Translational project will create the first detailed 3D maps of human glioblastomas with an integrated ‘tissue time machine’ to predict response to therapies

Geneva, Switzerland – The Wyss Center announced today that it will lead a collaborative project, as part of Wellcome Leap’s Delta Tissue Program, to improve understanding of the brain cancer glioblastoma (GBM) and help develop more effective therapies. The project, in collaboration with the University of Geneva and the Paris Brain Institute, will map the GBM microenvironment in whole human tumors.

GBM is an incurable disease and is the most common and aggressive brain tumor worldwide. The tumor microenvironment (TME) includes tumor cells, immune cells, molecules released by these cells, blood vessels and hypoxic areas of low oxygen all of which change over time and may contribute to the recurrence of GBM. By accurately mapping the TME in recurrent tumors from the same patient, before and after treatment, the team will build a model – a ‘tissue time machine’ – that helps predict response to therapies.

Investigations are typically performed on very thin GBM slices, only about 10 microns thick, rather than on complete human tumors, and so fail to capture the complexity of the TME in its entirety. In addition, standard analyses do not reveal the way that the microenvironment changes over time with treatment, nor the reasons why treatment might be failing.

“To address this challenge, we are bringing together a dynamic group of scientists. Our colleagues at the Paris Brain Institute are experts in tissue preparation and computational analysis, and at the Wyss Center, we have deep expertise with fast and high-resolution lightsheet microscopy. We will look to understand the role of specific genes and proteins in the development of the tumor,” said Stéphane Pagès, PhD, Principal Investigator at the Wyss Center.

By combining state-of-the-art molecular and cellular techniques, with advanced lightsheet imaging, the team will develop an innovative approach to map the TME. They will create 3D maps of RNA sequences associated with specific genes thought to be involved in tumor development. They will also label specific proteins and use lightsheet microscopy to visualize, and understand the interplay between, cell types, blood vessels and hypoxic regions in the TME. Lightsheet microscopy will allow whole GBM tumors to be imaged with a sheet of light without damaging the sample.

Co-Principal Investigator, Nicolas Renier, PhD, Research Group Leader at the Laboratory of Structural Plasticity, Paris Brain Institute said: “We will combine state-of-the-art imaging and computational analysis to reveal the 3D anatomy of brain cancer tumors at a cellular level. Using these novel tools, we will map the distribution of biomarkers and tumor blood vessels to help predict responses to new therapies.”

The 3D maps will be integrated with clinical data from patients to understand how the disease progresses following therapy. When GBM is first diagnosed, the tumor is usually removed before treatment. Following treatment, GBM patients may have to undergo additional tumor resections.

“Our collaboration includes colleagues at the University of Geneva. They are working with patients on a new glioblastoma therapy, and we hope to be able to apply the new microenvironment analysis approach to the tumors from these patients,” added the Wyss Center’s Stéphane Pagès.

The approach will be applied to tumors resected from two separate patient cohorts with recurrent GMB. One cohort consists of patients who are being treated with standard care – radio and chemotherapy -, the other includes patients who have participated in an immunotherapy vaccine clinical trial.

The GBM TME has a local immunosuppressive effect which plays a role in tumor development. A new generation of recently developed immunotherapies can reverse the immunosuppressive effect by boosting the immune response; but they don’t work for everyone.

Co-Principal Investigator, Valérie Dutoit, PhD, Co-Research Group Leader at the University of Geneva said: “We will assess composition of the GBM microenvironment, including presence of immune cells and of a hypoxic milieu and investigate correlation with response to standard treatment. In addition, we will interrogate correlation with an experimental intervention of therapeutic peptide vaccination in patients with recurrent GBM. In this phase I/II clinical trial currently taking place in our institution in Geneva, we are using a GBM-derived vaccine to stimulate the patient’s immune system to fight his/her tumor. Hopefully, the current project will lead to a better understanding of the role of the tumor microenvironment in patients’ response to standard or experimental intervention and help to identify those patients likely to respond.”

“We hope that the unique insights of this ‘tissue time machine’ will mean that we can intervene in brain cancer earlier with a truly personalized approach based on the genetic profiles of individual tumors.” said Wyss Center’s CEO, Mary Tolikas, PhD, MBA.