Walter S. and Lucienne Driskill
Graduate Training Program in Life Sciences

DGP Northwestern

Shi-Yuan Cheng

Shi-Yuan Cheng,  PhD Professor Neurology and Northwestern Brain Tumor Institute Oncogenic signaling in human glioblastomas and breast cancers Research cluster: Cancer Biology E-mail:   shiyuan.cheng@northwestern.edu

Our research interests focus on the molecular mechanisms of human cancer tumorigenesis, progression, invasion/metastasis and angiogenesis. We have been investigating oncogenic receptor tyrosine kinase signaling, their mediators including guanine nucleotide exchange factors (GEFs), activators for Rac1 and Cdc42 in human glioblastomas and breast cancers.  Glioblastomas are the most common malignant tumors in the brain.  Breast cancer is the most common cancer in women.  Recently, we started to study glioma stem cells that were derived from clinical glioma tumor tissues.  We are also interested in developing novel approaches for cancer therapies using novel anti-tumor and anti-angiogenic inhibitors in combination with non-invasive evaluation methods.  

The Role of Oncogenic Signaling in Glioma Tumorigenesis, Growth and Invasion: Recent genomic analyses in a large cohort of clinical specimens validated EGFR and PDGFR alpha as top amplified genes in gliomas.  Further analyses based on distinct gene signatures identified four clinical relevant subtypes of gliomas, proneural, neural, classical and mesenchymal gliomas.  PDGFR alpha is overexpressed in proneural subtype of gliomas while EGFR amplification is concentrated in neural and classic subtypes of gliomas.  Additionally, loss of IkBa, an inhibitor of NF-kB is preferentially found in non-classic glioma and such loss is mutually exclusive to EGFR amplifications in gliomas.  We investigated whether PDGF-A/PDGFR alpha signaling is critical in glioma formation when astrocytes or neural stem cells lost tumor suppressors Ink4A/Arf.  We recently reported that activation of PDGF-A/PDGFR alpha signaling drives glioma formation in the brain by mouse astrocytes and human glioma cells deficient in Ink4A/Arf through PI3K- and SHP-2-signaling.  Additionally, SHP-2 interacts with dynamin 2 and mediates PDGFR alpha stimulation of glioma tumorigenesis and invasion.  We are currently studying whether and how other oncogenic signalings act in concert with PDGFR alpha and EGFR signaling to drive glioma tumorigenesis, angiogenesis and invasion of different subtypes of gliomas and glioma stem cells.  We are also investigating the roles and mechanisms of cellular metabolic pathways and microRNAs in these oncogenic signaling-driven glioma tumorigenesis, invasion and malignancy.  Additionally we are using genomic analyses to determine whether distinct gene sets are required for tumorigenesis in different subtypes of gliomas and for maintaining the stemness of glioma stem cells and their function as “tumor propagating/initiating cells” in vitro and in vivo.  Afterwards, we will focus on molecular and biochemical mechanisms by which these critical proteins mediate distinct oncogenic signaling in both glioma stem cells and non-stem glioma cells.

The Role of Small Rho GTPases and GEFs in EGFR- and PDGFR alpha-promoted Glioma Migration and Invasion:  A hallmark of malignant human gliomas is the intrinsic tumor cell infiltration into normal brain parenchyma that render these aggressive tumors difficult to treat and resistant to combination therapies.  Small Rho GTPases such as Rac1 and Cdc42 play critical roles in modulating cell migration, invasion, growth and survival. Recently, we described mechanisms by which EGFR and its mutant EGFRvIII, and PDGFR alpha promote glioma growth and invasion through Src family kinase-dependent protein phosphorylation of Dock180, activating Rac1-mediated signaling.  We are currently investigating involvement of other modulators/GEFs for Rac1 and Cdc42 and other Rho GTPases in oncogenic signaling-induced glioma invasion.

