Ivy Glioblastoma Atlas Project

Ivy Glioblastoma Atlas Project

http://glioblastoma.alleninstitute.org/

The Ivy Glioblastoma Atlas Project is a foundational resource for exploring the anatomic and genetic basis of glioblastoma at the cellular and molecular levels.

Partnership

It is a collaborative partnership between the Ben and Catherine Ivy Foundation, the Allen Institute for Brain Science, and the Ben and Catherine Ivy Center for Advanced Brain Tumor Treatment.

Funding Support

This project was supported by the Ben and Catherine Ivy Foundation (PIs: Ralph Puchalski, PhD, Allen Institute for Brain Science and Greg Foltz, MD, Swedish Neuroscience Institute).


Glioblastoma multiforme (GBM), an aggressive brain tumor, is characterized histologically by the presence of a necrotic center surrounded by so-calledpseudopalisading cells. Pseudopalisading necrosis has long been used as a prognostic feature. However, the underlying molecularmechanism regulating the progression of GBMs remains unclear.

Wang et al., hypothesized that the gene expression profilings of individual cancers, specifically necrosis-related genes, would provide objective information that would allow for the creation of a prognostic index. Gene expression profiles of necrotic and nonnecrotic areas were obtained from the Ivy Glioblastoma Atlas Project (IVY GAP) database to explore the differentially expressed genes.A robust signature of seven genes was identified as a predictor for glioblastoma and low-grade glioma (GBM/LGG) in patients from The Cancer Genome Atlas (TCGA) cohort. This set of genes was able to stratify GBM/LGG and GBM patients into high-risk and low-risk groups in the training set as well as the validation set. The TCGA, Repository for Molecular Brain Neoplasia Data (Rembrandt), and GSE16011 databases were then used to validate the expression level of these seven genes in GBMs and LGGs. Finally, the differentially expressed genes (DEGs) in the high-risk and low-risk groups were subjected to gene ontology enrichmentKyoto Encyclopedia of Genes and Genomes pathway, and gene set enrichment analyses, and they revealed that these DEGs were associated with immune and inflammatory responses. In conclusion, the study identified a novel seven-gene signature that may guide the prognostic prediction and development of therapeutic applications 1).


The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project data demonstrated that IL-8 transcript expression is negatively correlated with GBM patient survival (p = 0.001) and positively correlated with that of genes associated with the GIC phenotypes, such as KLF4, c-Myc, and HIF2α (p < 0.001). Immunohistochemical analysis of patient samples demonstrated elevated IL-8 expression in about 60% of recurrent GBM tumors relative to matched primary tumors and this expression also positively correlates with time to recurrence. Exposure to IL-8 significantly enhanced the self-renewing capacity of PDX GBM (average threefold, p < 0.0005), as well as increasing the expression of GIC markers in the CXCR2 population. Furthermore, IL-8 knockdown significantly delayed PDX GBM tumor growth in vivo (p < 0.0005). Finally, guided by in silico analysis of TCGA data, we examined the effect of therapy-induced IL-8 expression on the epigenomic landscape of GBM cells and observed increased trimethylation of H3K9 and H3K27. Our results show that autocrine IL-8 alters cellular plasticity and mediates alterations in histone status. These findings suggest that IL-8 signaling participates in regulating GBM adaptation to therapeutic stress and therefore represents a promising target for combination with conventional chemotherapy in order to limit GBM recurrence 2).


Immunohistochemical staining and the RNA-seq (sequencing) data from the IVY Glioblastoma Atlas Project showed FGF13 expression in glioma cells in the invasive edges of tumor specimens. Also, the intracellular distribution was mainly in the cytoplasm of tumor cells and colocalized with tubulin. Overexpression of FGF13 stabilized tubulin dynamics in vitro and knockdown of FGF13 decreased glioma invasion both in vitro and in vivo and prolonged overall survival of several xenograft models. FGF13 was negatively regulated by hypoxic condition. Silencing of FGF13 also decreased in vivo bevacizumab-induced glioma invasion. In conclusion, FGF13 regulated glioma cell invasion and bevacizumab-induced glioma invasion, and could be a novel target for glioma treatment 3).


