RT Journal Article
SR Electronic
T1 Multidimensional hydrogel models reveal endothelial network angiocrine signals increase glioblastoma cell number, invasion, and temozolomide resistance
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.01.18.911396
DO 10.1101/2020.01.18.911396
A1 Mai T. Ngo
A1 Elijah Karvelis
A1 Brendan A.C. Harley
YR 2020
UL http://biorxiv.org/content/early/2020/04/09/2020.01.18.911396.abstract
AB Glioblastoma is the most common primary malignant brain tumor. The tissue microenvironment adjacent to vasculature, termed the perivascular niche, has been implicated in promoting biological processes involved in glioblastoma progression such as invasion, proliferation, and therapeutic resistance. However, the exact nature of the cues that support tumor cell aggression in this niche are largely unknown. Soluble angiocrine factors secreted by tumor-associated vasculature have been shown to support such behaviors in other cancer types. Here, we exploit macroscopic and microfluidic gelatin hydrogel platforms to profile angiocrine factors secreted by self-assembled endothelial networks and evaluate their relevance to glioblastoma biology. Aggregate angiocrine factors support increases in U87-MG cell number, migration, and therapeutic resistance to temozolomide. We also identify a novel role for TIMP1 in facilitating glioblastoma tumor cell migration. Overall, this work highlights the use of multidimensional hydrogel models to evaluate the role of angiocrine signals in glioblastoma progression.Insight, Innovation, and Integration Glioblastoma progression is linked to interactions between tumor and vascular cells, which can influence invasion and therapeutic response. In co-culture studies to investigate tumor-vascular crosstalk, endothelial cells often are not presented in three-dimensional structures mimicking vasculature and the exact identity of secreted factors is not explored. Here, we use tissue engineering strategies to generate three-dimensional endothelial networks from which to collect soluble angiocrine signals and assess the impact of these signals on glioblastoma behavior. Furthermore, we use secretomic analysis to identify specific factors influencing glioblastoma invasion. We identify a novel role for TIMP1 in supporting glioblastoma migration and demonstrate that soluble angiocrine signals support chemoresistance to temozolomide.Competing Interest StatementThe authors have declared no competing interest.