Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC H3T 1E2, Canada; Gerald Bronfman Department of Oncology and Division of Experimental Medicine, McGill University, Montréal, QC H4A 3T2, Canada.
Department of Human Genetics, McGill University, Montréal, QC H3A OC7, Canada; McGill Genome Centre, Montréal, QC H3A 0G1, Canada.
Cell Rep. 2021 Aug 31;36(9):109647. doi: 10.1016/j.celrep.2021.109647.
Brain tumor stem cells (BTSCs) and intratumoral 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 the mesenchymal subtype of glioblastoma. Using a combination of pharmacological and genetic approaches, we establish that inhibition of LGALS1 signaling in BTSCs impairs self-renewal, suppresses tumorigenesis, 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 the BTSC transcriptional landscape. Our data unravel an oncogenic signaling pathway by which the galectin1/HOXA5 complex maintains BTSCs and promotes glioblastoma.
脑肿瘤干细胞（BTSCs）和肿瘤内异质性是胶质母细胞瘤治疗的主要挑战。在这里，我们报告 LGALS1 基因（编码糖结合蛋白半乳糖凝集素 1）是 BTSCs 和胶质母细胞瘤对治疗耐药性的关键调节因子。LGALS1 的基因缺失改变了 BTSC 的基因表达谱，并导致与胶质母细胞瘤间充质亚型相关的基因集下调。通过药理学和遗传学方法的结合，我们确定抑制 BTSCs 中的 LGALS1 信号会损害自我更新，抑制肿瘤发生，延长寿命，并改善临床前动物模型中胶质母细胞瘤对电离辐射的反应。从机制上讲，我们表明 LGALS1 是 STAT3 的直接转录靶标，其表达受配体 OSM 的强烈调节。重要的是，我们确定半乳糖凝集素 1 与转录因子 HOXA5 形成复合物，从而重新编程 BTSC 的转录景观。我们的数据揭示了一种致癌信号通路，通过该通路，半乳糖凝集素 1/HOXA5 复合物维持 BTSC 并促进胶质母细胞瘤。
