|Title:||Assistant Professor / Biochemistry and Molecular Biology
|Department of Chemistry and Biochemistry|
Office: GSRC 309
Lab: GSRC 324, 803-777-6323
Lab 2: GSRC 325
Lab 3: GSRC 335A
Mythreye Karthikeyan Group Website
B.Sc., 1996, University of Delhi
M.Sc., 1998, Hamdard University
Ph.D., 2005, University of North Carolina
Honors and Awards
Liz Tilberis Scholar Award, Ovarian Cancer Research Fund, 2013-2016; Career Development Award, Ovarian Cancer Research (Department of Defense), 2009-2012.
Key Words: Growth factor-receptor signaling mechanisms and signal transduction pathways, Epithelial and Tumor cell biology including Cell survival mechanisms, Cell migration and invasion biology, Cell adhesion and Mechanobiology.
The overall goal of the lab is two fold: 1) Discover the molecular and cellular basis of cancer initiation and metastasis as controlled by growth factors. Specific emphasis is laid on the TGF-β superfamily of growth factors, their receptors, co-receptors and their crosstalk with the integrin family of cell adhesion receptors in cancer. 2) To translate these discoveries into a source of novel therapeutic targets as well as strategies to reduce cancer incidence and improve/predict patient outcomes. The transforming growth factor-β (TGF-β) superfamily of growth factors, including the TGF-β ligands, the Bone morphogenetic proteins (BMPs), Activins and Inhibin have physiological roles in regulation of growth, cell differentiation and apoptosis in a cell and context-specific manner. TGFβ family ligands induce phenotypic changes in cancer cells including altered morphology, adhesion, motility and invasive behavior via a signal transduction cascade illustrated in Figure 1 and play dichotomous roles in cancer progression switching from tumor suppressors to tumor promoters. Understanding the mechanism of this dichotomy of TGF-β superfamily function remains a fundamental problem in the cancer biology field and affects our ability to target these pathways in various pathologies.
Three core research areas include:
• Role of integrins in regulating TGF-β's effects on carcinogenesis. We have recently determined that TGF-β coreceptors traffic with integrins that impacts their subcellular distribution in cells and cancer tissues. Emphasis will be laid on the intersection of TGF-β and BMP signaling and integrin biology in the context of gynecological cancers, ovarian and breast cancer.
• BMP's are emerging as regulators of breast and ovarian physiology. The aim is to determine the contribution of BMP's in cell survival in ovarian and breast cancer.
• Defining the intersection between growth factor/biochemical signals and mechanical signals received by cells as the extracellular matrix environment changes in disease. Specifically, the lab investigates how changes in the TGF-β pathways during epithelial to mesenchymal transition may act as a mechanism utilized by cancers to evade mechanical cues to impact cancer cell behavior in breast and ovarian cancer.
Mechanistic studies will be conducted in cell line models of cancer either in two dimension (Figure 2), or in specialized three dimensional organotype culture models (Figure 3).
Identified mechanisms will be translated into preclinical work using small molecule inhibitors, TGF-β antibodies and chemotherapeutic agents in xenograft models and transgenic mice to determine invivo impact.
Kumar S, Pan CC, Shah N, Wheeler SE, Hoyt KR, Hempel N, Mythreye K, Lee NY. Activation of Mitofusin2 by Smad2-RIN1 Complex during Mitochondrial Fusion. Mol Cell. 2016 May 19;62(4):520-31. DOI: 10.1016/j.molcel.2016.04.010. [Epub 2016 May 12.]
Pan CC, Shah N, Kumar S, Wheeler SE, Cinti J, Hoyt DG, Beattie CE, An M, Mythreye K, Rakotondraibe LH, Lee NY. Angiostatic actions of capsicodendrin through selective inhibition of VEGFR2-mediated AKT signaling and disregulated autophagy. Oncotarget. 2016 May 11. DOI: 10.18632/oncotarget.9307. [Epub ahead of print.]
Varadaraj A, Patel P, Serrao A, Bandyopadhay T, Lee NY, Jazaeri AA, Huang Z, Murphy
SK, Mythreye K. Epigenetic regulation of GDF2 suppresses anoikis in ovarian and breast
epithelia Neoplasia. 2015 Nov 17; (11):826-38.
Osborne, L.; Li, G. Z.; O Brian, E. T.; How, T.; Blobe, G. C.; Superfine, R.; K. Mythreye.
TGF-β Regulates LARG and GEF-H1 During EMT to Impact Stiffening Response to Force
and Cell Invasion. Mol. Biol. Cell. 2014, 25:22, 3528 - 3540.
Knelson, E. H.; Gaviglio, A. L.; Tewari, A. K.; Armstrong, M. B.; Karthikeyan Mythreye, Blobe, G. B. Type III TGF-Beta Receptor Promotes FGF2-mediated Neuronal Differentiation in Neuroblastoma. J Clin Invest. 2013 Nov 1; 123(11), 4786 - 98 ( equal senior author). DOI: 10.1172/JCI69657.