Gilbertson Group

Cancer origins and aging

Almost one in two adults will be diagnosed with cancer in their lifetime. 

This dismal statistic means that preventative measures are desperately needed to reduce cancer risk and incidence. Our research has recently shown that the lifelong risk of cancer in young mice is significantly lower compared to adult mice, an observation that suggests that during a time of rapid growth, there are biological mechanisms that actively protect against cancer formation, and this is lost in adulthood. If we can understand this protective mechanism, we could reactivate them in adults as a way of reducing cancer risk. 

To get to the heart of the protective mechanism we have built an epigenetic, transcriptomic and proteomic atlas of mouse stem cell ageing. Using natural language processing and other machine learning approaches, we are understanding the process of ageing in a completely holistic and agnostic way. This approach is unlocking the biological mechanisms that are unique to the process of development and therefore the processes that protect against cancer. 

By perturbing this biology in our adult animal models of cancer through our target discovery approach, we aim to reduce cancer risk in adults and therefore identify mechanisms that will be taken into the clinic as an approach to reduce the risk of cancer in adults. 

Metastasis is not just a cancer problem

Ninety-percent of cancer deaths are a result of metastasis. This process, by which cancer cells spread from the primary tumour to other organs in the body, remains shrouded in mystery. 

Metastasis is poorly understood, even though it has been studied extensively over several decades. It is regarded as an abnormal process, mediated by primary cancers, that is resistant to treatment. However, our work has, for the first time, divorced metastasis from upstream tumorigenesis, uncovering a completely new paradigm for metastasis. Specifically, we found that the Sodium Leak Channel Non-Selective Protein (NALCN) regulates epithelial cell trafficking into the blood from both normal and malignant tissues unmasking this cascade as a cancer-independent phenomenon and a novel treatment target (Rahrmann EP et al., Nature Genetics, in press). 

The NALCN channel regulates cell dissemination. Among 10,022 human cancers, NALCN loss-of-function mutations were enriched in gastric, lung, prostate, head & neck, and colorectal cancers. Deletion of Nalcn from gastric, intestinal or pancreatic adenocarcinomas in mice did not alter tumour incidence. Instead, it markedly increased metastasis and the number of circulating tumour cells (CTCs) in the blood of these mice. CTCs passage from the primary tumours to form metastasis somewhere else in the body. Treatment of mice with gadolinium (GdCl3)–an imaging contrast agent and NALCN channel blocker–similarly increased CTCs and metastasis.  

Deletion of Nalcn from mice that lacked oncogenic mutations and never developed cancer, caused shedding of epithelial cells into the blood at levels equivalent to those seen in tumour-bearing animals. These cells travel to distant organs to form typical structures, including lung epithelium, kidney glomeruli, and tubules. Thus, NALCN regulates cell shedding from solid tissues independent of cancer status, suggesting a degree of separation between the initial stages of metastasis and tumourigenesis. In our view, the findings of this study will improve the current model of metastasis and have unmasked a potential novel target for anti-metastatic therapies. 

Dissecting the Cellular and Molecular Origins of WNT-Medulloblastomas

Medulloblastoma is the most common malignant childhood brain tumour.  Accounting for about 20% of all childhood brain tumours, medulloblastoma occurs most often in children younger than 16 years. Classified as a malignant embryonal hindbrain tumour, the disease displays various histological forms including classic, nodular anaplastic and large-cell tumours1. Histology can differentiate medulloblastoma from other hindbrain tumours, but it is of limited value in predicting outcome or understanding tumour biology. 

The combined efforts of our group and international collaborators have identified four subtypes of medulloblastoma that display distinct patterns of gene expression, DNA copy number alteration, and clinical behaviour (WNT, Sonic Hedgehog [SHH], Group-3 and Group-4)2.  Despite these differences, all medulloblastomas are treated with the same combination of surgery, radiation, and chemotherapy.  This ‘blanket’ treatment fails to cure the majority of children with the most aggressive medulloblastomas (Group-3), and inflicts debilitating, long-term side effects on children with the most curable form (WNT subtype). 

Therefore, future efforts to cure all children with medulloblastoma must provide an understanding of disease biology that can guide the development of curative, relatively non-toxic, subtype-specific therapies.  To this end, our group is focusing on understanding the origins and biology of the most curable form of medulloblastoma: WNT medulloblastoma.  By studying this subtype we hope to unmask the basis of this tumours susceptibility to therapy since this knowledge may be applied to render the more resistant variants more curable.

Understanding how ZFTA-RELA drives ependymoma

Ependymoma, a type of brain and spinal cord tumour, is the third most common brain tumour in children. With 40% of the cases currently being incurable, this disease is a tricky one to research. While they are histologically similar, ependymomas from the different sites of the central nervous system differ in lineage, transcriptome, genetic alterations, and clinical outcome. To understand Ependymomas better, we completed a series of comprehensive genomic assays of human ependymomas, including whole-genome sequencing (WGS) experiments, and identified the ZFTA-RELA translocation as the most recurrent genetic alteration in any brain tumour. ZFTA-RELA is a highly potent oncogene, transforming mouse neural stem cells into brain tumours. 

Choroid Plexus Carcinomas

Background 

Choroid plexus carcinomas (CPCs) are rare, aggressive malignant tumours of the central nervous system occurring mainly in children under the age of one. While advances in clinical and molecular stratification have enabled risk-adapted treatment planning and improvements in outcome for many types of childhood brain tumours, there has not been equivalent progress for children with CPC. In order to elucidate a coordinated therapeutic strategy for children with CPC, it is imperative to develop in vitro and in vivo models to improve our understanding of the mechanisms underlying tumourigenesis.  

 Current research 

 Our efforts aim to improve understanding of CPC formation and the transformation of the choroid as well as new and improved treatments for patients affected by choroid plexus carcinoma. Not only are we looking for a “standard of care” that is currently nonexistent for CPC, but we are also looking for one that will have minimal side effects and, therefore, not jeopardise the future of affected children.