Dedhar, Shoukat

The cells of the various tissues and organs of the body are in intimate contact with an extracellular matrix (ECM). This matrix, which consists of glycoproteins, proteoglycans and carbohydrates, is synthesized either by the very cells which interact with it, or by other cell types in close proximity. The epithelial cells interact with a highly organized ECM called the basement membrane which consists of laminin, entactin, collagen type IV and proteoglycans. The ECM surrounding cells of the mesenchyme (stroma), e.g. fibroblasts and muscle cells, consists of fibronectin, various types of collagens and proteoglycans.

The components of the ECM provide specific cellular growth and differentiation signals to the cells as well as providing substrates for cell migration. The interaction of cells with these ECM components occurs via a family of integral plasma membrane receptors called integrins. These are heterodimeric glycoproteins composed of one alpha and one beta subunit which non-covalently associate with each other. Both subunits span the plasma membranes and have cytoplasmic tails which interact with intracellular proteins which include components of the actin cytoskeleton and calcium binding proteins.

Dr. Dedhar’s laboratory is investigating the interaction of the integrin subunits with intracellular proteins and the mechanism of signal transduction mediated by these receptors. Members of the laboratory have recently obtained evidence for the interaction of a 60 kilodalton calcium binding protein with a highly conserved amino acid sequence found in the cytoplasmic domain of all integrin alpha subunits. This protein, also called calreticulin, is essential for integrin function since integrins in calreticulin “knock out” cells fail to interact with their ligands. Calreticulin may also be involved in transducing signals to the nucleus where it may influence gene expression by binding to nuclear transcription factors such as steroid receptors. Evidence has also been obtained in the laboratory for the interaction of a novel serine/threonine protein kinase (ILK) with the cytoplasmic domain of the integrin beta1 subunit. Overexpression of this kinase in epithelial cells induced anchorage-independent growth and tumorigenicity. ILK regulates adhesion dependent cell cycle progression as well as epithelial-mesenchymal transformation. Elevated expression of, or mutations in, this kinase may be crucial in transformation.

Besides a kinase domain, ILK also contains 4 ankyrin-like repeats at its N-terminus, and a pleckstrin-homology (PH)-like domain in between the ankyrin-repeats and the kinase domain. This PH domain contains a phosphatidylinositol lipid binding motif, highly homologous to other such motifs found in PH domains. ILK kinase activity is stimulated by phosphotidyl inositol 3, 4, 5 trisphosphate. We now know that ILK activity is regulated by integrins and growth factor receptors via phosphoinositide 3-OH kinase. ILK then couples this kinase to downstream effector molecules such as GSK-3 and PKB, resulting in the regulation of diverse phenotypic effects such as cell survival and proliferation, gene expression, and cell differentiation.

Tumor hypoxia, pH regulation and Carbonic Anhydrases IX/XII

The Dedhar lab has identified Carbonic Anhydrases IX and XII ( CAIX/XII) as major therapeutic targets for the treatment of Solid tumors with significant hypoxic regions. CAIX/XII play major roles in tumor cell invasion and in metastasis through localization within Invadopodia  where CAIX “activates” the matrix metalloprotease MMP-14.  The Dedhar lab has developed potent and specific inhibitors of CAIX/XII, and demonstrated significant efficacy of these compounds in the treatment of breast, pancreatic and melanoma cancers in pre-clinical models.

Phase 1/2 clinical trials are currently being carried out in Vancouver and Toronto:  ClinialTrials.Gov:  NCT02215850; Clinical Trials.Gov: NCT03450018

