cell biology • bioinformatics • genetics • cancer drivers • therapeutic outcomes • DNA mutations • tissue specificity
Professor Stephen Elledge and his international team of researchers are stepping up to the plate, and are looking to answer this question once and for all. By carefully mapping cancer drivers in our cells – molecules that are known to cause cancer – they hope to shed light on which drivers cause cancer in different tissues throughout the body.
In a collaboration that involves researchers from multiple disciplines – including geneticists, cell biologists and bioinformaticians – this Grand Challenge project aims to generate a comprehensive map of cancer drivers and their specificity to different tissues. This has the potential to improve our basic understanding of cancer, and provide information that will impact therapeutic choices for patients.
Our international team is made up of researchers from:
The University of Manchester, UK
Utrecht University, Utrecht, Netherlands
New York University School of Medicine, USA
Baylor College of Medicine, Houston, USA
Institute of Cancer Sciences, University of Glasgow, UK
Brigham and Women's Hospital, Boston, USA
University of Copenhagen, Copenhagen, Denmark
Harvard University, Harvard Medical School, Boston, USA
Beth Israel Deaconess Medical Center, Boston, USA
We are going to look at our cells’ DNA to identify which genes control whether cells divide or not. By looking at the DNA in different locations in the body, this screen will allow the team to look at whether certain genes are only active in specific tissues. This will provide vital information on known cancer drivers, as well as allowing the team to identify new potential drivers of cancer. Alongside this, the researchers will be assessing how well different cancer drugs work in different types of cancer, and if this can be linked to the activity of cancer drivers.
If successful, this map of ‘tissue specificity’ will give us a complete overview of which cancer drivers play a role in the different tissues throughout the body. This understanding could transform the way doctors treat cancer, as they will be able to select which drugs are more likely to work based on exactly how and where the cancer originated.
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The last 30 years of research have identified more than 500 genes that are mutated (i.e. defective) in human cancer. A central mystery has been why the vast majority of these genes cause cancer in one group of tissues/organs, but not in others. If scientists are able to understand why different genes cause specific types of cancer, then we will be able to use this insight to develop new, more effective treatments. The goal of the SPECIFICANCER team is to unravel this mystery and begin to use this information to design new therapeutic strategies.
Recent research from our laboratories suggests that different tissues/organs respond quite differently to the “stop” and “go” signals that cause cancer. For example, a go signal in one tissue (e.g. a mutated gene) will cause cells to divide uncontrollably, while the same signal will have no effect on another tissue. We think that tissues respond so differently to these signals because they are “programmed” differently. For example, a nerve cell is programmed to transmit pain, while a hair follicle cell is programmed to produce hair. In both cases, these cells possess all of the same DNA, but the DNA in each cell type is organized into a specific network, that dictates a very specific response. Understanding how the DNA from different tissues is programmed will be essential for understanding how specific genes cause cancer in different organs and, ultimately, how we might prevent or treat cancers.
To accomplish this task, the SPECIFCANCER team is taking a multidisciplinary approach. First, we will take normal cells from the 8 tissue types that give rise to most human cancers (liver, pancreas, breast, lung, skin, brain, kidney, colon) and perform massive genetic and biochemical analyses to determine how their DNA networks are programmed. Next, we will introduce hundreds of cancer-causing genes into each of these cell types and determine how they respond to each gene - Do they divide uncontrollably or not? We will then determine how each cancer-causing gene affects the DNA network and transmits a specific signal (or not) in that tissue.
We will also perform a similar type of analysis in mice so that we can understand how these genes function in a living organism. Specifically, we will select the most common cancer-causing genes and will use genetic engineering techniques to turn them on in tissues in mice. We will then examine different tissues before and after these genes are activated. Our idea is that by comparing the changes in tissues that are responsive – those that begin to divide and/or develop into a tumor - versus tissues that are not responsive, we will discover key pathways that either allow or prevent cancer formation. These pathways can then become targets for cancer therapies. We believe that cracking this “tissue code” will be essential for understanding, treating, and ultimately preventing cancer.
Another related problem facing cancer researchers and physicians is that even if cancers arising from different organs contain the same initial mutated gene, they may respond very differently to the same therapy. We believe that the same inborn differences that establish how the tissue is programmed, also dictates how cancer in that tissue responds to a given therapy. Therefore, we will also use these systems to perform extensive genetic studies, so that we may identify a unique “Achilles heel” for each type of cancer, in a specific tissue, that carries the specific cancer-causing genes.
Finally, we will add one more layer of complexity to these studies. It is becoming clear that the future of cancer research lies in “precision medicine”, where physicians match the right drug to the right patient based on the specific defective genes in that patient’s cancer. However, every tumor carries at least 4 different cancer-causing genes. Unfortunately, these genes can cooperate to alter a cell's program in unpredictable ways. This may impair responses to specific treatments, but it may also create unforeseen vulnerabilities. Therefore, we will create an entire library of cells derived from the 8 tissues listed above, that each contains a different combination of cancer-causing genes that we see in human tumors. We will then test the effects of 100s of cancer drugs in each of these cells. Using this approach, we can determine which specific gene combinations – and in which tissue type – respond best to which drugs. This insight will help guide the development of new clinical trials designed to bring the right drug to the right patient, thus increasing the chance of success.
Altogether, these studies aim to pull together the expertise of scientists in different disciplines (i.e. geneticists, bioinformaticians, mouse modelers, biochemists, translational scientists) with expertise in many types of cancer (e.g. colon, skin, breast, lung, brain etc.) to unlock the secret of how and why different genes cause cancers in different tissues. These efforts will improve our understanding of cancer development and will also impact the development of new therapies.