Education:
BS 1969 Medicine - Our Lady of Peace University, Namur, Belgium
MD 1973 Medicine - Louvain University, Belgium
Postdoctoral Research Fellowship:
1979-1980 University of Liege, Belgium
Started at USC: 1979
Research Topics: Cancer Cell Biology
Research Description
Cancer progression is not only influenced by genetic changes that occur at higher frequency in malignant cells but also by changes that occur in the tumor microenvironment. This tumor environment is made of host-derived cells such as fibroblasts, endothelial cells and inflammatory cells, and numerous proteins that form the extracellular matrix (ECM). The central theme of the research conducted in our laboratory is to understand at a molecular level the mechanisms by which changes in the tumor microenvironment influence the behavior of malignant cells. A first focus of research in our laboratory is on proteases, including matrix metalloproteases (MMPs) and serine proteases (like plasminogen activators) and their inhibitors in tumor progression. Stromal cells contribute to the production of MMPs that degrade the ECM and activate growth factors and growth factor receptors. We have recently demonstrated that MMP-9 contributes to angiogenesis by promoting the recruitment of pericytes along endothelial cells that vascularize the tumor. We also observed that an inhibitor of serine proteases, the plasminogen activator inhibitor-1 (PAI-1), is paradoxically more abundantly expressed in more aggressive forms of neuroblastoma, the second most common solid tumor in children. In support of a positive effect of this inhibitor on cancer progression, we determined that PAI-1 plays a positive role in angiogenesis by promoting the migration of endothelial cells and by protecting them from apoptosis. A second focus of our research is on the ECM and its control on cell proliferation. In melanoma cells, we have observed that cells are arrested at the G1/S checkpoint when they are maintained in the presence of intact fibrillar type I collagen. This block is associated with a specific increase in the levels of p27, a CDK2 inhibitor and a decrease in cyclin E associated kinase activity, and a simultaneous decrease in Skp2, a protein involved in p27 proteasomal degradation.
G1/S block is lifted when the collagen loses its fibrillar structure as a result of proteolytic degradation initiated by the tumor cells (Ref. 4). A third focus of our research is on the contribution of bone marrow mesenchymal stem cells to bone invasion and metastasis. Using a novel bone invasion model developed in our laboratory, we have discovered that neuroblastoma cells invade the bone by stimulating the maturation and the activity of osteoclasts. Accordingly bone invasion is inhibited by agents blocking osteoclast activity like bisphosphonates. This stimulatory effect on osteoclasts requires the contribution of bone marrow mesenchymal stem cells which in the presence of neuroblastoma cells secrete the osteoclast activating cytokine, IL6. A fourth focus of our laboratory is on understanding the role of MMPs in early stages of malignant transformation and epithelial to mesenchymal transformation (EMT). We have observed that MMP-3 actively contributes to EMT by cleaving E-cadherin, and that MMP inhibitors can reverse EMT and also delay mammary tumor formation in transgenic mice prone to mammary cancer.
Selected Publications
Fukaya Y, Shimada H, Wang LC, Zandi E, Declerck YA. - Identification of Gal-3 binding protein as a factor secreted by tumor cells that stimulates interleukin-6 expression in the bone marrow stroma. - J Biol Chem [ 2008 ] May 1; . PubMed
Peng H, Sohara Y, Moats RA, Nelson MD Jr, Groshen SG, Ye W, Reynolds CP, DeClerck YA. - The activity of zoledronic Acid on neuroblastoma bone metastasis involves inhibition of osteoclasts and tumor cell survival and proliferation. - Cancer Res [ 2007 ] Oct 1;67(19):9346-55 . PubMed
Song L, Ara T, Wu HW, Woo CW, Reynolds CP, Seeger RC, DeClerck YA, Thiele CJ, Sposto R, Metelitsa LS. - Oncogene MYCN regulates localization of NKT cells to the site of disease in neuroblastoma. - J Clin Invest [ 2007 ] Sep;117(9):2702-12 . PubMed
Wall SJ, Zhong ZD, DeClerck YA. - The cyclin-dependent kinase inhibitors p15INK4B and p21CIP1 are critical regulators of fibrillar collagen-induced tumor cell cycle arrest. - J Biol Chem [ 2007 ] Aug 17;282(33):24471-6 . PubMed
De Clerck YA, Weissman BE, Yu D, Parsons R, Bar-Eli M, Roy-Burman P, Seewaldt VL, Cress AE, Languino LR, Batra SK, Tang CK, Sheng S, Chen WT, Chellappan S, Cheng SY, Ladisch S, McCarthy JB, Coussens LM, Cohen MB. - Tumor progression and metastasis from genetic to microenvironmental determinants: a workshop of the tumor progression and metastasis NIH study section in honor of Dr. Martin L. Padarathsingh, May 31, 2006, Georgetown, Washington, DC. - Cancer Biol Ther [ 2006 ] Dec;5(12):1588-99 . PubMed
Ara T, DeClerck YA. - Mechanisms of invasion and metastasis in human neuroblastoma. - Cancer Metastasis Rev [ 2006 ] Dec;25(4):645-57 . PubMed
Mouchess ML, Sohara Y, Nelson MD Jr, DeCLerck YA, Moats RA. - Multimodal imaging analysis of tumor progression and bone resorption in a murine cancer model. - J Comput Assist Tomogr [ 2006 ] May-Jun;30(3):525-34 . PubMed
Jodele S, Blavier L, Yoon JM, DeClerck YA. - Modifying the soil to affect the seed: role of stromal-derived matrix metalloproteinases in cancer progression. - Cancer Metastasis Rev [ 2006 ] Mar;25(1):35-43 . PubMed
Blavier L, Lazaryev A, Dorey F, Shackleford GM, DeClerck YA. - Matrix metalloproteinases play an active role in Wnt1-induced mammary tumorigenesis. - Cancer Res [ 2006 ] Mar 1;66(5):2691-9 . PubMed
Chantrain CF, Henriet P, Jodele S, Emonard H, Feron O, Courtoy PJ, DeClerck YA, Marbaix E. - Mechanisms of pericyte recruitment in tumour angiogenesis: a new role for metalloproteinases. - Eur J Cancer [ 2006 ] Feb;42(3):310-8 . PubMed
