Transcriptional Control of Brain Tumour Stem Cells by a Carbohydrate Binding Protein. Transcriptional Control of Brain Tumour Stem Cells by a Carbohydrate Binding Protein

Brain tumour stem cells (BTSCs) and intratumoural heterogeneity represent major challenges in glioblastoma therapy. Here, we report that the LGALS1 gene, encoding the carbohydrate binding protein, galectin1, is a key regulator of BTSCs and glioblastoma resistance to therapy. Genetic deletion of LGALS1 alters BTSC gene expression profiles and results in downregulation of gene sets associated with mesenchymal subtype of glioblastoma. Using a combination of pharmacological and genetic approaches, we establish that inhibition of LGALS1 signalling in BTSCs impairs self-renewal, suppresses tumourigenesis, prolongs lifespan, and improves glioblastoma response to ionizing radiation in preclinical animal models. Mechanistically, we show that LGALS1 is a direct transcriptional target of STAT3 with its expression robustly regulated by the ligand OSM. Importantly, we establish that galectin1 forms a complex with the transcription factor HOXA5 to reprogram BTSC transcriptional landscape. Our data unravel an oncogenic signalling pathway by which galectin1/HOXA5 complex maintains BTSCs and promotes glioblastoma. Overall design: Identification of LGALS1 target genes in brain tumour stem cell, three LGALS1 KO and three control samples.

脑肿瘤干细胞（Brain tumour stem cells, BTSCs）与肿瘤内异质性是胶质母细胞瘤治疗的主要挑战。本研究发现，编码半乳糖结合蛋白半乳凝素1（galectin1）的LGALS1基因，是BTSCs与胶质母细胞瘤治疗抗性的关键调控因子。LGALS1基因的敲除可改变BTSCs的基因表达谱，并导致与胶质母细胞瘤间质亚型相关的基因集表达下调。本研究结合药理学与遗传学手段，证实于BTSCs中抑制LGALS1信号通路，可损害其自我更新能力、抑制肿瘤发生、延长模型小鼠生存期，并在临床前动物模型中增强胶质母细胞瘤对电离辐射的响应。从机制层面分析，本研究证实LGALS1是信号转导与转录激活因子3（STAT3）的直接转录靶标，其表达受配体制瘤素M（OSM）的强力调控。值得注意的是，本研究证实半乳凝素1可与转录因子HOXA5形成复合物，从而重编程BTSCs的转录调控网络。本研究数据揭示了一条致癌信号通路：半乳凝素1/HOXA5复合物通过该通路维持BTSCs并促进胶质母细胞瘤进展。实验整体设计：在脑肿瘤干细胞中鉴定LGALS1的靶基因，共设置3组LGALS1基因敲除（KO）样本与3组对照样本。