Stanzani Elisabetta, Pedrosa Leire, Bourmeau Guillaume, Anezo Oceane, Noguera-Castells Aleix, Esteve-Codina Anna, Passoni Lorena, Matteoli Michela, de la Iglesia Núria, Seano Giorgio, Martínez-Soler Fina, Tortosa Avelina
Apoptosis and Cancer Unit, Department of Physiological Sciences, IDIBELL, Faculty of Medicine and Health Sciences, Universitat de Barcelona, 08907 L'Hospitalet del Llobregat, Spain.
Haematology and Oncology Unit, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, Spain.
Cancers (Basel). 2021 Jun 19;13(12):3055. doi: 10.3390/cancers13123055.
Therapeutic resistance after multimodal therapy is the most relevant cause of glioblastoma (GBM) recurrence. Extensive cellular heterogeneity, mainly driven by the presence of GBM stem-like cells (GSCs), strongly correlates with patients' prognosis and limited response to therapies. Defining the mechanisms that drive stemness and control responsiveness to therapy in a GSC-specific manner is therefore essential. Here we investigated the role of integrin a6 () in controlling stemness and resistance to radiotherapy in proneural and mesenchymal GSCs subtypes. Using cell sorting, gene silencing, RNA-Seq, and in vitro assays, we verified that expression seems crucial for proliferation and stemness of proneural GSCs, while it appears not to be relevant in mesenchymal GSCs under basal conditions. However, when challenged with a fractionated protocol of radiation therapy, comparable to that used in the clinical setting, mesenchymal GSCs were dependent on integrin a6 for survival. Specifically, GSCs with reduced levels of displayed a clear reduction of DNA damage response and perturbation of cell cycle pathways. These data indicate that inhibition is able to overcome the radioresistance of mesenchymal GSCs, while it reduces proliferation and stemness in proneural GSCs. Therefore, integrin a6 controls crucial characteristics across GBM subtypes in GBM heterogeneous biology and thus may represent a promising target to improve patient outcomes.
多模态治疗后的治疗抵抗是胶质母细胞瘤（GBM）复发的最主要相关原因。广泛的细胞异质性，主要由GBM干细胞样细胞（GSCs）的存在驱动，与患者的预后和对治疗的有限反应密切相关。因此，以GSC特异性方式确定驱动干性并控制治疗反应性的机制至关重要。在此，我们研究了整合素α6（ ）在控制神经干细胞样和间充质GSCs亚型的干性和放疗抗性中的作用。通过细胞分选、基因沉默、RNA测序和体外试验，我们证实， 的表达对于神经干细胞样GSCs的增殖和干性似乎至关重要，而在基础条件下，它在间充质GSCs中似乎无关紧要。然而，当用与临床环境中使用的类似的分次放疗方案进行挑战时，间充质GSCs的存活依赖于整合素α6。具体而言， 水平降低的GSCs显示出DNA损伤反应明显减少和细胞周期途径紊乱。这些数据表明， 抑制能够克服间充质GSCs的放射抗性，同时降低神经干细胞样GSCs的增殖和干性。因此，整合素α6在GBM异质性生物学中控制着GBM各亚型的关键特征，因此可能是改善患者预后的一个有前景的靶点。
