Title: Mapping the spatio-temporal heterogeneity of glioblastoma invasion
Funder: The Brain Tumour Charity

Abstract: Glioblastoma is the most common type of brain cancer in adults. Current treatments are surgery, chemotherapy and radiotherapy, but while they extend survival, they are not cures. A major obstacle to a cure is that the cancer spreads into the normal brain, a process called invasion. Invasion makes it impossible to remove the cancer fully with surgery and leads to recurrence within months. Unfortunately, we don’t understand what makes glioblastoma spread so extensively. In other words, we don’t understand what molecules are used by cancer cells to communicate with the surrounding normal brain cells during invasion. This lack of understanding results from three properties of glioblastoma, which make studying invasion very challenging. First, cancer cells spread in regions deep inside the brain, which cannot be easily visualized and studied. Second, the genetic make-up of glioblastoma is very diverse both between patients and in different parts of the same tumour. This means that cancer cells may use a range of different molecules to spread. Third, the brain is incredibly complex, containing many types of cells and molecules that vary from region to region. It is likely therefore that each region of the healthy brain communicates with invading tumour cells differently. Therefore, to develop more effective therapies we must first understand the diversity of invading cancer cells in all the regions of the brain, even those that have remained inaccessible to date. The goal of this programme is to overcome the current challenges of studying invasion and achieve such understanding. We will systematically determine the molecules that drive invasion and how they vary across the brain. Of the molecules we identify, we will then study in greater detail the ones that support invasion along the nerve bundles that connect the two brain hemispheres. This is the most common but least understood route of glioblastoma spread. To do this, we assembled a mutli-disciplinary team that builds on existing collaborations and resources, making this project cost-effective and likely to succeed. We will combine experiments and mathematics and use two new techniques: 1) a method called spatial transcriptomics which determines the full molecular make-up of cells while preserving information about their position in the brain; 2) an advanced imaging method which uses sound and light to see and record cells deep inside the living brain. This work will provide a complete map of how glioblastoma cells spread throughout the brain and lay the groundwork for future studies. It will determine whether treatments should be tailored to where in the brain the cancer has formed. Finally, it will identify new molecules against which drugs can be developed to block cancer spread and recurrence. Findings will be disseminated to other researchers through scientific publications and conferences, and the public via outreach activities such as the Cheltenham Science Festival, which is directed by one of the applicants. We will engage patients and families through close interaction with the BTC and the RIN. Any translational aspect of the work will be progressed through collaborations with clinicians and industry.

Lay abstract: Glioblastoma is the most common type of brain cancer in adults. Current treatments are surgery, chemotherapy and radiotherapy, but while they extend survival, they are not cures. A major obstacle to a cure is that the cancer spreads into the normal brain, a process called invasion. Invasion makes it impossible to remove the cancer fully with surgery and leads to recurrence within months. Unfortunately, we don’t understand what makes glioblastoma spread so extensively. In other words, we don’t understand what molecules are used by cancer cells to communicate with the surrounding normal brain cells during invasion. This lack of understanding results from three properties of glioblastoma, which make studying invasion very challenging. First, cancer cells spread in regions deep inside the brain, which cannot be easily visualized and studied. Second, the genetic make-up of glioblastoma is very diverse both between patients and in different parts of the same tumour. This means that cancer cells may use a range of different molecules to spread. Third, the brain is incredibly complex, containing many types of cells and molecules that vary from region to region. It is likely therefore that each region of the healthy brain communicates with invading tumour cells differently. Therefore, to develop more effective therapies we must first understand the diversity of invading cancer cells in all the regions of the brain, even those that have remained inaccessible to date. The goal of this programme is to overcome the current challenges of studying invasion and achieve such understanding. We will systematically determine the molecules that drive invasion and how they vary across the brain. Of the molecules we identify, we will then study in greater detail the ones that support invasion along the nerve bundles that connect the two brain hemispheres. This is the most common but least understood route of glioblastoma spread. To do this, we assembled a mutli-disciplinary team that builds on existing collaborations and resources, making this project cost-effective and likely to succeed. We will combine experiments and mathematics and use two new techniques: 1) a method called spatial transcriptomics which determines the full molecular make-up of cells while preserving information about their position in the brain; 2) an advanced imaging method which uses sound and light to see and record cells deep inside the living brain. This work will provide a complete map of how glioblastoma cells spread throughout the brain and lay the groundwork for future studies. It will determine whether treatments should be tailored to where in the brain the cancer has formed. Finally, it will identify new molecules against which drugs can be developed to block cancer spread and recurrence. Findings will be disseminated to other researchers through scientific publications and conferences, and the public via outreach activities such as the Cheltenham Science Festival, which is directed by one of the applicants. We will engage patients and families through close interaction with the BTC and the RIN. Any translational aspect of the work will be progressed through collaborations with clinicians and industry.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: CANCER AND NEOPLASMS