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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: firstname.lastname@example.org
Research in the Rivera laboratory 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.
Read more about the Rivera Lab from the Center for Cancer Research Annual Report and the Pathology Basic Science Research Brochure.
Kshitij Arora, MD Gaylor Boulay, PhD Niyati Desai, MD Beverly Naigles Shruthi RengarajanMiguel N. Rivera, MD Angela Volorio
Role of the WTX gene family in cancer and development
Wilms tumor, the most common pediatric kidney cancer, is a prime example of the connection between cancer and development because it arises from kidney-specific stem cells and is composed of several cell types that resemble the earliest stages of kidney formation. We identified WTX, an X-linked tumor suppressor gene which is inactivated in up to 30% of cases of Wilms tumor, by comparing the DNA of primary tumor samples with that of normal tissues using array comparative genomic hybridization (CGH). More recently, large tumor sequencing studies have shown that WTX is also inactivated in several other tumor types. WTX is the founding member of a new protein family (FAM123) and is expressed in the stem cells of the developing kidney as well as in a variety of other tissues during embryogenesis. In collaboration with the Haber and Bardeesy laboratories, we have demonstrated that inactivation of WTX in mice leads to profound alterations in the development of several organs including kidneys, bones and fat by causing changes in the differentiation programs of mesenchymal stem cells. In particular, we observed an expansion of mesenchymal kidney stem cells, suggesting that WTX regulates the balance between proliferation and differentiation in these cells. We are now using a combination of in vitro and in vivo approaches to elucidate the molecular mechanisms by which WTX and related proteins regulate stem cells. Given that the same mechanisms are likely to be operative in tumors where WTX is inactivated, we expect that our studies may reveal new therapeutic opportunities for a variety of tumor types.
Epigenomic approaches to the identification of novel pathways in cancer
While genetic studies have led to the development of important cancer therapies, most genetic alterations in cancer do not point to specific therapeutic targets. In the case of pediatric cancers, which are usually driven by low numbers of recurrent mutations, the identification of therapeutic targets through genetic studies has been particularly challenging. In order to discover new pathways involved in pediatric cancer, we are using new genomic technologies to identify abnormalities in the mechanisms that regulate gene expression in these tumors.
One of these technologies is genome-wide chromatin profiling, which combines chromatin immunoprecipitation and high-throughput sequencing. This approach has been used to study how genes are activated or repressed by regulatory elements in the genome such as promoters and enhancers. As a complement to gene expression studies, chromatin profiling provides a unique view of gene regulation programs by allowing the identification of both active and repressed genomic domains based on patterns of histone modification. Several studies have shown that prominent active histone marks are associated with genes that play key roles in cell identity and proliferation, including oncogenes that promote the growth of tumor cells. In contrast, repressive marks are found at loci that are maintained in an inactive state to prevent cellular differentiation.
In recent studies we have applied chromatin profiling to Wilms tumor and Ewing sarcoma, two pediatric tumors that are thought to arise from stem cell precursors and that have been linked to abnormalities in transcriptional regulation. Our work has uncovered novel genes and pathways involved in these diseases by comparing chromatin patterns in primary tumor samples and normal stem cells. In addition, we have identified specific gene regulation mechanisms that play critical roles in tumor formation through functional studies of transcription factors and chromatin regulators. We are now characterizing these pathways in detail and extending our epigenomic analysis to other tumor types where oncogenic pathways are poorly defined.
EWS-FLI1 utilizes divergent chromatin remodeling mechanisms to directly activate or repress enhancer elements in Ewing sarcoma. Riggi N, Knoechel B, Gillespie SM, 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. Cancer Cell. 2014 Nov 10;26(5):668-81.
The WTX tumor suppressor regulates mesenchymal progenitor cell fate specification. 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. Dev Cell. 2011 May 17;20(5):583-96. Erratum in: Dev Cell. 2012 May 15;22(5):1109-17.
Wilms tumor chromatin profiles highlight stem cell properties and a renal developmental network. Aiden AP, Rivera MN, Rheinbay E, Ku M, Coffman EJ, Truong TT, Vargas SO, Lander ES, Haber DA, Bernstein BE. Cell Stem Cell. 2010 Jun 4;6(6):591-602.
An X chromosome gene, WTX, is commonly inactivated in Wilms tumor. 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. Science. 2007 Feb 2;315(5812):642-5.
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