Manjeet K. Rao, Ph.D.Assistant Professor
University of Delhi, India, 1999
Dr. Rao's laboratory is housed in the Greehey Children's Cancer Research Institute.
Manjeet Rao, Ph.D., joined the Greehey Children's Cancer Research Institute in January of 2007 with major faculty responsibilities as a Principal Investigator in Molecular Oncogenesis and Assistant Professor in the Department of Cellular and Structural Biology. Dr. Rao completed his post-doctoral research at The University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA. Dr. Rao pioneered the in vivo RNA-interference (RNAi) approach that can be used to silence virtually any gene in a tissue-specific manner. The simplicity of his RNAi approach will facilitate the generation of mouse models mimicking human conditions caused by various degrees of genetic hypomorphism, such as ectodermal dysplasia, T-cell immunodeficiency, autosomal dominant polycystic kidney diseases, and various types of cancer. Selective expression of siRNAs may be crucial to effective therapy, as undesired toxicity is a major problem of gene therapy.
- Research in my laboratory is directed towards understanding the molecular mechanism of oncogenesis in adult cancers (breast and ovarian cancer) as well as in pediatric tumors (pediatric renal tumor and acute lymphoblastic leukemia). We are particularly interested in studying the role of molecules/factors such as non-coding RNAs "micro RNAs" and epigenetic modulators (polycomb group of proteins) in tumor growth and progression, which are otherwise crucial for normal cell proliferation and differentiation. Recently, we have discovered a novel miRNA that acts as a potent tumor suppressor by inhibiting expression of Six1 homeobox gene, a potent oncogene known to be overexpressed in several aggressive solid tumors including breast cancer, ovarian cancer, hepatocellular carcinoma, rhabdomyosarcoma and Wilms' tumors. We are currently investigating the role of this tumor suppressor miRNA (and other miRNA/s that we have identified) in normal cell growth and the molecular mechanism by which their expression is altered in tumor.
- A second project in the laboratory revolves around the emerging theory of tumorigenesis that involves existence of "cancer stem cells". These aberrant cells, which set up the stage for abnormal growth within tumor tissues, are likely to be multipotent progenitors that are capable of propagating neoplastic phenotypes. Though the existence of cancer initiating cells has been documented in several adult cancers, very little is known about the molecules, factors and mechanisms that are key to the aberration of normal stem/progenitor cell self-renewal process resulting into cancers. We are currently investigating the role of specific miRNA/s and homeobox gene/s in regulating breast cancer stem cell self-renewal. We believe that identification and characterization of novel effectors that are instrumental for the cancer stem cell self-renewal will ultimately be amenable to therapeutic interventions.
Mammosphere from MCF10A mammary epithelial cells grown in serum free MEBM media on low adhesion plates for 14 days (left panel)shows stem cell-like characteristics as revealed by real-time PCR analysis using primers specific for known stem cell markers (right panel)
- Besides well established gate keeper genetic changes in cancer, such as loss of heterozygosity, mutation in tumor suppressor genes and amplification of oncogenes; epigenetic alterations including global DNA hypomethylation, hypermethylation of specific tumor suppressor genes as well as histone modifications have emerged as common characteristics of many cancers. Recent developments suggesting an epigenetic progenitor origin of human cancers further underscores the importance of epigenetic regulation in tumorigenesis. We believe that the identification and validation of novel molecular targets regulating early epigenetic changes in normal cells will be key to the development of effective therapeutic regimens for treating cancer. To accomplish that, we are currently using loss-of- function RNA interference screen to identify molecular effectors that are in synthetic lethal relationship with specific polycomb group of proteins, which are best known as epigenetic regulators and are implicated in the maintenance of normal stem cell pluripotency and pathogenesis of several human cancers.
Chang YF, Lee-Chang JS, Imam JS, Buddavarapu KC, Subaran SS, Sinha-Hikim AP, Gorospe M, Rao MK. (2012) Interaction between microRNAs and actin-associated protein Arpc5 regulates translational suppression during male germ cell differentiation. Proc Natl Acad Sci U S A. 2012 Mar 23.
Chang YF, Lee-Chang JS, Harris KY, Sinha-Hikim AP, Rao MK. (2011) Role of β-catenin in post-meiotic male germ cell differentiation. PLoS One. 6(11):e28039. Epub 2011 Nov 18.
Imam JS, Buddavarapu K, Lee-Chang JS, Ganapathy S, Camosy C, Chen Y, Rao MK. (2010) MicroRNA-185 suppresses tumor growth and progression by targeting the Six1 oncogene in human cancers. Oncogene. 2010 Sep 2;29(35):4971-9.
Bansal H, Bansal S, Rao M, Foley KP, Sang J, Proia DA, Blackman RK, Ying W, Barsoum J, Baer MR, Kelly K, Swords R, Tomlinson GE, Battiwalla M, Giles FJ, Lee KP, Padmanabhan S. (2010) Heat shock protein 90 regulates the expression of Wilms tumor 1 protein in myeloid leukemias. Blood. 2010 Nov 25;116(22):4591-9.
Rao MK, Pham J, Imam JS, MacLean JA, Murali D, Furuta Y, Sinha-Hikim AP, Wilkinson MF. (2006) Tissue-specific RNAi reveals that WT1 expression in nurse cells controls germ cell survival and spermatogenesis. Genes Dev. 2006 Jan 15;20(2):147-52.
Maclean JA 2nd, Chen MA, Wayne CM, Bruce SR, Rao M, Meistrich ML, Macleod C, Wilkinson MF. (2005) Rhox: a new homeobox gene cluster. Cell. 2005 Feb 11;120(3):369-82.