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Shoukat Dedhar, PhD

Distinguished Scientist - Genetics Unit, Integrative Oncology

sdedhar@bccrc.ca   Rm 3-110 ▪ 675 West 10th Avenue, Vancouver, B.C., V5Z 1L3, Canada

Dedhar_Noble

Current Appointments:

Distinguished Scientist - Genetics Unit, Integrative Oncology, BC Cancer Research Centre

Professor Biochemistry and Molecular Biology, University of British Columbia


Recent Awards:

Robert L. Noble Prize (2013): Canadian Cancer Society Award of Research Excellence for Outstanding Achievement in Cancer Research Canadian Cancer Society


Research Interests

Major Research areas:

1.      Cell-Extracellular Matrix interactions

2.      Coordination of Integrin and Growth factor Signal Transduction

3.      Physiological and Pathological roles of Integrin-Linked Kinase (ILK)

4.      Mitotic Spindle Organization and Centrosome Clustering

5.      Epithelial to Mesenchymal Transition (EMT) and Wnt Signaling

6.      Models of Metastasis

7.      Genes Regulating Metastatic Potential

8.      Hypoxia and Carbonic Anhydrases IX and XII as Therapeutic Targets

9.      Cancer cell Metabolism and Tumor Microenvironment

Key discoveries have been the identification of Integrin-mediated signaling pathways leading to regulation of cell proliferation, survival and migration. The discovery of Integrin-Linked Kinase (ILK) in 1996 in the Dedhar laboratory has demonstrated how integrin receptors on different types of cells coordinate signals to regulate cellular homeostasis. ILK is required for embryonic development, for the formation of blood vessels and for cardiac function. It is also essential for the regulation of the proper development of neurons as well as the function of other cell types such as chondrocytes, smooth muscle cells, skin cells and hair follicle cells.

ILK was found to induce oncogenic transformation of epithelial cells and subsequently has been shown to be expressed at abnormally high levels in many types of human cancers. In many cases the amount of ILK protein in cells predicts for long term patient survival, i.e. the higher the amount, the worse the prognosis, suggesting that ILK contributes to the disease process and to therapeutic resistance.

ILK activation promotes the survival and growth of tumor cells and also promotes the HIF-1 and VEGF mediated angiogenesis

Recent work using sophisticated Proteomics technology has revealed that ILK localizes to the centrosome, in addition of focal adhesions where integrins are present. In the centrosome ILK controls the assembly of the mitotic spindle during cell division. It also regulates the clustering of supernumerary centrosomes that exist in many cancer cells. The clustering of centrosomes in cancer cells allows them to survive and divide normally. Blocking the function of ILK in centrosomes in such cancer cells results in centrosome “declustering” and cell death. Therefore blocking ILK can induce the death of cancer cells but not of normal cells which o not require centrosome clustering.

 

ILK is a Cancer Therapeutic Target.

Inhibition of ILK activity suppresses tumor growth and progression to metastasis, and compounds that inhibit ILK activity are under development. Inhibitors developed so far appear to selectively kill tumor cells relative to “normal” counterparts. Collaborative research has shown that ILK inhibitors could be used therapeutically for breast cancer, prostate cancer, pancreatic cancer, colon cancer, non small cell lung cancer, malignant melanoma, glioblastoma, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML)

 

Models of Cancer Metastasis, Hypoxia and Carbonic Anhydrases IX and XII

Patient mortality results from the formation of metastases in distant (vital) organs. The metastatic potential of primary tumors is variable and likely depends of the biology of the tumor. We have established mouse models to study metastasis. Our initial work with breast cancer models of metastasis has identified a gene signature that is unique to metastatic tumors. Many of the genes are induced by “hypoxia” and function to protect the cells and promote survival in a hypoxic environment. Two of the genes CAIX and CAXII regulate the pH of the cells in hypoxia, and we have discovered that blocking the function of CAIX results in the death of the metastatic cells in a hypoxic environment, and in tumor regression as well as formation of metastasis.

