Gender	Female
E-mail	qin.yu@mssm.edu
Education and Training	Ph.D., Tufts University
	M.S., Shanghai Institute of Cell Biology, Academia Sinica
	B.S., Hangzhou University
	Fellowship, Massachusetts General Hospital-East, Harvard Medical School

Education and Training	Ph.D., Tufts University
	M.S., Shanghai Institute of Cell Biology, Academia Sinica
	B.S., Hangzhou University
	Fellowship, Massachusetts General Hospital-East, Harvard Medical School

The Effects of Microenvironment on Tumor Progression and Metastasis:

Post-doctoral Fellows: Ingar Lau

Graduate Students: Murray, Lucas Murray; Melissa Brunckhorst;

Crystal Tonnessen

The overall goal of my lab is to identify the elements in microenvironment of tumors and vasculature that are essential for the initiation and progression tumors and vascular diseases and to understand how these elements contribute to these diseases. We hope that the knowledge gained from our studies can be used to slow down, stop, and/or reverse malignant cancers and cardiovascular diseases in the future.
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/or by proteolytic cleavage/ shedding through 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 how and why these molecules and their proteolytic cleavage products contribute to vascular health, angiogenesis, and tumor initiation and progression.

There are three specific research projects ongoing in the lab:

To determine the roles of angiopoietins in tumor angiogenesis and the mechanisms regulating the bioactivities of angiopoietins
Angiopoietin-1, -2, and -3/4 are the ligands of Tie-2 receptor tyrosine kinase that is expressed primarily by endothelial cells. 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 are working to determine the roles of angiopoietins in the progression of human ovarian cancer and glioma and how angiopoietin bioactivities are regulated during tumor angiogenesis. We anticipate that the knowledge gained from these studies will guide us to generate angiopoietin derivatives/fragments that display more stable and potent pro- or anti-angiogenic activity that can be used to inhibit tumor angiogenesis and treat vascular diseases in the future.

To determine how full-length ADAMTS-1 and its proteolytic cleavage fragments affect growth and metastasis of breast and lung cancers, and the molecular mechanisms underlying their effects
ADAMTS-1 is a m ember 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 exact 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.

To determine the role of merlin in tumorigenesis and the mechanisms whereby merlin exerts its tumor suppressor function
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 also been reported in other types of cancers. Merlin is closely related to the ERM (Ezrin-Radixin-Moesin) proteins and serves as a cross-linker between the cortical actin filaments and plasma membrane proteins including CD44 and integrin. CD44 is the principal cell surface receptor of hyaluronan (HA), a major component of the ECM. CD44 plays important roles in promoting tumor invasion and metastasis (Yu et al., 1997; Yu and Stamenkovic 1999 and 2000). 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). Furthermore, we showed that merlin is a potent inhibitor of high-grade human glioma and that merlin activates the mammalian sterile 20-like1/2 (MST1/2)-large tumor suppressor 2 (Lats 2) signaling pathway and inhibits the Wnt signaling pathway (Lau et al., 2008). We are working to determine the role of merlin in initiation and progression of several different types of cancers and how the tumor suppressor function of merlin is exerted through and regulated by CD44.

 

 

 

Lau YK, Murray LB, Houshmandi SS, Xu Y, Gutmann DH, Yu Q. Merlin is a potent inhibitor of glioma growth. Cancer Res 2008 Jul 15; 68(14): 5733-5742.

Bai Y, Liu YJ, Wang H, Xu Y, Stamenkovic I, Yu Q. Inhibition of the hyaluronan-CD44 interaction by merlin contributes to the tumor-suppressor activity of merlin. Oncogene 2007 Feb 8; 26(6): 836-850.

Liu YJ, Xu Y, Yu Q. Full-length ADAMTS-1 and the ADAMTS-1 fragments display pro- and antimetastatic activity, respectively. Oncogene 2006 Apr 20; 25(17): 2452-2467.

Yu Q. The dynamic roles of angiopoietins in tumor angiogenesis [review]. Future Oncol 2005 Aug; 1(4): 475-484.

Xu Y, Liu YJ, Yu Q. Angiopoietin-3 inhibits pulmonary metastasis by inhibiting tumor angiogenesis. Cancer Res 2004 Sep 1; 64(17): 6119-6126.

Xu Y, Liu YJ, Yu Q. Angiopoietin-3 is tethered on the cell surface via heparan sulfate proteoglycans. J Biol Chem 2004 Sep 24; 279(39): 41179-41188.

Yu Q, Stamenkovic I. Transforming growth factor-beta facilitates breast carcinoma metastasis by promoting tumor cell survival. Clin Exp Metastasis 2004; 21(3): 235-242.

Xu Y, Yu Q. E-cadherin negatively regulates CD44-hyaluronan interaction and CD44-mediated tumor invasion and branching morphogenesis. J Biol Chem 2003 Mar 7; 278(10): 8661-8668.

Yu Q, Stamenkovic I. Angiopoietin-2 is implicated in the regulation of tumor angiogenesis. Am J Pathol 2001 Feb; 158(2): 563-570.

Xu Y, Yu Q. Angiopoietin-1, unlike angiopoietin-2, is incorporated into the extracellular matrix via its linker peptide region. J Biol Chem 2001 Sep 14; 276(37): 34990-34998.

Yu Q, Stamenkovic I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev 2000 Jan 15; 14(2): 163-176.