In support of potential clinical relevance, expression of selected GSC-enriched ion channels evaluated in human glioblastoma databases of The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project correlated with patient survival times. Finally, genetic knockdown as well as pharmacological inhibition of individual or classes of GSC-enriched ion channels constrained growth of GSCs compared to normal neural stem cells. This first-in-kind global examination characterizes ion channels enriched in GSCs and explores their potential clinical relevance to glioblastoma molecular subtypes, gene mutations, survival outcomes, regional tumor expression, and experimental responses to loss-of-function. Together, the data support the potential biological and therapeutic impact of ion channels on GSC malignancy and provide strong rationale for further examination of their mechanistic and therapeutic importance 4).

References

1)

Wang J, Ma J. Integrated Transcriptomic Analysis of Necrosis-related Gene in Diffuse Gliomas. J Neurol Surg A Cent Eur Neurosurg. 2019 Apr 1. doi: 10.1055/s-0039-1683448. [Epub ahead of print] PubMed PMID: 30934097.
2)

Hasan T, Caragher SP, Shireman JM, Park CH, Atashi F, Baisiwala S, Lee G, Guo D, Wang JY, Dey M, Wu M, Lesniak MS, Horbinski CM, James CD, Ahmed AU. Interleukin-8/CXCR2 signaling regulates therapy-induced plasticity and enhances tumorigenicity in glioblastoma. Cell Death Dis. 2019 Mar 29;10(4):292. doi: 10.1038/s41419-019-1387-6. PubMed PMID: 30926789.
3)

Otani Y, Ichikawa T, Kurozumi K, Inoue S, Ishida J, Oka T, Shimizu T, Tomita Y, Hattori Y, Uneda A, Matsumoto Y, Michiue H, Date I. Fibroblast growth factor 13 regulates glioma cell invasion and is important for bevacizumab-induced glioma invasion. Oncogene. 2018 Feb 8;37(6):777-786. doi: 10.1038/onc.2017.373. Epub 2017 Oct 23. PubMed PMID: 29059154.
4)

Pollak J, Rai KG, Funk CC, Arora S, Lee E, Zhu J, Price ND, Paddison PJ, Ramirez JM, Rostomily RC. Ion channel expression patterns in glioblastoma stem cells with functional and therapeutic implications for malignancy. PLoS One. 2017 Mar 6;12(3):e0172884. doi: 10.1371/journal.pone.0172884. eCollection 2017. PubMed PMID: 28264064; PubMed Central PMCID: PMC5338779.

PASSION Resident project

The PASSION Resident project is a European study that aims at establishing a new training syllabus for neurosurgical residents.
see Neurosurgical training in Europe.
The main goal is to shape young neurosurgeons in their resident years through the implementation of new training modules, including simulation courses that will improve their neurosurgical skills in an innovative way. Moreover this new methodology will allow standardised measurements with an objective perspective of their progress and achievements. Besides, we will assess all participants by means of some validated professional questionnaires.
This study will take place at the Besta NeuroSim Centre, within the IRCCS Carlo Besta Neurological Institute in Milan (Italy). It foresees the use of the most sophisticated and modern neurosurgical simulators available today. These simulators provide haptic feedback and a threedimensional virtual reality. Along with these technologically advanced systems (SimLab) the resident students participating will also have to perform microsurgical tasks at the WetLab station of the Center.
The PASSION Resident study project has been approved by our local Ethical Board (IRB). The study will start in March 2018.

WHO CAN PARTICIPATE?

All neurosurgery residents currently enrolled in any Center or Institute in Europe (currently enrolled in a residency program across Europe – PGY1, PGY2, PGY3, PGY4). All residents must have no neurosurgical simulation training or experience.
All participants must have completed these pre-requisites: three (3) EVD placement procedures and three (3) microscope-assisted dural sutures (at the end of an intra-cerebral lesion removal surgery).