Comprehensive List

• PubMed

Selected Publications

1. Chafe SC, McDonald PC, Saberi S, Nemirovsky O, Venkateswaran G, Burugu S, Gao D, Delaidelli A, Kyle AH, Baker JHE, Gillespie JA, Bashashati A, Minchinton AI, Zhou Y, Shah SP, Dedhar S. Targeting Hypoxia-Induced Carbonic Anhydrase IX Enhances Immune-Checkpoint Blockade Locally and Systemically. Cancer Immunol Res. 2019 Jul;7(7):1064-1078. doi: 10.1158/2326-6066.CIR-18-0657. Epub 2019 May 14. PubMed PMID: 31088846.
2. McDonald PC, Chafe SC, Brown WS, Saberi S, Swayampakula M, Venkateswaran G, Nemirovsky O, Gillespie JA, Karasinska JM, Kalloger SE, Supuran CT, Schaeffer DF, Bashashati A, Shah SP, Topham JT, Yapp DT, Li J, Renouf DJ, Stanger BZ, Dedhar S. Regulation of pH by Carbonic Anhydrase 9 Mediates Survival of Pancreatic Cancer Cells With Activated KRAS in Response to Hypoxia. Gastroenterology. 2019 May 9. pii: S0016-5085(19)40862-7. doi: 10.1053/j.gastro.2019.05.004. [Epub ahead of print] PubMed PMID: 31078621.
3. Bozdag M, Carta F, Ceruso M, Ferraroni M, McDonald PC, Dedhar S, Supuran CT. Discovery of 4-Hydroxy-3-(3-(phenylureido)benzenesulfonamides as SLC-0111 Analogues for the Treatment of Hypoxic Tumors Overexpressing Carbonic Anhydrase IX. J Med Chem. 2018 Jul 26;61(14):6328-6338. doi: 10.1021/acs.jmedchem.8b00770. Epub 2018 Jul 17. PubMed PMID: 29962205.
4. McDonald PC, Swayampakula M, Dedhar S. Coordinated Regulation of Metabolic Transporters and Migration/Invasion by Carbonic Anhydrase IX. Metabolites. 2018 Mar 8;8(1). pii: E20. doi: 10.3390/metabo8010020. Review. PubMed PMID: 29517989; PubMed Central PMCID: PMC5876009.
5. Boyd NH, Walker K, Fried J, Hackney JR, McDonald PC, Benavides GA, Spina R, Audia A, Scott SE, Libby CJ, Tran AN, Bevensee MO, Griguer C, Nozell S, Gillespie GY, Nabors B, Bhat KP, Bar EE, Darley-Usmar V, Xu B, Gordon E, Cooper SJ, Dedhar S, Hjelmeland AB. Addition of carbonic anhydrase 9 inhibitor SLC-0111 to temozolomide treatment delays glioblastoma growth in vivo. JCI Insight. 2017 Dec 21;2(24). pii: 92928. doi: 10.1172/jci.insight.92928. PubMed PMID: 29263302; PubMed Central PMCID: PMC5752277.
6. Morris EJ, Dedhar S. Stat3 in mitosis: A new role in clustering excess centrosomes. Cell Cycle. 2017;16(17):1557-1559. doi: 10.1080/15384101.2017.1348064. Epub 2017 Aug 7. PubMed PMID: 28783441; PubMed Central PMCID: PMC5587029.
7. Yoon SO, Shin S, Karreth FA, Buel GR, Jedrychowski MP, Plas DR, Dedhar S, Gygi SP, Roux PP, Dephoure N, Blenis J. Focal Adhesion- and IGF1R-Dependent Survival and Migratory Pathways Mediate Tumor Resistance to mTORC1/2 Inhibition. Mol Cell. 2017 Aug 3;67(3):512-527.e4. doi: 10.1016/j.molcel.2017.06.033. Epub 2017 Jul 27. PubMed PMID: 28757207; PubMed Central PMCID: PMC5698809.
8. Swayampakula M, McDonald PC, Vallejo M, Coyaud E, Chafe SC, Westerback A, Venkateswaran G, Shankar J, Gao G, Laurent EMN, Lou Y, Bennewith KL, Supuran CT, Nabi IR, Raught B, Dedhar S. The interactome of metabolic enzyme carbonic anhydrase IX reveals novel roles in tumor cell migration and invadopodia/MMP14-mediated invasion. Oncogene. 2017 Nov 9;36(45):6244-6261. doi: 10.1038/onc.2017.219. Epub 2017 Jul 10. PubMed PMID: 28692057; PubMed Central PMCID: PMC5684442.
9. Morris EJ, Kawamura E, Gillespie JA, Balgi A, Kannan N, Muller WJ, Roberge M, Dedhar S. Stat3 regulates centrosome clustering in cancer cells via Stathmin/PLK1. Nat Commun. 2017 May 5;8:15289. doi: 10.1038/ncomms15289. PubMed PMID: 28474672; PubMed Central PMCID: PMC5424153.
