Sequencing analysis revealed that all sublines harboured the anaplastic lymphoma kinase (ALK) F1174L mutation, indicating that they were tumour derived. Surprisingly, over 74% resembled S-type cells. In coculture experiments, S-type cells protected N-type cells from apoptosis induced by the oncogenic ALK inhibitor TAE684. Western blotting analyses showed that ALK, protein kinase A (AKT) and STAT3 signalling were stimulated in the cocultures. Furthermore, the conditioned medium from S-type cells activated these downstream signalling molecules in the N-type cells. The activation of STAT3 in the N-type cells was ALK-independent, while AKT was regulated by the ALK activation status. To identify the responsible soluble factors, we used a combination of transcriptomic and proteomic analysis and found that plasminogen activator inhibitor 1, secreted protein acidic and cysteine rich, periostin and galectin-1 were potential mediators of STAT3 signalling. The addition of recombinant proteins to the tumour cells treated with the ALK inhibitor partially enhanced cell viability. Overall, the tumour-derived S-type cells prevented apoptosis in the N-type cells via ALK-independent STAT3 activation triggered by secreted factors. The inhibition of these factors in combination with ALK inhibition could provide a new direction for targeted therapies to treat high-risk NB.
出版社接受日期14.04.2021
著者Li J, Wang Y, Li L, Or PM, Wong CW, Liu T, Ho WLH, Chan AM
期刊名稱Molecular Oncology
出版年份2021
國際標準期刊號1574-7891
語言英式英語
關鍵詞ALK, STAT3, neuroblastoma, substrate-adherent cells, tumour microenvironment

上次更新時間 2021-12-06 於 01:29