Examination of the expression of CAIX in about 4000 breast cancer samples demonstrated that CAIX expression predicts for poor patient prognosis as well as for the formation of distant metastasis. Current work is focused on determining how CAIX controls the survival of hypoxic tumor cells and why it is needed for the formation of metastases. We are also developing compounds that could be used therapeutically to block CAIX function and also to image CAIX and identify hypoxic and potentially metastatic tumors.

An excellent summary of work on this topic by the Dedhar lab can be found here (links to PDF).

 

Dedhar Laboratory:

Paul McDonald; Research Scientist

Shawn Chafe; Research Associate 

Jordan Gillespie; Research Tech

Oksana Nemirovsky, Research Assistant

Shannon Awrey, Research Assistant

Ashley Westerback, Research Assistant

Edward Morris; Post doc

Mridula Swayampakula; Post doc

Wells Brown; Post doc

Geetha Venkateswaran, Graduate Student

Jennifer Nagel, Graduate Student

 

Dedhar Lab

Recent Members:

Andrew Fielding, PhD:  Post-Doctoral Fellow

Frances Lock, PhD: Post-Doctoral Fellow

Isabella Serano, PhD: Post-Doctoral Fellow

Mikola Maydan, PhD: Post-Doctoral Fellow

Jamie Lim, BSc: Graduate Student

Daiana Becker dos Santos, BSc: Graduate Student

Timothy McPhee, BSc: PhD student

Maria Lourdes, BSc: PhD student

Manuel Diego Puyol, PhD: Visiting Professor, Professor of Medicine, University of Alcala, Spain

Arusha Oloumi, PhD: Post-Doctoral Fellow

Iveta Dobreva, PhD: Post-Doctoral Fellow

Virginia Gray, MSc: Research Technician

Marylou Vallejo Espi (Maria de Lourdes); Grad Student

Yuanmei Lou; Research Scientist

Eva-Maria Hedlund; visiting Post Doc

Eiko Kawamura; Post doc

 

 


Recent Research Funding:

Canadian Institute For Health Research (CIHR) Foundation Scheme, The Role of Tumor Microenvironment in Cancer Progression: Identification and Therapeutic Intervention of Novel Targets. 2015-2022; $4,164,493

Canadian Cancer Society Research Institute (CCSRI), New therapeautic strategy targeting tumour hypoxia and carbonic anhydrase IX for the treatment of pancreatic cancer. 2015-2020; $1,248,667

Canadian Institute For Health Research (CIHR), Development of therapeutic antibodies targeting Carbonic Anhydrase IX: 2014-2018; $609,976

Canadian Cancer Society Research Institute (CCSRI), Identification and development of novel anti-cancer agents targeting centrosome clustering in cancer cell: 2014-2016; $186,224

Pancreas Centre BC/BC Cancer Foundation/VGH Foundation, Evaluation of tumor hypoxia and therapeutic targeting of Carbonic Anhydrase IX and Integrin-linked kinase (ILK) in pancreatic cancer: 2013-2015; $94,620

BC Cancer Foundation, Evaluation of tumor hypoxia and therepeutic targeting of Carbonic Anhydrase IX/XII in pancreatic cancer: 2013-2014; $20,000

Canadian Cancer Society Research Institute (CCSRI), Cell-Extracellular Matrix Interactions in Differentiation and Oncogenesis: 2008-2013; $682,500

Canadian cancer Society Research Institute (CCSRI), Targeting stem cells to improve treatment of chronic myeloid leukemia: 2010-2013; $414,000. Co-Applicant. PI Dr Xiaoyan Jiang

Canadian Institutes for Health Research (CIHR), Regulation of Wnt signaling and Epithelial-Mesenchymal Transition by Integrin-Linked Kinase: 2007-2012; $645,000

Canadian Institutes for Health research (CIHR), Role of Integrin Linked Kinase in Mitotic spindle assembly and centrosome clustering in cancer cells. 2009-2014; $675,000

Canadian Institutes for Health research (CIHR), Targgeting carbonic anhydrase IX for the diagnosis and treatment of aggressive breast cancer; 2010-2015; $926,275

Terry Fox Foundation Program Project, Role of Integrin Linked Kinase in Prostate cancer progression; 2006-2011; $770,000