10. McDonald PC, Chafe SC, Dedhar S. Overcoming Hypoxia-Mediated Tumor Progression: Combinatorial Approaches Targeting pH Regulation, Angiogenesis and Immune Dysfunction. Front Cell Dev Biol. 2016 Mar 31;4:27. doi: 10.3389/fcell.2016.00027. eCollection 2016. Review. PubMed PMID: 27066484; PubMed Central PMCID: PMC4814851.
11. Al-Ghabkari A, Deng JT, McDonald PC, Dedhar S, Alshehri M, Walsh MP, MacDonald JA. A novel inhibitory effect of oxazol-5-one compounds on ROCKII signaling in human coronary artery vascular smooth muscle cells. Sci Rep. 2016 Aug 30;6:32118. doi: 10.1038/srep32118. PubMed PMID: 27573465; PubMed Central PMCID: PMC5004178.
12. Chafe SC, Dedhar S. Carving out its niche: A role for carbonic anhydrase IX in pre metastatic niche development. Oncoimmunology. 2015 Jun 26;4(12):e1048955. eCollection 2015 Dec. PubMed PMID: 26587316; PubMed Central PMCID: PMC4635843.
13. Morris EJ, Assi K, Salh B, Dedhar S. Integrin-linked kinase links dynactin-1/dynactin-2 with cortical integrin receptors to orient the mitotic spindle relative to the substratum. Sci Rep. 2015 Feb 11;5:8389. doi: 10.1038/srep08389. PubMed PMID: 25669897; PubMed Central PMCID: PMC4323648.
14. Chafe SC, Lou Y, Sceneay J, Vallejo M, Hamilton MJ, McDonald PC, Bennewith KL, Möller A, Dedhar S. Carbonic anhydrase IX promotes myeloid-derived suppressor cell mobilization and establishment of a metastatic niche by stimulating G-CSF production. Cancer Res. 2015 Mar 15;75(6):996-1008. doi: 10.1158/0008-5472.CAN-14-3000. Epub 2015 Jan 26. PubMed PMID: 25623234.
15. Peng H, Talebzadeh-Farrooji M, Osborne MJ, Prokop JW, McDonald PC, Karar J, Hou Z, He M, Kebebew E, Orntoft T, Herlyn M, Caton AJ, Fredericks W, Malkowicz B, Paterno CS, Carolin AS, Speicher DW, Skordalakes E, Huang Q, Dedhar S, Borden KL, Rauscher FJ 3rd. LIMD2 is a small LIM-only protein overexpressed in metastatic lesions that regulates cell motility and tumor progression by directly binding to and activating the integrin-linked kinase.  Cancer Res. 2014 Mar 1;74(5):1390-403. doi: 10.1158/0008-5472.CAN-13-1275. PubMed PMID: 24590809; PubMed Central PMCID:  PMC4183205.
16. Serrano I, McDonald PC, Lock F, Muller WJ, Dedhar S. Inactivation of the Hippo tumour suppressor pathway by integrin-linked kinase. Nat Commun. 2013;4:2976. doi: 10.1038/ncomms3976. PubMed PMID: 24356468; PubMed Central PMCID: PMC3905719.
17. McDonald PC, Dedhar S. Carbonic anhydrase IX (CAIX) as a mediator of hypoxia-induced stress response in cancer cells. Subcell Biochem. 2014;75:255-69. doi: 10.1007/978-94-007-7359-2_13. Review. PubMed PMID: 24146383.
18. Kawamura E, Fielding AB, Kannan N, Balgi A, Eaves CJ, Roberge M, Dedhar S. Identification of novel small molecule inhibitors of centrosome clustering in cancer cells. Oncotarget. 2013 Oct;4(10):1763-76. PubMed PMID: 24091544; PubMed Central PMCID: PMC3858562.
19. Lim S, Kawamura E, Fielding AB, Maydan M, Dedhar S. Integrin-linked kinase regulates interphase and mitotic microtubule dynamics. PLoS One. 2013;8(1):e53702. doi: 10.1371/journal.pone.0053702. Epub 2013 Jan 21. PubMed PMID: 23349730; PubMed Central PMCID: PMC3549953.
