Dr Nicolo Riggi | Dr Ivan Stamenkovic – Shining Light on Paediatric Cancers
Paediatric tumours often follow different developmental pathways than adult cancers, and may require different approaches to treatment for the best outcomes. Drs Ivan Stamenkovic and Nicolo Riggi work to unravel the mysteries of paediatric cancer by illuminating the epigenetic pathways that cause them.
While a cancer diagnosis can be devastating at any age, a diagnosis of paediatric cancer is particularly shocking, both for the afflicted child and their family. Paediatric tumours often develop and behave differently than their adult counterparts, and recent studies have demonstrated that this is due to major differences in mechanisms of gene regulation between the two. Drs Ivan Stamenkovic and Nicolo Riggi and their research teams at the University of Lausanne in Switzerland, work to understand the genetic and epigenetic factors that cause paediatric tumours and make them unique from adult cancers. Their findings are shaping clinical practices and treatment strategies, to help make childhood tumours a thing of the past.
It All Starts with Stem Cells
Your body is composed of many different types of specialised cells, such as the spindly muscle cells in your heart, the flattened cells that make up your skin, and the unique neuron cells that compose the network building your brain. Each of these types of cells are defined as terminally differentiated cells; and although they may divide to form identical daughter cells, they are unable to generate a different cell type. A skin cell can make more skin cells, but a skin cell can’t make a neuron. Most of the cells in an adult’s body are differentiated cells, but our organism didn’t start that way. Every cell in your body originated from a single fertilised egg, the original undifferentiated cell from which all of your other cells eventually formed. Undifferentiated cells, commonly known as stem cells, are cells that have the potential to form multiple types of differentiated cells. Healthy adults and older children have limited reserves of stem cells that only occur in specific parts of the body, except in one situation: cancer.
Cancer cells do not behave like normal, healthy cells. They divide and grow out of check, can spread to other parts of the body, and in some cases, may display stem cell like abilities allowing them to retain some of the key biological features of normal stem cells. Cells with this ability, deemed cancer stem cells, are able to renew themselves and form many types of cells within a growing tumour, but it has only been in recent years that scientists have begun to understand how these cells are able to do this. Several research groups around the world have shown that a single cancer is not a homogenous mass of cells, but, on the contrary, is composed by several different cell types, displaying a wide spectrum of differentiation and proliferation abilities. Therefore, one of the major areas of focus while trying to unravel the mysteries of cancer has been looking at the genes involved in cancer stem cell formation.
‘We utilise a translational approach involving several national and international collaborations, facilitating the access to cutting-edge technologies and the rapid bench-to-bedside translation of the most relevant and clinical impactful findings’
Genes act as the fundamental instructions for forming the protein blocks required to build every cell in your body. The combination of all the genes active in a given cell type at a precise time point, will finally determine the identity of the cell itself. While the cells in your body have differentiated into many different specialised cells, they all have one thing in common: every cell contains the exact same set of genes. What distinguishes them is the specific set of genes that are turned on, or expressed. For example, though a neuron cell has all of the same genes as a skin cell, it only expresses the genes needed to keep a neuron functioning. Dr Riggi’s cancer biology career began under the mentoring of Dr Stamenkovic, with an interest in understanding what was going on with the genes in cancer stem cells that allowed them to switch on stem cell like capabilities.
When comparing embryonic stem cells to cancer stem cells in paediatric and adult tumours, Dr Riggi and his colleagues discovered a few interesting similarities, and important differences. Abnormal behaviour of adult cancer cells can often be attributed to the build-up of genetic mutations in genes that normally tell a cell that it cannot keep dividing. This means adult cancers most often occur when a gene that was supposed to be on is damaged such that it is permanently turned off. However, Drs Stamenkovic and Riggi found a different situation in paediatric cancer cells. Unlike adult cancer cells, paediatric cancer cells have very few genetic mutations, but numerous genes turned on that are normally only expressed in normal stem cells. The gene profiles of paediatric tumours more closely resemble those of embryonic stem cells, in some cases requiring only a single mutation of a key gene to start the cancer development. To Drs Stamenkovic and Riggi this indicated that paediatric tumours have a different cause and distinctive behaviour compared to adult tumours, spurring further research into the unique biology of paediatric cancer.
