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Read the Dyson Lab 2017-2018 Annual Report
Nicholas Dyson, PhDProfessor of Medicine; Mary B. Saltonstall Chair in Oncology Harvard Medical School
Scientific DirectorMass General Cancer CenterGeneticistCenter for Cancer ResearchJames and Shirley Curvey MGH Research Scholar
The Dyson Laboratory studies the role of the retinoblastoma tumor suppressor (RB). RB is expressed in most cell types and its functions enable cells to stop dividing. RB is inactivated in many types of cancer. We have three main goals: we want to understand the molecular details of how RB acts, we want to know how the inactivation of RB changes the cell, and we are using these insights to target tumor cells.
Nicholas Dyson, PhDPrincipal Investigator
My laboratory investigates mechanisms that limit cell proliferation in normal cells and the ways that these controls are eroded in cancer cells. Our research focuses on RB, the protein product of the retinoblastoma susceptibility gene (RB1), and on E2F, a transcription factor regulated by RB. RB/E2F control the expression of a large number of genes that are needed for cell proliferation. This transcription 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 activities but one of its key roles is to limit the transcription of E2F targets. As a result, most tumor cells select for changes that compromise RB function. Our research program spans three areas of RB/E2F biology.
Dissecting the molecular functions of RB
RB’s precise mechanism of action remainsan enigma. RB has been linked to hundreds of proteins and has been implicated in many cellular processes. However, purification of endogenous RB complexes has been a major challenge and, consequently,it isuncertainwhich proteins physically interact with RB in any specific context. We have solved this problem and, in collaboration with the Haas lab, are using Mass Spectrometry to take detailed snapshots of RB in action. We have used these technologies to examine the hypothesis that RB’s activity is tailored by mono-phosphorylation. Our data shows that the variousmono-phosphorylated forms of RB interact with different cellular proteins, regulate different sets of genes and have distinct functional properties.
Proteomic proﬁles give a new perspective on the effects of RB loss
We have also used proteomic and metabolic profiling to better understand the impact of RB loss on a cell. Since RB and E2F are both transcription factors, the effects of RB loss are typically studied by examining changes in the levels of mRNAs synthesized from target genes. Our results show that this RNA-centric approach gives an incomplete picture of the changes that occur following RB loss. Although changes in cell cycle-regulated genes are thought to be hallmarks of RB inactivation, the proteomic changes associated with RB loss are dominated by changes in mitochondrial proteins and the metabolic profiles show changes in glycolysis and in purine and pyrimidine synthesis. These changes may be useful biomarkers in tumor samples, but they may also highlight vulnerabilities ofRB1-mutant tumor cells.
Targeting tumor cells with RB1 mutations.
Our long-term goal is to use information gleaned from these molecular studies to improve cancer treatment. RB is functionally compromised in most types of cancer, but the specific mutation of the RB1 gene is a hallmark of just three tumor types (retinoblastoma, osteosarcoma and small cell lung cancer (SCLC)). This implies that the complete elimination of RB function is especially important in these tumors. In collaboration with Dr. Anna Farago, our clinical collaborator, and with help from members of the Haber/Maheswaran laboratories we have generated an extensive panel of patient derived xenograft (PDX) models of SCLC. These PDX models accurately reflect the genomic features and the drug sensitivities of the tumors from which they were derived. We are now using this panel of models to compare the effectiveness of different therapies, and to understand which SCLC tumors respond best to each type of treatment. Our goal is to use these models to identify new strategies for targeting RB1-mutant tumors.
View a list of publications by researchers at the Dyson Laboratory
Drapkin BJ, George J, Christensen CL, Mino-Kenudson M, Dries R, Sundaresan T, Phat S, Myers DT, Zhong J, Igo P, Hazar-Rethinam MH, LiCausi JA, Gomez-Caraballo M, Kem M, Jani KN, Azimi R, Abedpour N, Menon R, Lakis S, Heist RS, Büttner R, Haas S, Sequist LV, Shaw AT, Wong KK, Hata AN, Toner M, Maheswaran S, Haber DA, Peifer M, Dyson N, Thomas RK, Farago AF. Genomic and functional fidelity of small cell lung cancer patient-derived xenografts. Cancer Discovery. 2018; 8(5):600-615.
Dick FA, Goodrich DW, Sage J, Dyson NJ. Non-canonical functions of the RB protein in cancer. Nature Reviews Cancer. 2018; 18(7):442-451.
Wang H, Nicolay BN, Chick JM, Gao X, Geng Y, Ren H, Gao H, Yang G, Williams JA, Suski JM, Keibler MA, Sicinska E, Gerdemann U, Haining WN, Roberts TM, Polyak K, Gygi SP, Dyson NJ, Sicinski P. The metabolic function of cyclin D3-CDK6 kinase in cancer cell survival. Nature. 546 (7658):426-430. 2017.
Guarner A, Morris R, Korenjak M, Boukhali M, Zappia MP, Van Rechem C, Whetstine JR, Ramaswamy S, Zou L, Frolov MV, Haas W, Dyson NJ. E2F/DP prevents cell cycle progression in endocycling fatbody cells by suppressing dATM expression, Developmental Cell. 2017;43(6):689-703
Dyson NJ. RB1: a prototype tumor suppressor and an enigma. Genes and Development. 30(13):1492-502. 2016.
Nicolay BN, Danielian PS, Kottakis F, Lapek JD, Sanidas I, Miles WO, Dehnad M, Tschop K, Gierut J, Manning AL, Morris R, Haigis K, Bardeesy N, Lees JA, Haas W, and Dyson NJ. Proteomic analysis of pRb loss highlights a signature of decreased mitochondrial oxidative phosphorylation. Genes and Development. 29(17):1875-89. 2015.
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