20. Lock FE, McDonald PC, Lou Y, Serrano I, Chafe SC, Ostlund C, Aparicio S, Winum JY, Supuran CT, Dedhar S. Targeting carbonic anhydrase IX depletes breast cancer  stem cells within the hypoxic niche. Oncogene. 2013 Oct 31;32(44):5210-9. doi: 10.1038/onc.2012.550. Epub 2012 Dec 3. PubMed PMID: 23208505.
21. Serrano I, McDonald PC, Lock FE, Dedhar S. Role of the integrin-linked kinase (ILK)/Rictor complex in TGFβ-1-induced epithelial-mesenchymal transition (EMT). Oncogene. 2012 Feb 6. doi: 10.1038/onc.2012.30. [Epub ahead of print] PubMed PMID: 22310280.
22. Becker-Santos DD, Guo Y, Ghaffari M, Vickers ED, Lehman M, Altamirano-Dimas M, Oloumi A, Furukawa J, Sharma M, Wang Y, Dedhar S, Cox ME. Integrin-linked kinase as a target for ERG-mediated invasive properties in prostate cancer models. Carcinogenesis. 2012 Oct 10. [Epub ahead of print] PubMed PMID: 23027626.
23. Lou Y, McDonald PC, Oloumi A, Chia S, Ostlund C, Ahmadi A, Kyle A, Auf dem Keller U, Leung S, Huntsman D, Clarke B, Sutherland BW, Waterhouse D, Bally M, Roskelley C, Overall CM, Minchinton A, Pacchiano F, Carta F, Scozzafava A, Touisni N, Winum JY, Supuran CT, Dedhar S. Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors. Cancer Res. 2011 May 1;71(9):3364-76. Epub 2011 Mar 17. Erratum in: Cancer Res. 2011 Jun 15;71(12):4325. Cancer Res. 2011 Jul 1;71(13):4733. PubMed PMID: 21415165.
24. McDonald PC, Winum JY, Supuran CT, Dedhar S. Recent developments in targeting carbonic anhydrase IX for cancer therapeutics. Oncotarget. 2012 Jan;3(1):84-97. Review. PubMed PMID: 22289741; PubMed Central PMCID: PMC3292895.
25. Touisni N, Maresca A, McDonald PC, Lou Y, Scozzafava A, Dedhar S, Winum JY, Supuran CT. Glycosyl coumarin carbonic anhydrase IX and XII inhibitors strongly attenuate the growth of primary breast tumors. J Med Chem. 2011 Dec 22;54(24):8271-7. Epub 2011 Nov 22. PubMed PMID: 22077347.
26. Pacchiano F, Carta F, McDonald PC, Lou Y, Vullo D, Scozzafava A, Dedhar S, Supuran CT. Ureido-substituted benzenesulfonamides potently inhibit carbonic anhydrase IX and show antimetastatic activity in a model of breast cancer metastasis. J Med Chem. 2011 Mar 24;54(6):1896-902. Epub 2011 Mar 1. PubMed PMID: 21361354.
27. Fielding AB, Lim S, Montgomery K, Dobreva I, Dedhar S. A critical role of integrin-linked kinase, ch-TOG and TACC3 in centrosome clustering in cancer cells. Oncogene. 2011 Feb 3;30(5):521-34. Epub 2010 Sep 13. PubMed PMID: 20838383.
28. Maydan M, McDonald PC, Sanghera J, Yan J, Rallis C, Pinchin S, Hannigan GE, Foster LJ, Ish-Horowicz D, Walsh MP, Dedhar S. Integrin-linked kinase is a functional Mn2+-dependent protein kinase that regulates glycogen synthase kinase-3β (GSK-3beta) phosphorylation. PLoS One. 2010 Aug 23;5(8):e12356. PubMed PMID: 20827300; PubMed Central PMCID: PMC2932980.
29. Oloumi A, Maidan M, Lock FE, Tearle H, McKinney S, Muller WJ, Aparicio SA, Dedhar S. Cooperative signaling between Wnt1 and integrin-linked kinase induces accelerated breast tumor development. Breast Cancer Res. 2010;12(3):R38. Epub 2010 Jun 21. PubMed PMID: 20565980; PubMed Central PMCID: PMC2917033.
30. McDonald PC, Fielding AB, Dedhar S. Integrin-linked kinase–essential roles in physiology and cancer biology. J Cell Sci. 2008 Oct 1;121(Pt 19):3121-32. Review. PubMed PMID: 18799788.
