kinase signaling and extracellular matrix proteolysis in ... · 3/12/2019 · extracellular...
TRANSCRIPT
Kinase Signaling and Extracellular Matrix Proteolysis
in Kidney Cancer
Dimitra Bourboulia, PhD
Assistant Professor of Urology
SUNY Upstate Medical University
@bourboulialab
No actual or potential conflict of interest in relation to this
presentation
Hallmarks of Cancer
Douglas Hanahan and Robert A. Weinberg, Cell, 2000
Tumor spread and disease progression
• Renal sinus invasion - worse prognosis
• Invasion into the renal sinus increases chances of distant
metastasis
• 5-year disease-specific survival
• 50-69% (no metastasis),
• 10% (with metastasis)
Targeting invasion
Extracellular Matrix
Targeting invasion in renal cancer
Invading cancer cells
Tumor growth
AngiogenesisMMP14
MMP2 Basement
Membrane
EMT: Snail
Vimentin
MMPs
Extracellular Matrix
MMPs in renal cancer
• VHL-/- RCC increased cell invasion (via MMP2)
• VHL-/- RCC MMP14 promotes tumor (via MMP2); is a HIF2α target
• Strong correlation - increased MMP2, MMP9 expression and tumor stage
• MMP2 and MMP9 expression associate with poor outcome
• Inhibitor TIMP2 is downregulated in ccRCC progression
• Kugler A, et al. 1998. J Urol 160:1914–1918
• Koochekpour S, et al. 1999. Mol Cell Biol 19:5902-5912.
• Petrella et al. 2006. Mol Cancer, 5: 66
• Lu et al. 2012. Experimental and therapeutic medicine 5: 890-896
• Lin et al. 2019. Cancers, 11: 303
• Cortes S, et al. 2018. Methods Mol Biol. 1709:321-329
• Sánchez-Pozo, et al. 2018. iScience. 1:87-96.
• Baker-Williams AJ, et al. 2019. Cell Rep. 28(7):1894-1906
Extracellular
Cytosol
Regulation of MMP2 activity and matrix proteolysis
Extracellular
Cytosol
Regulation of MMP2 activity and matrix proteolysis
eHSP90/MMP2 axis
MMP2 eHSP90
Stability
TIMP2
Inhibitory
Invasion, angiogenesis, metastasis
• Cortes S, et al. 2018. Methods Mol Biol. 1709:321-329
• Sánchez-Pozo, et al. 2018. iScience. 1:87-96.
• Baker-Williams AJ, et al. 2019. Cell Rep. 28(7):1894-1906 Cytosol
Drugs, Abs
Targeting the eHSP90/cAbl axis in ccRCC
• Caki-1 (+/+ VHL)
• 786-O (-/- VHL)
• Tumors from pts with RCC
c-ABL
• Dunn D, et al. 2015. Cell Rep. 12, 1006–1018
HSP90
apoptosis
Drugs
+
MMP2 eHSP90
Stability
Invasion, angiogenesis, metastasis
• Cortes S, et al. 2018. Methods Mol Biol. 1709:321-329
• Sánchez-Pozo, et al. 2018. iScience. 1:87-96.
• Baker-Williams AJ, et al. 2019. Cell Rep. 28(7):1894-1906 Cytosol
c-ABL/eHSP90/MMP2 axis
c-ABL
cAbl/eHSP90/MMP2 signaling in ccRCC
c-Abl is active in ccRCC
cAbl/eHSP90/MMP2 signaling in ccRCC
c-Abl phosphorylates MMP2 Y524
c-Abl is active in ccRCC
cAbl/eHSP90/MMP2 signaling in ccRCC
GNF5 inhibits MMP2 phosphorylation
c-Abl phosphorylates MMP2 Y524
c-Abl is active in ccRCC
Cellular Secreted
cAbl/eHSP90/MMP2 signaling in ccRCCMMP2 pY524 interacts with eHSP90
GNF5 inhibits MMP2 phosphorylation
c-Abl phosphorylates MMP2 Y524
c-Abl is active in ccRCC
Cellular Secreted
Secreted
cAbl/eHSP90/MMP2 signaling in ccRCCMMP2 pY524 interacts with eHSP90
GNF5 inhibits MMP2 phosphorylation
c-Abl phosphorylates MMP2 Y524
c-Abl is active in ccRCC
Cellular Secreted
Secreted
Conclusions
Inhibit extracellular targets
c-Abl/eHSP90/MMP2
Developed extracellular c-Abl
Inhibitors to be used in
Combination with HSP90 drugs
Minimize tumor cell spread
Extracellular
Intracellular
MMP2
Y524
Binding
c-Abl
c-Abl
P
P
Hsp90
Stability
Invasion
Motility/
Wound
healing
MMP2
DrugsDrugs
Significance
Impact
eHsp90
MM
P2
Syracuse UniversityJohn Chisholm
Acknowledgements
Bourboulia LabAlexander J. Baker-WilliamsFiza HashmiStephanie GleicherDerek Friedman
Bratslavsky Lab Gennady BratslavskyBritannia Smith
Mollapour LabMark R. WoodfordSarah BackeAlan MakedonRebecca SagerElham Ahanin
The NCI/NIH
William Stetler-Stevenson
Åbo Akademi University,
Turku, Finland
Lea Sistonen
Department of BMB
Alaji Bah
Department of Urology