Nicholas Dyson, PhD
Professor of Medicine
Harvard Medical School
James and Shirley Curvey MGH Research Scholar
Mass General Cancer Center
Center for Cancer Research
The Dyson Laboratory studies the role of the retinoblastoma tumor suppressor gene (RB). RB is found in most cell types and it enables cells to stop dividing. RB is inactivated in many types of cancer; a change that is thought to be an important step in tumor progression. We have three main goals. First, we want to understand the molecular details of how RB acts. Second, we want to understand how the inactivation of RB changes the cell. Third, we want to be able to use these insights to target tumor cells. There are three general opportunities. If we can identify the specific defects that promote tumor development it may be possible to suppress these changes. Alternatively, the properties of RB-deficient cells may represent points of weakness that are specific to tumor cells and that can be enhanced. Another possibility stems from the knowledge that RB is actually expressed in many tumor cells but it has insufficient activity to stop cell division. For these tumors, the challenge is to find ways to enhance the activity of RB.
Nicholas Dyson, PhD
Principal InvestigatorGroup Members
We investigate the mechanisms that limit cell proliferation in normal cells and the ways that these controls are eroded in cancer cells. Our research focuses on the retinoblastoma tumor suppressor (RB) and its target, the E2F transcription factor. E2F controls the expression of a large number of target genes that are needed for cell proliferation. This transcriptional program is activated when normal cells are instructed to divide, but it is deregulated in tumor cells, providing a cellular environment that is permissive for uncontrolled proliferation. RB has multiple functions, but one of its most important roles is to limit the activity of E2F. As a result, most tumor cells select for changes that compromise RB function. Publications in the past year include progress in three different aspects of E2F/RB biology.
The original discovery of the RB1 gene was made possible by the fact that its mutation is a causal and rate-limiting event in the development of retinoblastoma. An exciting development in this area of research has been the discovery that the loss of pRB undermines genomic stability. A careful analysis of pRB-deficient cells revealed that pRB loss leads to centromere dysfunction, reduced cohesion, and whole chromosome instability (CIN). CIN is a common feature in tumor cells. High levels of CIN correlate with poor prognosis and promote tumor relapse after seemingly effective anticancer treatments. The finding that pRB loss causes CIN raised the possibility that the functional inactivation of pRB may be an underlying source of much of the aneuploidy seen in tumor cells. We discovered that pRB-loss reduces the level of both condensin II complexes and cohesin complexes on chromosomes. Our recent results (Manning et al 2014) show that reducing the levels of Wapl, a negative regulator cohesin loading, remarkably corrects the centromeric defects of RB-depleted cells and strongly suppresses CIN. Wapl-depletion also suppressed CIN in a panel of tumor cells in which pRB was functionally compromised. Reducing CIN may limit the ability of tumor cells to evolve, and these observations will make it possible to test whether reducing CIN can improve the effectiveness of targeted therapies in RB-mutant tumors.
In many tumors the regulation of RB is altered by mutations, such as loss-of-function mutations in p16INK4A (CDKN2A), that elevate the activity of CDK4 or CDK6). CDK/6 inhibitors are currently in clinical trials but these often have only modest or transient effects. We searched for targeted therapies that might enhance the effects of CDK4/6 inhibitors and found a strong synergy between CDK4/6 inhibitors and the IGF1R/IR inhibitor BMS-754807. This combination blocked proliferation of p16INK4-deficient pancreatic ductal adenocarcinoma (PDAC) cells that are inherently resistant to CDK4/6 inhibitors (Heilmann et al 2014). Sensitivity to this drug combination was seen in vitro and in vivo and correlated with reduced activity of the master growth regulator mechanistic target of rapamycin complex 1 (mTORC1). Accordingly, replacing the IGF1R/IR inhibitor with the rapalog inhibitor temsirolimus broadened the sensitivity of PDAC cells to CDK4/6 inhibition. These results establish targeted therapy combinations with robust cytostatic activity in p16INK4-deficient PDAC cells and have potential implications for improving treatment of a broader spectrum of human cancers characterized by p16INK4 loss.
Working with the premise that the key targets of RB/E2F regulation are likely to have been maintained during evolution, we searched genome–wide datasets for groups of evolutionary conserved, functionally-related genes that are directly bound by pRB/E2F proteins. In this way, we discovered that the expression of NANOS, a key facilitator of the Pumilio post-transcriptional repressor complex, is directly repressed by pRB/E2F in flies and humans (Miles et al 2014). In both species, NANOS expression increases following inactivation of pRB/RBF1 and becomes important for tissue homeostasis. Interestingly, analysis of datasets from normal retinal tissue and pRB-null retinoblastomas revealed that there is a strong enrichment for putative PUM substrates among genes de-regulated in tumors. Functional assays indicate that NANOS increases in importance in pRB-deficient cells and helps to maintain homeostasis by repressing the translation of PRE-containing transcripts. We hypothesize that increased translational control helps to limit the consequences of deregulated E2F-dependent transcription in tumor cells.
Postdoctoral Research Fellow at the MGH Cancer Center
A post-doctoral position is available immediately in the laboratory of Nick Dyson at the Massachusetts General Hospital Cancer Center in Boston, Massachusetts. The laboratory is affiliated with Harvard Medical School and is a member of the Dana-Farber/Harvard Cancer Center.
The Dyson laboratory investigates the function of pRB, the protein product of the retinoblastoma tumor susceptibility gene. The RB gene is mutated in wide variety of human cancers. The objective of our research is to understand the molecular and cellular functions of pRB, with the long-term goal to find strategies to target RB mutant tumors. A list of publications can be found via the Cancer Center website at http://www.massgeneral.org/cancerresearch/ourinvestigators/
We are seeking a highly motivated and creative post-doctoral scientist with a successful track record in academic research. Previous experience in studies of protein function and cancer biology is preferred. This project will focus on the analysis of recently discovered proteomic and metabolic signatures of pRB inactivation. These profiles reveal that there are extensive changes in RB-mutant cells and the challenge is to understand why the changes occur, and how they can be exploited.
Applications can be submitted by e-mail to Nick Dyson c/o DysonPostdocSearch@mgh.harvard.edu and should include a one-page cover letter, CV, and contact information of three referees.
Dr. Dyson, a senior scientist at the Center for Cancer Research, has made breakthroughs in our understanding of the way cells divide, whether it is the regulated division of a normal cell or the abnormal proliferation of a malignant cancer.
Nick Dyson, PhD, has been appointed scientific director of the Mass General Cancer Center.
The second group of MGH Research Scholars – recipients of unrestricted five-year grants to support innovative investigations – was announced at the hospital’s Research Advisory Council (RAC) annual meeting on May 11.