Inference of Low and High-Grade Glioma Gene Regulatory Networks Delineates the Role of Rnd3 in Establishing Multiple Hallmarks of Cancer

Abstract

Gliomas are a highly heterogeneous group of brain tumours that are refractory to treatment, highly invasive and pro-angiogenic. Glioblastoma patients have an average survival time of less than 15 months. Understanding the molecular basis of different grades of glioma, from well differentiated, low-grade tumours to high-grade tumours, is a key step in defining new therapeutic targets. Here we use a data-driven approach to learn the structure of gene regulatory networks from observational data and use the resulting models to formulate hypothesis on the molecular determinants of glioma stage. Remarkably, integration of available knowledge with functional genomics datasets representing clinical and pre-clinical studies reveals important properties within the regulatory circuits controlling low and high-grade glioma. Our analyses first show that low and high-grade gliomas are characterised by a switch in activity of two subsets of Rho GTPases. The first one is involved in maintaining normal glial cell function, while the second is linked to the establishment of multiple hallmarks of cancer. Next, the development and application of a novel data integration methodology reveals novel functions of RND3 in controlling glioma cell migration, invasion, proliferation, angiogenesis and clinical outcome.

PARP-1-dependent RND1 transcription induced by topoisomerase I cleavage complexes confers cellular resistance to camptothecin

“…However, genes are differentially affected by CPT and a fraction of them, primarily the short and low-expressed genes, are upregulated 27 – 29 . In accordance with this, RND1 is a short gene (8.7 Kbp), with a low-expression in most healthy tissues apart from brain and liver 2 and in addition, RND1 expression is significantly downregulated in several aggressive tumors compared to normal tissues 39 , 59 , 60 . The mechanisms by which CPT enhances transcription of some genes are largely unknown.…”

“…RND1 expression levels decrease in several aggressive tumors 39 , 59 , 60 , and RND1 loss in immortalized mammary cells can initiate breast tumorigenesis and promotes metastasis 39 . Even in tumor cell lines expressing low levels of RND1 such as MCF-7 cells 39 , U87 cells 59 and U2OS cells, RND1 could be transiently induced by TOP1cc to resist to CPT derivatives. This potential selective advantage of tumor cells suggests that inhibiting RND1-dependent signaling could sensitize them to CPT derivatives.…”

Rnd3-induced cell rounding requires interaction with Plexin-B2

“…It is plausible that plexin-B2 brings Rnd3 and p190RhoGAP together to enhance Rnd3-induced rounding. The role of plexin-B2 as a target for Rnd3 signalling could explain the apparently opposing effects of plexin-B2 in cancer cell invasion and cancer progression: in some cancer types such as breast cancer, both Rnd3 and plexin-B2 appear to inhibit hallmarks of tumorigenesis (Malik et al, 2015; Zhu et al, 2014), whereas in gliomas they promote tumour progression (Clarke et al, 2015; Le et al, 2015). …”

A Network Biology Approach Identifies Molecular Cross-Talk between Normal Prostate Epithelial and Prostate Carcinoma Cells

“…The study we have performed relies on cross-sectional data and therefore the correlations we estimate do not take into consideration the hierarchical sequence of events that characterize cell communication dynamically. However, such dynamics can be captured using in vivo models of tumor expansion [ 37 ]. In such scenarios, different computational methodologies may be used to reverse engineer underlying gene regulatory networks [ 38 ].…”