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The c-Met receptor contributes to motility and invasion in high grade STS;

The c-Met receptor contributes to motility and invasion in high grade STS; a potential therapeutic target. Sarah E. Myers, Theresa G. Nguyen, Quan-Sheng Zhu, Alexander J.F. Lazar, Raphael E. Pollock, Dina C. Lev Presented by Gonzalo Lopez, MS Sarcoma Research Laboratory

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The c-Met receptor contributes to motility and invasion in high grade STS;

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  1. The c-Met receptor contributes to motility and invasion in high grade STS; a potential therapeutic target Sarah E. Myers, Theresa G. Nguyen, Quan-Sheng Zhu, Alexander J.F. Lazar, Raphael E. Pollock, Dina C. Lev Presented by Gonzalo Lopez, MS Sarcoma Research Laboratory MD Anderson Cancer Center Houston, TX

  2. Sarcomas are heterogeneous • Complex karyotype: • Leiomyosarcoma • MFH/UPS • MPNST • Generally poor prognosis

  3. Migration and invasion critical for STS metastasis Proliferation/ angiogenesis Migration /invasion Primary tumor Embolism/circulation Adherence to vessel wall Transport Arrest in organs Extravasation Proliferation/ angiogenesis Establishment of a microenvironment Metastasis What are the molecular drivers of these processes???

  4. RTKs: c-Met, EGFR, VEGFR, c-Kit, etc. RTKs: central components of signaling networks (embryogenesis, cell proliferation, apoptosis) RTK deregulation: diabetes, developmental defects, and cancer Activated RTKs: induce pathways of cell migration and invasion Candidate mechanisms: receptor tyrosine kinases (RTK)

  5. c-Met receptor: relevant biology • Found in mesenchymal and epithelial tissues • Ligand HGF (hepatocyte growth factor) • Involved in embryogenesis, wound healing • Broad range of downstream effects

  6. WG Jiang et al. 2005 c-Met receptor

  7. Experimental goal To evaluate the impact of c-Met activation and inhibition on complex karyotype STS migration and invasion

  8. c-Met is expressed in human STS tissue Leiomyo/UPS TMA MPNST TMA

  9. HGF Total c-Met Phospho c-Met Phosphorylated c-Met correlates with dismal outcome (HR 2.32; p=0.012)

  10. c-Met is expressed in human STS cell lines SKLMS1 MES-SA HT1080 SW684 SW872 A204 NHF RD c-Met -actin HT1080 SKLMS1 A204 - + - + - + HGF p c-Met c-Met

  11. Birchmeier,C. Nature Reviews. 2003

  12. HGF activates ERK and AKT SKLMS1 A204 - + - + HGF p c-Met c-Met p ERK ERK p AKT AKT β-actin

  13. HGF induces migration SKLMS1 HGF (-) Avg. # of cells/HPF HGF (+) - + - + HGF SKLMS1 A204

  14. HGF induces invasion SKLMS1 HGF (-) Avg. # of cells/HPF HGF (+) - + - + HGF SKLMS1 A204

  15. Inhibition of c-Met • Small molecule inhibitor (PHA-665752, Pfizer) • Anti c-Met siRNA

  16. PHA inhibits c-Met activation and downstream signaling 2.5 uM 1 uM 5 uM - - + + + PHA - + + + + HGF p c-Met c-Met pERK ERK pAKT AKT

  17. c-Met siRNA effect on downstream signaling Mock NT siRNA - + - + - + HGF p c-Met c-Met pERK ERK pAKT AKT

  18. c-Met blockade abrogates HGF induced invasion DMSO DMSO + HGF PHA PHA + HGF Avg. # of cells/HPF - + - + HGF DMSO PHA

  19. HGF induces migration and invasion genes HGF - HGF + HGF - + FN1 ITGB5 FN1 ITGB5 LAMB1 LAMB1 LAMA5 LAMA5 MMP2 MMP2 GAPDH

  20. Conclusions • Human STS samples highly express c-Met, HGF, and activated c-Met • Activated c-Met expression correlates with dismal outcome in MPNST • Activation of c-Met receptor on STS induces migration and invasion • c-Met blockade abrogates these processes

  21. Acknowledgements • Sarcoma Research Laboratory at UTMDACC • Dina C. Lev, MD • Raphael E. Pollock, MD/PhD • Alex J.F. Lazar, MD/PhD • Sarah E. Myers, BS • Wenhong Ren, MD • Colleagues and Staff

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