br Materials and methods br Results br Discussion
Materials and methods
Conclusions First, we replicated the association of DDR1 with SZ in an independent Spanish sample and demonstrated that a SNP-SNP interaction within DDR1 played a role in the association with the disease. Second, we observed that SZ subjects with the rs2267641CC genotype had decreased PS scores. Third, SZ subjects with the rs1264323AA genotype showed decreased FA in WM regions in association with decreased PS. We conclude that DDR1 variants may confer a risk of SZ through WM microstructural alterations leading to cognitive dysfunction.
Acknowledgements This work was supported by the Spanish ‘Instituto de Salud Carlos III’ from the Ministry of Economy, Industry and Competitivity and FEDER (project grants to [EV] #SAF2007-60086, #PI12/02111 and [JR] # PI14/00292; and contract grants Miguel Servet #CPII16/00018 to [EP-C] and #MS14/00041 to [JR]) and Generalitat de Catalunya Agency ‘AGAUR’ (research grant to [EV] #2017-SGR-444 and to [EP-C] #2017-SGR-1271). Nerea Abasolo was the recipient of a predoctoral fellowship from the Universitat Rovira i Virgili. The Authors have declared that there are no conflicts of interest in relation to the subject of this study.
Introduction Glioblastoma (GBM; World Health Organization [WHO] grade IV gliomas) remains one of the most difficult-to treat-tumor types, as multiple genetic lesions promote therapy resistance, complemented by severe destructive infiltration of the surrounding R406 free base (Louis et al., 2016, Weller et al., 2015). GBM is routinely treated by surgery followed by radiotherapy and chemotherapy using the DNA-methylating agent temozolomide (TMZ) (Stupp et al., 2009). Despite advances in treatment regimens and our understanding of genetics and molecular mechanisms underlying GBM development and progression, patients with GBM still have a poor prognosis, with an estimated 5-y overall survival of less than 5% (Cancer Genome Atlas Research Network, 2008, Stupp et al., 2009). While resistance to therapy has been mainly attributed to inter- and intratumoral heterogeneity as well as GBM stem cells (GSCs), increasing evidence points at the importance of cell-extracellular matrix (ECM) interactions within the tumor microenvironment as a further essential mechanism (Eke et al., 2012, Eke et al., 2015, Fidoamore et al., 2016, Vehlow and Cordes, 2013, Vehlow et al., 2017). Cell-ECM interactions are mainly, but not exclusively, facilitated by the integrin family of cell adhesion molecules (Seguin et al., 2015, Tabatabai et al., 2011). It is generally accepted that cell adhesion molecules fundamentally impact cancer cell therapy resistance, as they convey pro-angiogenic, survival-, and invasion-promoting microenvironmental cues in GBM as well as numerous other cancers (Cabodi et al., 2010, Eke and Cordes, 2015, Eke et al., 2012, Vehlow et al., 2017). Despite promising data from preclinical cancer models, integrin-targeting agents have so far demonstrated low efficacy in clinical trials. In GBM, targeting of the pro-angiogenic αvβ3 and β5 integrins with cilengitide failed to improve patient outcome in a phase III clinical trial (Stupp et al., 2014). However, other integrin receptors, such as the laminin-binding α6 and α7 integrins or the RGD receptor αvβ8 integrin, are regarded as putative therapeutic targets, as their expression on GSCs promotes self-renewal, proliferation, and tumor formation (Guerrero et al., 2017, Haas et al., 2017, Lathia et al., 2010). In addition to integrins, the receptor tyrosine kinase discoidin domain receptor 1 (DDR1) binds to and is activated by collagens in the ECM (Xu et al., 2012), which are expressed in brain tumors and are associated with patient prognosis (Huijbers et al., 2010, Pointer et al., 2017). Type I collagen (Col I) was shown to populate microenvironmental niches where GBM GSCs reside, survive treatment, and propagate into recurrence (Motegi et al., 2014). In GBM, elevated DDR1 mRNA expression has been reported and potentially correlated with poor prognosis, advanced tumor stage, and invasiveness (Ram et al., 2006, Weiner et al., 2000). This renders DDR1 a potential therapeutic target as part of the current multimodal treatment for GBM including radiotherapy and TMZ. However, a direct link to therapy resistance has not been established, and it remains to be elucidated how and which mechanisms are controlled by DDR1.