Miguel N. Rivera, MD
Assistant Molecular Pathologist
Massachusetts General Hospital
Assistant Professor of Pathology
Harvard Medical School
Our research focuses on the identification and characterization of pathways implicated in pediatric solid tumors and sarcomas. An important feature linking many of these malignancies is their strong association with developmental processes and, in particular, with the mechanisms that regulate the differentiation of stem cell populations during organogenesis. Our work combines the use of genomic technologies for direct analysis of tumors with functional analysis of novel pathways that are common to development and cancer.
Miguel N. Rivera
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 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.
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 (2007). An X chromosome gene, WTX, is commonly inactivated in Wilms tumor. Science, 315: 642-5.
Rivera MN, Kim WJ, Wells J, Stone A, Burger A, Coffman E, Zhang J, Haber DA. 'The tumor suppressor WTX shuttles to the nucleus and modulates WT1 activity'. PNAS 2009, 106 (20): 8338-8343.
Rothenberg SM*, Mohapatra G*, Rivera MN*, Winokur D, Greninger P, Nitta M, Sadow PM, Sooriyakumar G, Brannigan BW, Ulman MJ, Perera RM, Wang R, Tam A, Ma XJ, Erlander M, Sgroi DC, Rocco JW, Lingen MW, Cohen EE, Louis DN, Settleman J, Haber DA. A genome-wide screen for microdeletions reveals disruption of polarity complex genes in diverse human cancers. Cancer Res. 2010 Mar 15;70(6):2158-64. PMID: 20215515
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 Jun 4;6(6):591-602. PMID: 20569696