MicroRNAs and Major Possibility
Since every cell shares the same set of genes, the team turned their focus to the factors that control which genes are turned on and off – a diverse set of mechanisms commonly lumped under the term epigenetics.
Epigenetics literally means ‘above genetics’ and refers to a suite of controls that our cells use to regulate gene activity. These controls determine how cells differentiate from stem cells, and how differentiated cells behave under different conditions. While epigenetic mechanisms are massively important to understanding many aspects of biology, most of them have only been discovered in the past 20 years, and as such epigenetics is a relatively new branch of science.
In the team’s initial paediatric Cancer Cell work, they discovered that deregulation of an epigenetic mechanism governed by microRNAs (miRNAs), may underlie the emergence of cancer stem cells in some paediatric tumours. miRNAs are tiny strands of nucleotides that bind to certain pieces of our gene sequence to regulate normal gene activity. Drs Stamenkovic and Riggi found that the activity of a specific group of microRNAs was reduced in both embryonic stem cells and paediatric cancer stem cells. Further, the expression level of a gene known as TARBP2 predicted the levels of microRNA that would be found in the tumour. Whereas tumour cells with higher levels of TARBP2 mostly displayed terminal differentiation, the depletion of TARBP2 was associated with an increase in cancer stem cell properties.
Drs Stamenkovic and Riggi took this discovery a step further and treated cancer stem cells with a compound that stimulates the activity of TARBP2. To their excitement, the addition of this compound disrupted stem cell-like growth. The cancer cells were no longer able to continue cloning themselves or forming new growths of differentiated cells. The compound restored normal microRNA levels and tumour growth was effectively halted. This discovery provides the possibility of a promising treatment for this class of aggressive paediatric cancers – one that could prevent the cancer from growing and surviving traditional cancer treatments.
Stopping Paediatric Cancer Before It Starts
While microRNAs led Drs Stamenkovic, Dr Riggi and their colleagues to a promising treatment option, they were still interested in understanding how the cancer came to be in the first place. The paediatric cancers that the research team focuses on – a class of bone cancers known as Ewing sarcomas – tend to be very aggressive and fast growing, so pinpointing the processes at the initiation of the tumour could provide a basis for future early detection and prevention that could save lives. Unlike the vast majority of adult cancers, which are typically associated with genetic mutations in numerous genes, Ewing sarcoma is invariably tied to a single abnormal gene product. Despite the discovery of this genetic alteration more than 20 years ago, the mystery of how this abnormality tied into the onset of Ewing sarcoma remained unsolved.
The gene product in question is known as EWS-FLI1. The presence of the abnormal EWS-FLI1 protein characterises paediatric Ewing sarcoma. It had been previously shown that Ewing sarcoma cancer cells cannot survive without the protein, and the protein has the ability to transform normal cells into cancerous cells. This alteration occurs when the normal EWS gene, whose function is poorly understood, fuses with a gene coding for a transcription factor known as FLI1, during a rare abnormal genetic event known as a chromosomal translocation. Transcription factors are proteins that bind to specific sequences in our genome, and dictate the increase or decrease in expression of specific target genes.
The team made the fascinating discovery that the abnormal EWSFLI1 protein is so effective at creating tumours because it utilises two distinct modes of driving cancer cell formation. The strategy it takes depends on the ability of EWS-FLI1 to bind different but specific genomic sequences: at some genomic locations EWS-FLI1 works by displacing healthy transcription factors and turning off target genes needed to prevent a tumour, while at others it hijacks normal epigenetic processes to turn on and enhance genes that lead to cell proliferation and cancer development. While the team focused on the intricacies of Ewing sarcoma to make these discoveries, this new understanding of how the malfunction of a solitary gene product creates multiple routes to cancer has the potential to serve as a template for understanding the development of other types of paediatric tumours where a single genetic event may play the key roles.
