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Research at Mass General
Miguel N. Rivera, MD
Assistant Professor of Pathology, Harvard Medical SchoolAssistant in Pathology, Massachusetts General HospitalAssociate Member, Broad Institute
Molecular Pathology UnitMassachusetts General Hospital149 13th Street, 6th FloorCharlestown, MA 02129Phone: 617-726-6257Email: email@example.com
Our research focuses on using genomic tools to identify and characterize critical pathways in pediatric tumors. An important feature shared by these tumors is their strong association with developmental processes and, in particular, with the gene regulation mechanisms that control stem cell populations during organ formation. Our work combines the use of genomic technologies for the direct identification of gene regulation abnormalities in tumors with functional analysis of critical pathways in several model systems. Given that the mechanisms that drive pediatric tumors are poorly understood at present, we anticipate that our work will point to new therapies for these diseases.
Role of the WTX gene family in cancer and development
Wilms tumor, the most common pediatric kidney cancer, arises from kidney-specific stem cells and is a prime example of the connection between cancer and development. Through mapping genomic deletions in Wilms tumor we identified WTX, an X-linked tumor suppressor gene commonly inactivated in this disease and recently implicated in other tumor types. WTX is the founding member of a new protein family (FAM123) and our work using a conditional knockout mouse model has shown that it regulates mesenchymal stem cells in several organs, including kidneys, bones and fat. We are now studying the function of WTX and related proteins using several in vitro and in vivo model systems.
Epigenomic approaches to the identification of novel pathways in cancer
Given that alterations in transcriptional programs play critical roles in transformation, we are using genomic technologies to identify abnormal patterns of gene regulation in pediatric cancer. In particular, genome-wide chromatin profiling, which combines chromatin immunoprecipitation and high-throughput sequencing, is a powerful technology that can identify activation and repression states based on patterns of histone modification. Our initial work using this technology has shown that Wilms tumors exhibit chromatin features typical of stem cells and that patterns of chromatin remodeling can reveal the function of aberrant transcriptional regulators such as the EWS-FLI1 fusion protein in Ewing sarcoma. We are now extending our epigenomic analysis to other tumor types and other key transcriptional pathways in pediatric cancer.
Read more about the Rivera Lab from the Center for Cancer Research Annual Report and the Pathology Basic Science Research Brochure.
Nicolo Riggi, MD, PhD Visiting ScientistGaylor Boulay, PhD InstructorAngela Volorio, MD PhD studentBeverly Naigles, Research Technician IShruthi Rengarajan, Research Technician I
Wilms tumor, the most common pediatric kidney cancer, is a prime example of the connection between cancer and development since it arises from kidney specific stem cells and histologically resembles the earliest stages of kidney development. Using high resolution array CGH (comparative genomic hybridization) we recently identified WTX, a new X-linked tumor suppressor gene which is inactivated in 30 percent of cases of Wilms tumor. WTX is the founding member of a new protein family (FAM123) and is expressed in the stem cell compartment of the developing kidney as well as in a variety of other tissues during embryogenesis. We are now studying the functional properties of WTX and related proteins using several in vitro and in vivo model systems.Epigenomic approaches to the identification of novel pathways in cancer
Genome-wide chromatin profiling, which combines chromatin immunoprecipitation and high-throughput sequencing, is a recently developed technology that has been used to study the ‘epigenetic code’ of embryonic stem cells. As opposed to expression arrays, chromatin profiling allows the identification of both activation and repression marks in the genome and thus provides a unique view of cellular differentiation programs. We have applied this technology to Wilms tumor and have uncovered a new set of genes with potentially critical functions in the maintenance of undifferentiated tumor cells. We are now testing the role of these proteins in the control of differentiation pathways and extending our epigenetic analysis to other tumors types.
Riggi N*, Knoechel B*, Gillespie S*, Rheinbay E, Boulay G, Suvà ML, Rossetti NE, Boonseng WE, Oksuz O, Cook EB, Formey A, Patel A, Gymrek M, Thapar V, Deshpande V, Ting DT, Hornicek FJ, Nielsen GP, Stamenkovic I, Aryee MJ, Bernstein BE, Rivera MN. EWS-FLI1 Utilizes Divergent Chromatin Remodeling Mechanisms to Directly Activate or Repress Enhancer Elements in Ewing Sarcoma. Cancer Cell. 2014; 26(5):668-81.
Moisan A*, Rivera MN*, Lotinun S, Akhavanfard S, Coffman EJ, Cook EB, Stoykova S, Mukherjee S, Schoonmaker JA, Burger A, Kim WJ, Kronenberg HM, Baron R, Haber DA, Bardeesy N. The WTX tumor suppressor regulates mesenchymal progenitor cell fate specification. Developmental Cell. 2011; 20(5):583-96.
Aiden AP*, Rivera MN*, Rheinbay E, Ku M, Coffman EJ, Truong TT, Vargas SO, Lander ES, Haber DA, Bernstein BE. Wilms tumor chromatin profiles highlight stem cell properties and a renal developmental network. Cell Stem Cell. 2010; 6(6):591-602.
Rivera MN*, Kim WJ*, Wells J, Stone A, Burger A, Coffman EJ, Zhang J, Haber DA. The tumor suppressor WTX shuttles to the nucleus and modulates WT1 activity. Proc Natl Acad Sci U S A. 2009; 106(20):8338-43.
Rivera MN, Kim WJ, Wells J, Driscoll DR, Brannigan BW, Han M, Kim JC, Feinberg AP, Gerald WL, Vargas SO, Chin L, Iafrate AJ, Bell DW, Haber DA. An X chromosome gene, WTX, is commonly inactivated in Wilms tumor. Science. 2007; 315(5812):642-5.
Massachusetts General Hospital
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