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Meena Chellaiah, PhD

Associate Professor

Oncology and Diagnostic Sciences

mission

RESEARCH INTERESTS
I have been working with bone cells osteoclasts (OCs) since 1991 and prostate cancer since 2003. During my career in the field of OC biology, I made significant contribution in the study of podosomes assembly/disassembly and sealing ring formation. My lab projects are focused on the mechanisms of a) actin dynamics in OC migration and bone resorption; b) invasive property of prostate cancer (PC3) and human melanoma cells. Sealing (actin) ring formation is a prerequisite for OC bone resorption. We are the first to demonstrate 1) the formation of nascent sealing zones (NSZs) prior to formation of mature sealing rings in resorbing OCs; 2) the role of invadopodia in the invasion of prostate cancer PC3 cells. Our studies with OCs and prostate cancer cells reveal varied types of actin dynamics.
 
We currently focus on the role of an actin bundling protein L-plastin (LPL) in NSZs formation in OCs. While many of the proteins that compose the sealing ring have been identified, their function is still poorly understood. In particular, little is known about the role of LPL in OCs. I strongly believe that studies on understanding the role of LPL on actin dynamics in the formation of NSZs will significantly advance the field of clinical intervention to address osteoporosis. The outcome of our studies will provide a basis for peptidomimmetic therapeutics to target OC -associated bone loss.

Our focus in prostate cancer cells has been to identify the roles of the following proteins such as osteopontin, integrin αvβ3, CD44, and metalloproteases (MMPs) in invasion and metastasis. We used several prostate cancer cell lines to study prostate cancer metastasis to bone. To study bone metastasis, primarily we used PC3 cells derived from bone metastasis. PC3 cells metastasized to bone demonstrated expression of RANKL, a cytokine known to induce OC differentiation. CD44 and MMP9 knock down PC3 cells displayed reduced levels of RANKL and the conditioned media of these cells are less potent in inducing osteoclastogenesis in vitro. Investigating the effects of these cytokines on the signaling mechanisms would be very promising in modulating the treatment strategy. Our goal is to identify novel target for treatment strategies. Combination therapies that can block OC differentiation (anti-RANKL drugs e.g. denosumab) and activity (bisphosphonates) or migration/invasion (MMP inhibitor) and proliferation (docetaxel or paclitaxel) could understandably be employed in clinical trials, involving prostate cancer patients with bone metastasis. 
We have established collaboration with several high caliber scientists who complement well with the strength of my laboratory to make significant advances in OC and cancer biology associated with metastasis and osteoporosis.

PUBLICATIONS SINCE 2006
1) Chellaiah MA: Regulation of podosomes by integrin avb3 and Rho GTPase-facilitated phosphoinositide Signaling. Eur. J. Cell Biol. 2006 85: 311-317

2) Samanna V, Derek E, Wei H, Chellaiah MA. Regulation of MMP 2 activity by integrin avb3-mediated signaling in human melanoma cells. Exp.Cell Res. 2006 312(12): 2214-30

3) Chellaiah MA, Kuppuswamy D, Lasky L, Linder S (2007). Phosphorylation of a WASP-Associated Signal Complex Is Critical In Osteoclast Bone Resorption J Biol. Chem. 282: 10104-10116

4) Desai B, Samanna V, Rogers MJ, Mak TW, Chellaiah MA (2007) Mechanisms of osteopontin and MMP-9 as metastatic principles in prostate cancer. Molecular Cancer 6(18): 1-16

5) Samanna V, Ma T, Mak TW, Rogers M, and Chellaiah MA Actin Polymerization Modulates CD44 surface expression, MMP-9 Activation, and Osteoclast Function. Journal of Cellular Physiology 2007 213(3):710-20.

6) Desai B, Ma T, and Chellaiah MA Invadopodia and matrix degradation: a new property of prostate cancer cells during migration and invasion. J. Biol Chem. 2008 283 (20): 13856-13866

7) Ma T, Samanna V, and Chellaiah MA. Dramatic inhibition of osteoclast sealing ring formation and bone resorption in vitro by a WASP-peptide containing pTyr294 amino acid. J Mol Signal. 2008 20;3:4.