Illuminating the Role of Epigenetics in Cancer Biology
While Drs Stamenkovic and Riggi’s research has shed light on how tumours begin and a potential way to help end them, they are also interested in understanding what goes on within the tumour while it is growing. An important factor in the treatment strategy for a given tumour is the degree of tumour heterogeneity. Tumour heterogeneity refers to the presence of multiple different cell subpopulations, both within and between tumours in the same patient. Highly heterogeneous tumours can be more challenging to treat because different cell subpopulations often require different medications to destroy the cancer completely. Understanding the mechanisms that drive tumours to become more heterogeneous could help lead to novel treatments that require less medications and less strain on the patient.
Epigenetic processes, particularly those that allow cancer cells to behave like stem cells, likely play a large role in the development of distinct cell subpopulations within a single tumour. By studying the mechanisms that allow a differentiated cell to be reverted back into a stem cell, or to be directly converted into a different cell type, Dr Stamenkovic, Dr Riggi and their colleagues have identified multiple potential pathways by which cancer cells may be formed and may create heterogeneity in a tumour. Their work has determined numerous transcription factors and epigenetic mechanisms that may play a role in the development of stem cell properties in cancer cells, and begun to identify potential targets for future research that could inform treatment strategies for some of the most difficult to treat paediatric cancers.
Drs Stamenkovic and Riggi’s work has revealed some of the intricate mechanisms through which cancer hijacks our genes to create destructive cancer stem cells. Their current research seeks to continue shining light on the inner workings of cancer by delving deeper into the genetics and epigenetics that underlie tumour formation, particularly in paediatric cases. Drs Stamenkovic and Riggi’s primary goal is to use cutting-edge science to develop innovative and effective treatment and prevention measures for cancer.‘
MEET THE RESEARCHERS
Dr Ivan Stamenkovic
Institute of Pathology Centre Hospitalier Universitaire Vaudois Faculty of Biology and Medicine
University of Lausanne
Dr Nicolo Riggi
Institute of Pathology Centre Hospitalier Universitaire Vaudois Faculty of Biology and Medicine
University of Lausanne
Dr Nicolo Riggi completed his MD at the University of Lausanne in 2001, and went on to obtain a PhD in Cancer Biology in 2009. He completed his residency in Pathology at University Hospital Lausanne, Switzerland and worked as a post-doctoral research fellow in Cancer and Epigenetics at Massachusetts General Hospital and the Broad Institute of Harvard and MIT in Boston, Massachusetts. Dr Riggi is currently an Assistant Bursary Professor of Experimental Pathology at the University of Lausanne, where his laboratory’s research focuses on the epigenetic mechanisms involved in malignant cancer development and tumour composition in paediatric patients.
T: (+41) 21 314 71 10
Dr Stamenkovic obtained his MD from the University of Geneva in 1978. Following a residency in Internal Medicine and a residency in Pathology, he moved to Boston for a post-doctoral fellowship in the laboratory of Dr Brian Seed in the Department of Molecular Biology at the Massachusetts General Hospital and the Department of Genetics at Harvard Medical School. In 1988, he was appointed Assistant Professor of Pathology at Harvard Medical School and in 1990 he started his own laboratory in the Department of Pathology at the Massachusetts General Hospital, with a joint appointment at the MGH Cancer Centre. In 1992, Dr Stamenkovic was appointed to Associate Professor of Pathology at HMS and Director of the Molecular Pathology Unit within the MGH Cancer Centre. In 2001, he accepted a position as Professor of Experimental Pathology at the University of Lausanne.
T: (+41) 21 314 71 36
Maja Beck-Popovic, Raffaele Renella and Annick Mühlethaler, University Hospital of Lausanne
Mario Luca Suvà, Massachusetts General Hospital, Harvard Medical School
Miguel Rivera, Massachusetts General Hospital, Harvard Medical School
Bradley Bernstein, Massachusetts General Hospital, Harvard Medical School
Daniel Haber, Cancer Centre, Harvard Medical School Qin Yu, Mount Sinai School of Medicine
Swiss National Fund for Scientific Research Swiss Cancer League
ISREC Foundation MEDIC Foundation