Student Directory

Steven Steinway

Class Year: G4

 

Department/Institute/Center(s):

  • M.D./Ph.D. Program

 

Contact Information:

 

Biographical Information:

Hometown: Florham Park, NJ

 

Education:

Undergraduate Education:  BS/09 Biology/College of New Jersey

 

Research Interests:

Research Interest:  Solid tumor progression, invasion, metastasis (hepatocellular carcinoma as a model), epithelial-to-mesenchymal transition, network modeling, systems biology, mouse models of HCC progression

Advisor: Thomas Loughran co-advisor (HY); Reka Albert co-advisor (UP)
Graduate Program: Molecular Medicine

Thesis:

Description: 

 

Hepatocellular carcinoma (HCC) is the third most common cause of cancer death in the world and its incidence is rising in the United States. Over 90% of cancer deaths occur due to tumor metastasis. Epithelial-to-mesenchymal transition (EMT) is a developmental process hijacked by cancer cells to leave the primary tumor site and establish distant metastases. Cells undergoing EMT lose cell-cell adhesion properties and change cell morphology in order to migrate into the blood stream. Loss of expression of E-cadherin, a cell adhesion protein, is considered the hallmark of EMT, and molecular analyses have revealed complex signaling pathways regulating E-cadherin expression. The hepatocyte growth factor (HGF)/C-met receptor axis is a major EMT inducer and is dysregulated in 40% of HCC. TGF-beta signaling, another important EMT inducer, is dysregulated in 20% of HCC. To systematically understand signaling components that regulate HCC metastasis, we constructed an EMT network (74 nodes, 143 edges) by integrating the signaling pathways involved in developmental EMT and known dysregulations in metastatic HCC. This network was subsequently translated into a predictive, discrete, dynamic model. Using HGF and TGFß as our EMT inducers and E-cadherin expression as our EMT marker, we reveal that the EMT process, although robust, appears to be targetable through inhibition of a small subset of critical (EMT "driver") nodes. Our model suggests the following: (1) a critical eight node transcriptional network that is downstream of major growth signals is necessary for EMT induction. (2) Cross-activation of Sonic hedgehog and Wnt signaling pathways byTGFß is critical for transmission of the EMT signal. (3) Of the 135 nodes that did not block EMT transmission (termed "passenger" nodes), when combined with other EMT "passengers", 11 combination knockouts were able to inhibit transmission of the EMT signal. (4) Analysis of the states in the basin of attraction of the "EMT negative" steady states has revealed a critical sub-network (a strongly connected component of the larger EMT network) for EMT transmission. Initial testing has revealed that Snail1 inhibition blocksTGFß induced EMT. Further experimental analysis has revealed cross-activation of SHH and Wnt signaling pathways byTGFß. The predicted criticality of such cross-talk is currently underway. These results reveal network modeling as an important tool for identifying critical mediators in biological processes. Furthermore, we propose network modeling as a tool for rational drug targeting of disease pathways, specifically in liver cancer progression, invasion, and metastasis.

Meeting Presentations
  • 2007
    REU Bioinformatics, Research Symposium, Loyola U, Chicago, IL
    Semiannual Student Research Symposium, C of NJ
  • 2008
    11th Annual Celebration of Student Achievement, C of NJ
    Bioinformatics Summer Inst. Research Symposium, U of MN
  • 2012
    Penn State College of Medicine Graduate Research Forum, Hershey, PA (poster)
    AACR Chemical Systems Biology meeting, Boston, MA (oral)
  • 2014
    Systems Biology of Human Disease Meeting, Boston, MA (poster)

 

 

Publications:

Springer NM, Eichten S, Smith A, Steinway SN, Kaeppler SM (2009) Genome wide distribution and intraspecific variation of a middle-copy maize retrotransposon, SPRITE  Maydica  2009 54:417 PMCID:  (no number)

Steinway SN, Dannenfelser R, Laucius CD, Hayes JE, Nayak S (2009) JCoDA:  A tool for Detecting Evolutionary Selection, BMC Bioinformatics 11:284  PMCID:  PMC2887424

Steinway SN (2009) In Silico:  Retrieval and Cataloging of Genbank DNA Sequences Adjacent to Interspersed Repetitive Elements (2009) TCNJ J of Student Scholarship

Ding W, Dang H, You H, Steinway S, Takahashi Y, Wang HG, Liao J, Stiles B, Albert R, Rountree CB (2012) miR-200b restoration and DNA methyltransferase inhibitor block lung metastasis of mesenchymal-phenotype hepatocellular carcinoma Oncogenesis 1:e15.doi:10.1038/oncsis.2012.15 PMCID:  PMC3412647

Steinway SN, Loughran TP (2013) Targeting IL-15 in large granular lymphocyte leukemia Expert Rev Clin Immunol 9(5):405-8  PMID: 23634735  PMCID:  PMC3889194

Steinway SN, LeBlanc F, Loughran TPJr (2014) The pathogenesis and treatment of large granular lymphocyte leukemia Blood Rev 28(3):87-94  PMCID:  (no number)

Steinway SN, Gomez Tejeda Zanudo J, Ding W, Rountree CB, Feith DJ, Loughran TP Jr, Albert R (2014) Network modeling of TGFß signaling in hepatocellular carcinoma epithelial-to-mesenchymal transition reveals joint Sonic hedgehog and Wnt pathway activation" Cancer Res [Epub ahead of print]

 

 

 

Steven Steinway

 

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