Therapeutic studies of Anti-angiogenesis and Anti-angiogenic-induced glioma invasion and inhibition of glioma tumorigenesis: Vascular endothelial growth factor (VEGF) family and their receptors are the major angiogenic factors.  Recent studies showed that anti-VEGF therapies displayed adverse effects in treatments of clinical cancers including gliomas.  Currently, we are investigating the possible mechanisms by which inhibition of VEGF signaling evoke glioma cell invasion.  We are also evaluating therapeutic effects on inhibiting glioma growth and angiogenesis in vivo using clinically approved anti-tumor drugs, inhibitors of VEGFR and EGFR in combination with novel inhibitors that specifically target critical molecules.  Additionally, we will assess the effects of novel agents/inhibitors specific for newly identified targets such as SHP-2 on glioma tumor growth, invasion and angiogenesis using engineered glioma cell lines, primary short-term cultured glioma cells and clinical glioma tumor-derived glioma stem cells.

Signaling Pathways That Promotes Cell Motility and Survival in Breast Cancer Metastasis: We reported that that an angiogenic factor angiopoietin-2 (Ang2) induces tumor metastasis of human MCF-7 breast cancer cells, a poorly metastatic cell line through the integrin-linked kinase (ILK)-Akt/GSK 3 beta-Snail-E-cadherin pathway and promotes cancer cell survival through Akt-Bcl-2 signaling.  Interesting, Ang2-activated signaling pathways are similar to that of several other breast cancer metastatic promoters such as Her2 overexpression in breast cancer cells. We are currently investigating involvement of various signaling pathways such as small Rho GTPases, GEFs and their regulators that promote breast cancer cell motility, and modulators of Bcl-2 enhancing cell survival in distant organs leading to breast cancer metastasis.

Selected Publications:

Liu, K.-W., Feng, H., Bachoo, R., Kazlauskas, A., Smith, E.M., Symes, K., Hu, B. and Cheng, S.-Y. (2011) “SHP-2/PTPN11 is a critical mediator of gliomagenesis driven by PDGFRA and Ink4a/Arf aberrations” J. Clin. Invest. 121(3):905-917 [Epub Feb 14, 2011] PMID: 21393858, PMCID: PMC3049395

Feng, H., Hu, B., Liu, K.-W., Yiin, J.-J., Vuori, K., Hamilton, R.L., Nishikawa, R., Nagane, M. and Cheng, S.-Y. (2011) “Activation of Rac1 by Src-dependent Phosphorylation of Dock180^Y1811 Mediates PDGFR alpha-stimulated Glioma Tumorigenesis in Mice and Humans”. J. Clin. Invest. 121(12):4670–4684 [Epub Nov 14, 2011], PMID: 22080864

Feng, H., Liu, K.-W., Guo, P., Zhang, P., Cheng, T., McNiven, M.A., Johnson, G., Hu, B., and Cheng, S.-Y. (2012) “Dynamin 2 Mediates PDGFR Alpha-SHP-2-promoted Glioma Cell Growth and Invasion” Oncogene, 31(21):2691-702. [Epub Sept. 26, 2011], PMID: 21996738

Feng, H., Hu, B., Jarzynka, M.J., Liu, K.-W., Hamilton, R. L., Vuori, K., Furnari, F.B., Johns, T.G., Tang, C., Nishikawa, R., Cavenee, W.K. and Cheng, S.-Y. (2012) “Phosphorylation of Dock180^Y722 by Src Family Kinases Mediates EGFRvIII-driven Glioma Tumorigenesis.” Proc. Natl. Acad. Sci., USA, 109(8):3018-23 [Epub Feb 7, 2012], PMID: 22323579.

Song. L., Liu, L., Wu, Z., Li, Y., Ying, Z., Lin, C., Wu, J., Hu, B., Cheng, S.-Y., Li, M. and Li, J. (2012) “TGF-β  Induces miR-182 to Sustain NF-κB Activation by Glioma Subsets.” J. Clin. Invest. 122(10):3563–3578. Epub 2012 Sep 24; PMID: 23006329