Bio

Professional Education


  • Master of Science, Manipal University (2007)
  • Doctor of Philosophy, University of Delaware (2014)
  • Bachelor of Science, Manipal University (2006)

Stanford Advisors


Publications

All Publications


  • Overexpression of HOXA4 and HOXA9 genes promotes self-renewal and contributes to colon cancer stem cell overpopulation. Journal of cellular physiology Bhatlekar, S., Viswanathan, V., Fields, J. Z., Boman, B. M. 2017

    Abstract

    Because HOX genes encode master regulatory transcription factors that regulate stem cells (SCs) during development and aberrant expression of HOX genes occurs in various cancers, our goal was to determine if dysregulation of HOX genes is involved in the SC origin of colorectal cancer (CRC). We previously reported that HOXA4 and HOXD10 are expressed in the colonic SC niche and are overexpressed in CRC. HOX gene expression was studied in SCs from human colon tissue and CRC cells (CSCs) using qPCR and immunostaining. siRNA-mediated knockdown of HOX expression was used to evaluate the role of HOX genes in modulating CSC phenotype at the level of proliferation, SC marker expression, and sphere formation. All-trans-retinoic-acid (ATRA), a differentiation-inducing agent was evaluated for its effects on HOX expression and CSC growth. We found that HOXA4 and HOXA9 are up-regulated in CRC SCs. siRNA knockdown of HOXA4 and HOXA9 reduced: (i) proliferation and sphere-formation and (ii) gene expression of known SC markers (ALDH1, CD166, LGR5). These results indicate that proliferation and self-renewal ability of CRC SCs are reduced in HOXA4 and HOXA9 knockdown cells. ATRA decreased HOXA4, HOXA9 and HOXD10 expression in parallel with reduction in ALDH1 expression, self-renewal, and proliferation. Overall, our findings indicate that overexpression of HOXA4 and HOXA9 contributes to self-renewal and overpopulation of SCs in CRC. Strategies designed to modulate HOX expression may provide ways to target malignant SCs and to develop more effective therapies for CRC. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/jcp.25981

    View details for PubMedID 28464221

  • An miRNA expression signature for the human colonic stem cell niche distinguishes malignant from normal epithelia. Cancer research Viswanathan, V., Damle, S., Zhang, T., Opdenaker, L. M., Modarai, S., Accerbi, M., Schmidt, S., Green, P. J., Galileo, D., Palazzo, J. P., Fields, J., Haghighat, S., Rigoutsos, I., Gonye, G. E., Boman, B. M. 2017

    Abstract

    Malignant transformation of tissue stem cells may be the root of most cancer. Accordingly, we identified miRNA expression patterns in the normal human colonic stem cell (SC) niche to understand how cancer stem cells (CSCs) may arise. In profiling miRNA expression in SC-enriched crypt subsections isolated from fresh, normal surgical specimens, we identified 16 miRNAs that were differentially expressed in the crypt bottom, creating a SC signature for normal colonic epithelia (NCE). A parallel analysis of colorectal cancer (CRC) tissues showed differential expression of 83 miRNAs relative to NCE. Within the 16 miRNA signature for the normal SC niche, we found that miRNA-206, miRNA-007-3 and miRNA-23b individually could distinguish CRC from NCE. Notably, miRNA-23b, which was increased in CRC, was predicted to target the SC-expressed G protein-coupled receptor LGR5. Cell biology investigations showed that miRNA-23b regulated CSC phenotypes globally at the level of proliferation, cell-cycle, self-renewal, EMT, invasion, and resistance to the CRC chemotherapeutic agent 5-FU. In mechanistic experiments we found that miRNA-23b decreased LGR5 expression and increased ALDH+ CSCs. CSC analyses confirmed that levels of LGR5 and miRNA-23b are inversely correlated in ALDH+ CSCs and that distinct sub-populations of LGR5+ and ALDH+ CSCs exist. Overall, our results define a critical function for miRNA-23b, which, by targeting LGR5, contributes to overpopulation of ALDH+ CSCs and CRC.