HOW TO PARTICIPATE?

All applicants must send these following documents in the exact way in which they are described, to these email addresses: alessandro.perin@istituto-besta.it and nicole.riker@istituto-besta.it:
A. Pre and post-operative CT scan (or MRI) in DICOM format of three EVD operations done, specifying: a) number of attempts needed to reach the lateral ventricle; b) Role that the resident had (first/second operator; level of independence) during the procedure; please note that first-time positioned EVD will be eligible for the study, no EVD substitution will be considered; You can also upload the last EVDs you have positioned consecutively during the last period of your surgical activity (collection of this data does not necessarily need to be perspective).
B. Video Recordings (through the microscope) of the last three dural sutures done at the end of an intra-cerebral lesion removal surgery specifying: a) The microscopes magnification level and the caliber of the suturing stitch; b) the role that the resident had during the procedure (first/second operator; level of independence) and specify at what point of the registration the resident was actually operating at the microscope; c) Opening of any cisterns and/or of the cerebral ventricles; any post-operative complication referable to the dural suturing (CFS fistula, pseudomeningocele).
C. A document stating that the resident is officially enrolled in a residency program.
D. The attached form entirely and accurately filled out.
All data, namely DICOM images and microscope video recordings MUST be anonymous: they cannot and must not include any personal patient or surgeon information; the neurosurgeon’s Center must not be recognisable.
All data must be uploaded to Google Drive. Please share all of the requested information at passionstudy2017@gmail.com
The information sent will be examined by a commission of expert neurosurgeons, in an anonymous manner (blinded evaluation). The first 140 resident students to submit the required information will be selected as participants for this study.
NB: this study will not focus on patients but will only evaluate the neurosurgical actions done by residents; no personal data that belongs to patients will be shared, no personal information about patients/surgeons/Institutions will be posed at risk or published.

WHAT IS THE STRUCTURE OF THE STUDY?

At the end of the selection process the participants will be randomised into two groups: half of them will take part in the Wet Lab and the simulation sessions (SimLab), while the other half will take part in the Wet Lab only (Control group). The first group will be divided into smaller groups of six participants who will be at the Centre for five consecutive days; the second group (control) will be at the Center only on the first and last day. (Look at the scheme on the following page).
Every participant will undergo specific dexterity and spatial orientation tests along with a psychometric evaluation.
At the end of the candidates’ work at the Center, all residents must return to their medical activities and redo the exact pre-requisite tasks that were mandatory for the application process (3 EVD placements and 3 dural sutures) and send them back to the examining commission through the previously cited email addresses (POST-REQUISITES). This second data collection MUST be completed within 2 months after their return to their home Institutions.

FINANCIAL EXPENSES

The Best NeuroSim Center will cover all the expenses that regard the onsite study materials, namely brain tumour/dura models, mannequins, personnel and lunch tickets and accommodation for all participants. We ask participants to cover their travel expenses.

WHY SHOULD YOU PARTICIPATE?

First and foremost it would be a unique experience to work and collaborate within an international research group that for the first time ever aims at defining the potential beneficial impact that simulation might have on your learning process of both technical and non technical skills This would be achieved on a large scale by using top-notch, up-to-date simulators with haptic feedback that you will be entitled to use extensively. By participating in this innovative training you will have the chance to spend 5 days in one of the most renown and recognised neurosurgery Centres in the World, with a special focus on brain tumours and research and technology innovation. At the Besta Institute we operate on more than 3000 patients a year of whom 1000 are affected by CNS tumours; this is where the first European neurosurgical simulation Center was created. Here no matter whether part of the control group or the study groups you will be able to train some key neurosurgical tasks at the WetLab; moreover you will be using our simulators intensively (study group), or following all OR activities (control group).
Finally, as core members and contributors to this study you would all be named co-authors (in a study group publication entity) when the results of this study will be published.
ALL APPLICANTS MUST SEND THE REQUESTED ENROLMENT INFORMATION BY FEBRUARY 28th 2018.

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