31. Lou Y, Preobrazhenska O, auf dem Keller U, Sutcliffe M, Barclay L, McDonald PC, Roskelley C, Overall CM, Dedhar S. Epithelial-mesenchymal transition (EMT) is not sufficient for spontaneous murine breast cancer metastasis. Dev Dyn. 2008 Oct;237(10):2755-68. PubMed PMID: 18773493.
32. McPhee TR, McDonald PC, Oloumi A, Dedhar S. Integrin-linked kinase regulates E-cadherin expression through PARP-1. Dev Dyn.2008 Oct;237(10):2737-47. PubMed PMID: 18773488.
33. McDonald PC, Oloumi A, Mills J, Dobreva I, Maidan M, Gray V, Wederell ED, Bally MB, Foster LJ, Dedhar S. Rictor and integrin-linked kinase interact and regulate Akt phosphorylation and cancer cell survival. Cancer Res. 2008 Mar 15;68(6):1618-24. PubMed PMID: 18339839.
34. Dobreva I, Fielding A, Foster LJ, Dedhar S. Mapping the integrin-linked kinase interactome using SILAC. J Proteome Res. 2008 Apr;7(4):1740-9. Epub 2008 Mar 10. PubMed PMID: 18327965.
35. Fielding AB, Dobreva I, McDonald PC, Foster LJ, Dedhar S. Integrin-linked kinase localizes to the centrosome and regulates mitotic spindle organization. J Cell Biol. 2008 Feb 25;180(4):681-9. Epub 2008 Feb 18. PubMed PMID: 18283114; PubMed Central PMCID: PMC2265580.
36. Assi K, Mills J, Owen D, Ong C, St Arnaud R, Dedhar S, Salh B. Integrin-linked kinase regulates cell proliferation and tumour growth in murine colitis-associated carcinogenesis. Gut. 2008 Jul;57(7):931-40. Epub 2008 Mar 7.3 PubMed PMID: 18326560.
37. White DE, Coutu P, Shi YF, Tardif JC, Nattel S, St Arnaud R, Dedhar S, Muller WJ. Targeted ablation of ILK from the murine heart results in dilated cardiomyopathy and spontaneous heart failure. Genes Dev. 2006 Sep 1;20(17):2355-60. PubMed PMID: 16951252; PubMed Central PMCID: PMC1560410.
38. Lee JM, Dedhar S, Kalluri R, Thompson EW. The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol. 2006 Mar 27;172(7):973-81. Review. PubMed PMID: 16567498; PubMed Central PMCID: PMC2063755.
39. Mills J, Niewmierzycka A, Oloumi A, Rico B, St-Arnaud R, Mackenzie IR, Mawji NM, Wilson J, Reichardt LF, Dedhar S. Critical role of integrin-linked kinase in granule cell precursor proliferation and cerebellar development. J Neurosci. 2006 Jan 18;26(3):830-40. PubMed PMID: 16421303; PubMed Central PMCID: PMC2757417.
40. Troussard AA, McDonald PC, Wederell ED, Mawji NM, Filipenko NR, Gelmon KA, Kucab JE, Dunn SE, Emerman JT, Bally MB, Dedhar S. Preferential dependence of breast cancer cells versus normal cells on integrin-linked kinase for protein kinase B/Akt activation and cell survival. Cancer Res. 2006 Jan 1;66(1):393-403. PubMed PMID: 16397254.
41. Filipenko NR, Attwell S, Roskelley C, Dedhar S. Integrin-linked kinase activity regulates Rac- and Cdc42-mediated actin cytoskeleton reorganization via alpha-PIX. Oncogene. 2005 Sep 1;24(38):5837-49. PubMed PMID: 15897874.
42. Hannigan GE, Coles JG, Dedhar S. Integrin-linked kinase at the heart of cardiac contractility, repair, and disease. Circ Res. 2007 May 25;100(10):1408-14. Review. PubMed PMID: 17525380.
43. Oloumi A, Syam S, Dedhar S. Modulation of Wnt3a-mediated nuclear beta-catenin accumulation and activation by integrin-linked kinase in mammalian cells. Oncogene. 2006 Dec 14;25(59):7747-57. Epub 2006 Jun 26. PubMed PMID: 16799642.
44. Zhou FQ, Zhou J, Dedhar S, Wu YH, Snider WD. NGF-induced axon growth is mediated by localized inactivation of GSK-3beta and functions of the microtubule plus end binding protein APC. Neuron. 2004 Jun 24;42(6):897-912. PubMed PMID:15207235.