    View details for DOI 10.1158/0008-5472.CAN-16-2388

    View details for PubMedID 28487386

  • Somatostatin signaling via SSTR1 contributes to the quiescence of colon cancer stem cells BMC CANCER Modarai, S. R., Opdenaker, L. M., Viswanathan, V., Fields, J. Z., Boman, B. M. 2016; 16

    Abstract

    Neuroendocrine cells (NECs) reside adjacent to colonic stem cells (SCs) in the crypt stem cell (SC) niche, but how NECs are involved in regulation of SCs is unclear. We investigated NECs expressing somatostatin (SST) and somatostatin receptor type 1 (SSTR1) because SST inhibits intestinal proliferation.SSTR1 cells maintain SCs in a quiescent state, and aberrant SST signaling contributes to SC overpopulation in colorectal cancer (CRC).The proportion of SCs to NECs cells was quantified, by flow cytometry, in CRC cell lines and primary normal/tumor tissues based on cellular ALDH and SSTR1 levels, respectively. Doubling time and sphere-formation was used to evaluate cell proliferation and stemness. CRC cell lines were treated with exogenous SST and SST inhibitor cyclosomatostatin (cycloSST) and analyzed for changes in SCs and growth rate. Paracrine signaling between NECs and SCs was ascertained using transwell cultures of ALDH+ and SSTR1+ cells.In CRC cell lines, the proportion of ALDH+ cells inversely correlates with proportion of SSTR1+ cells and with rate of proliferation and sphere-formation. While primary normal tissue shows SST and SSTR1 expression, CRC shows only SSTR1 expression. Moreover, ALDH+ cells did not show SST or SSTR1 expression. Exogenous SST suppressed proliferation but not ALDH+ population size or viability. Inhibition of SSTR1 signaling, via cycloSST treatment, decreased cell proliferation, ALDH+ cell population size and sphere-formation. When co-cultured with SSTR1+ cells, sphere-formation and cell proliferation of ALDH+ cells was inhibited.That each CRC cell line has a unique ALDH+/SSTR1+ ratio which correlates with its growth dynamics, suggests feedback mechanisms exist between SCs and NECs that contribute to regulation of SCs. The growth suppression by both SST and cycloSST treatments suggests that SST signaling modulates this feedback mechanism. The ability of SSTR1+ cells to decrease sphere formation and proliferation of ALDH+ cells in transwell cultures indicates that the ALDH subpopulation is regulated by SSTR1 via a paracrine mechanism. Since ALDH+ cells lack SST and SSTR1 expression, we conjecture that SST signaling controls the rate of NEC maturation as SCs mature along the NEC lineage, which contributes to quiescence of SCs and inhibition of proliferation.

    View details for DOI 10.1186/s12885-016-2969-7

    View details for Web of Science ID 000389382400004

    View details for PubMedID 27927191

  • The miRNA23b-regulated signaling network as a key to cancer development-implications for translational research and therapeutics JOURNAL OF MOLECULAR MEDICINE-JMM Viswanathan, V., Fields, J., Boman, B. M. 2014; 92 (11): 1129-1138

    Abstract

    A growing body of evidence indicates that microRNA23b (miR23b) is pleiotropic-it plays important roles in regulating physiological functions of cells, in regulating differentiation of cells and in regulating cellular immune responses. Our review of the literature showed that dysregulation of miR23b expression is implicated in the disruption of these cellular mechanisms and development of diseases such as cancer. MiR23b dysregulation appears to do this by modulating the expression level of candidate gene products involved in a network of signaling pathways including TGF-beta and Notch pathways that govern malignant properties of cancer cells such as motility and invasiveness. More recently, miR23b regulation of gene expression has also been associated with cancer stem cells and chemoresistance. Our review covers miR23b's role in immunity, endothelial function, differentiation, and cancer as well as its potential for translation into future cancer diagnostics and therapeutics.

    View details for DOI 10.1007/s00109-014-1208-4

    View details for Web of Science ID 000344172200003

    View details for PubMedID 25301113