Research Interest: the effects of tumor microenvironment on tumor progression, tumor angiogenesis, and maintenance of cancer stem cells (CSCs); and therapeutic targeting of tumor microenvironment
Current Students: Lucas Murray; Melissa Brunckhorst
Postdoc/Clinical Fellows: Dimitry Lerner; Haiyan Huang
Research Personnel: Yin Xu; Rong Lu

Summary of Current Research:
The overall goal of my lab is to identify the elements in tumor microenvironment that play essential roles in cancer initiation and progression, in therapeutic resistance of cancer cells, and in maintaining cancer stem cell niche; and to understand the underlying mechanisms. We hope that the knowledge gained and therapeutic agents developed from these studies can be translated into clinic to slow down, stop, and/or reverse malignant cancers.
Specifically, we are interested in determining how functions and activities of the extracellular matrix (ECM) and adhesion receptors (CD44 and E-cadherin), transmembrane growth factor precursors (the EGF family growth factors), receptors tyrosine kinases (Tie-2), and the ECM-bound angiogenic factors (angiopoietins) are regulated by the ECM and by proteolytic cleavage/shedding through the activities of MMPs (Matrix Metalloproteinases), ADAMs (A Disintegrin And Metalloproteinases), and/or ADAMTSs (A Disintegrin And Metalloproteinase with ThromboSpondin motifs). In addition, we are interested in understanding the signaling pathways regulated by these molecules, determining how and why these signaling pathways contribute to vascular health, tumor angiogenesis, tumor progression, and responses of tumor cells to therapeutic interventions, and developing antagonists of these signaling pathways for cancer therapy.
There are three specific research projects ongoing in the lab:
To determine the roles of CD44, merlin, and the mammalian Hippo signaling pathway in tumorigenesis and therapeutically target components of the signaling pathway
Merlin is the gene product of Neurofibromatosis type 2 (NF2). Mutations and deletions of NF2 gene cause development of schwannomas and other nervous system tumors. In addition to mutational inactivation of the NF2 gene in the NF2-associated tumors, loss of merlin expression and merlin mutations have been reported in other cancer types. Merlin is closely related to the ERM (Ezrin-Radixin-Moesin) proteins and serves as a linker between the cortical actin filaments and plasma membrane proteins including CD44. CD44 is a major cell surface receptor of hyaluronan (HA), a component of the ECM. CD44 plays important roles in promoting tumor angiogenesis, invasion, and metastasis (Yu et al., 1997; Yu and Stamenkovic 1999 and 2000) and is a key marker of cancer stem cells. We showed that the negative regulation of the CD44-HA interaction by merlin contributes to the tumor suppressor function of merlin (Bai et al., 2007) and that merlin is a potent inhibitor of malignant human glioma and melanoma and that merlin activates mammalian Hippo signaling pathway and inhibits Wnt signaling pathway (Lau et al., 2008; Murray et al., manuscript). Furthermore, we established that CD44 functions upstream of the mammalian Hippo signaling pathway and promotes tumor cell resistance to reactive oxygen species- and cytotoxic agent-induced stress and apoptosis by attenuating activation of the Hippo signaling pathway. We identified CD44 as a prime therapeutic target for Glioblastoma multiforme (GBM) and established potent anti-glioma efficacy of our newly developed CD44 antagonists when used as single agents or in combinations with chemotherapeutic and other targeted agents (Xu et al., 2010). We are working to establish the roles of CD44 and the Hippo signaling pathway in the progression and therapeutic resistance of several different cancer types including glioma, melanoma, prostate cancer, and colon cancer and to develop therapeutic agents that target CD44 and activate the Hippo signaling pathway.

To determine the roles of angiopoietins in tumor angiogenesis and tumor progression and establish the mechanisms regulating angiopoietin bioactivities
Angiopoietin-1, -2, and -3/4 are the ligands of Tie-2 receptor tyrosine kinase. Angiopoietins and Tie-2 play important roles in angiogenesis during embryogenesis and tumorigenesis. We have shown that angiopoietins play different roles in tumor angiogenesis and their activities are differentially regulated by the ECM and heparan sulfate proteoglycans (HSPGs, Yu and Stamenkovic, 2001; Xu and Yu, 2001; Xu et al., 2004a and 2004b; and Yu, 2005). We have established that Ang-4-Tie-2 functional axis plays important role in promoting glioblastoma progression (Brunckhorst et al., 2010 in revision). We are working to determine the roles of angiopoietins in the progression of human ovarian cancer and glioma and the regulatory mechanisms of angiopoietin bioactivities during tumor angiogenesis. We anticipate that results derived from these studies will guide us to generate angiopoietin derivatives/fragments that display more stable and potent anti- or pro-angiogenic activity that can be used to inhibit tumor angiogenesis or treat vascular diseases in the future.

To determine the effects of ADAMTS-1 and its proteolytic cleavage fragments on tumor metastasis and the molecular mechanisms underlying these effects
ADAMTS-1 is a member of the ADAMTS family that contains multiple functional domains including the disintegrin and metalloproteinase domains, and the thrombospondin type I (TSP-1) like motifs. We have shown that full-length ADAMTS-1 and the proteolytic cleavage fragments of ADAMTS-1 display pro- and anti-metastatic activity, respectively, and that ADAMTS-1 is involved in shedding of precursors of the EGF family GFs that bind to heparin including HB-EGF and amphiregulin (AR). On the contrary, the ADAMTS-1 fragments that contain the TSP-1 motifs negatively regulate activity of soluble HB-EGF and AR (Liu et al., 2006). We are working to determine the roles of different ADAMTSs in progression of human breast, lung, and ovarian cancers and the mechanisms underlying the pro-metastatic activity of full-length ADAMTS-1 and anti-metastatic activity of the ADAMTS-1 fragments, and to establish that ADAMTS-1 is a prime target for cancer therapy and that the ADAMTS-1 fragments are potent anti-cancer agents.

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