8) Mani SK, Shiraishi H, Balasubramanian S, Yamane K, Chellaiah M, Cooper G, Banik NL, Zile MR, Kuppuswamy D. In vivo administration of calpeptin attenuates calpain activation and cardiomyocyte
loss in pressure overloaded feline myocardium. Am J Physiol Heart Circ Physiol. 2008 Jul;295(1):H314-26

9) Desai B, Ma T, Zhu J, Chellaiah MA. Characterization of the expression of variant and standard CD44 in prostate cancer cells: identification of the possible molecular mechanism of CD44/MMP9 complex formation on the cell surface.2009 J Cell Biochem. 2009 Sep 1;108(1):272-84.

10) Chellaiah MA, Schaller MD. Activation of Src kinase by protein-tyrosine phosphatase-PEST in osteoclasts: comparative analysis of the effects of bisphosphonate and protein-tyrosine phosphatase inhibitor on Src activation in vitro. J Cell Physiol. 2009 Aug;220(2):382-93

11) Robertson BW, Chellaiah MA. Osteopontin induces beta-catenin signaling through activation of Akt in prostate cancer cells. Exp Cell Res. 2010 Jan 1;316 (1):1-11

12) Ma T, Sadashivaiah K, and Chellaiah MA. Regulation of sealing ring formation by L-plastin and cortactin in Osteoclasts. J. Biol. Chem. 2010 J. Biol. Chem. 2010 Sept 24; 285 (39): 29911-24..

13) Robertson BW, Bonsal L, and Chellaiah MA. Regulation of Erk1/2 Activation by Osteopontin in Prostate Cancer Cells. Mol Cancer. 2010 Sep 26;9:260.

14) Gupta A, Cao W and Chellaiah MA. Integrin αvβ3 and CD44 pathways in metastatic prostate cancer cells support osteoclastogenesis via a RUNX2/Smad5/RANKL signaling axis 2012 Mol Cancer Sept 11, 11:66

15) Gupta A, Cao W, Sadashivaiah K,Chen W, Schneider A and Chellaiah MA. Promising non-invasive cellular phenotype in prostate cancer cells knock down of matrix metalloproteinase 9. 2013 Scientific world Journal Feb 6, 2013: 493689. doi: 10.1155/2013/493689. Epub 2013.

16) Chellaiah MA, Ma T . Membrane localization of MT1-MMP by CD44 regulates the activation of Pro-MMP9 in osteoclasts 2013 Bio Med Res Int 2013: 302392. doi: 10.1155/2013/302392. Epub 2013 Jul 28.

17) Gupta A, Zhou C, Chellaiah MA. Osteopontin and MMP9 associations with VEGF expression/Secretion and angiogenesis in PC3 prostate cancer cells. Cancers (Basel). 2013 May 27;5 (2):617-38. doi: 10.3390/cancers5020617

18) Chellaiah MA. CD44-Src signaling promotes invadopodia formation in prostate cancer (PC3) cells. 2014 OA Cancer 2013 Nov. 01;1(2):14 (IN Press)

EDUCATION, TRAINING and APPOINTMENTS

BSc and MSc, Madurai Kamaraj University, India (1972-1977)
PhD, School of Biological Sciences, Madurai Kamaraj University, India 1985
Postdoctoral fellow, St. Louis University 1987 to 1990
Research Associate, Jewish Hospital of St. Louis, St. Louis, MO Department of Pathology and
Medicine (1992-1997)
Research Instructor, Department of Medicine, Washington University School of Medicine,, St. Louis,
MO (1997 to1999)
Research Assistant Professor, Department of Medicine Washington University School of Medicine, St. Louis,
MO 1999 to 2000
Assistant Professor, Department of Biomedical Sciences, School of Dentistry, University of Maryland,
Baltimore, Maryland, 2000 July to 2006
Associate Professor, Department of Oncology and Diagnostic Sciences, School of Dentistry, University of
Maryland, Baltimore, MD 2007- present