Canadian Breast Cancer Research Alliance (CBCRA), Models for the identification of novel molecular targets for organ specific metastasis of breast cancer; 2005-2010; $ 3,364,710

 

Publications (Most Recent 5 Years, 208 Career total):

  1. McDonald PC, Swayampakula M, Dedhar S.  Coordinated regulation of metabolic transporters and Migration/Invasion by Carbonic Anhydrase IX.  Metabolites.  2018 Mar 8;8(1)
  2. Boyd,N H, Walker, K, Fried,J, Hackney, JR, McDonald, PC, Benavides, GA, Spina, R, Audia,A, Scott, SE, Libby, CJ, Tran, AN, Bevensee, MO, Criguer, C, Nozell, S, Gillespie,GY, Nabors,B, Bhat,KP, Bar,EE, Darley-Usmar,V, Xu,B, Gordon,E, Cooper,SJ, Dedhar,S, Hjelmeland,AB, JCI Insight, 92928, Dec 21 2017
  3. Yoon, S-O, Shin,S, Karreth,FA, Jedrychowski,MP, Dedhar,S, Gygi,N, Dephoure,N and Blenis,J. Focal adhesion=and IGF1R-dependent survival and migratory pathways mediate tumor resistance to mTORC1/2 inhibition.  Molecular Cell, 67, 512-527, 2017
  4. Morris, EJ and Dedhar, S. Stat3 in Mitosis: A New Role in Clustering Excess Centrosomes. Cell Cycle, 16, 1557-1559, 2017
  5. Swayampakula, M, McDonald PC, Vallejo,M, Coyaud, E,  Schafe, SC, Westerback,A, Venkateswaran,G, Shankar, J, Laurent,EMN,  Lou, Y, Bennewith,KL, Supuran, CT,  Nabi, R, Raught B, and  Dedhar, S.  The Interactome of metabolic enzyme Carbonic Anhydrase IX reveals novel roles in tumot migration and invadopodia/MMP-14-mediated invasion. Oncogene, 36, 6244-6261, 2017
  6. Morris, E,J,  Kawamura,E, Gillespie,J, Bagli,  Kannan,N, Muller, W,J, Roberge,M and Dedhar,S. Stat3 regulates supernumerary centrosome clustering in cancer cells via Stathmin/PLK1. Nature Communications, 8, 15289, 2017
  7. El Kharbili,M, Robert,C, Witkowski,T, Danty-Berger,E, Barbollat-Boutrand,L, Masse,I, Gadot,N, de La Fourchardiere,A, McDonald,PC, Dedhar,S, Le Naour,F, Degoul, F, Berthier-Vegnes,O. Tetraspanin 8 is a novel regulator of ILK-driven beta1 integrin adhesion and signaling in invasive melanoma cells. Oncotarget, 8, 17140-17155, 2017
  8. Al-Ghabkari,A, Deng,JT, McDonald,PC, Dedhar,S, Alsheri,M, Walsh,MP, MacDonald,JA. A novel inhibitor effect of oxazol-5-one compounds on ROCKII signaling in human coronary artery vascular smooth muscle cells. Sci Rep. 2016, 3: 32118
  9. McDomald, PC, Chafe,SC, Dedhar,S. Overcoming Hypoxia-mediated tumor progression: Combinatorial approaches targeting pH rehulation, angiogenesis and immune dysfunction. Front Cell Dev Biol, 2016, 4, 27
  10. Paolicchi, E, Gemignani,F, Krstic-Demonacos, Dedhar,S, Mutti,L, and Landi,S. Targeting hypoxic response for cancer therapy. Oncotarget, 2016, 7, 13464-13478
  11. 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.
  12. Shvab A, Haase G, Ben-Shmuel A, Gavert N, Brabletz T, Dedhar S, Ben-Ze'ev A. Induction of the intestinal stem cell signature gene SMOC-2 is required for L1-mediated colon cancer progression. Oncogene. 2016, 35, 549-557
  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.
  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. 75(6):996-1008, 2015
  15. Cano-Penalver,J,Griera, Serrano I, Rodriguez-Puyol,D, Dedhar,S, de Frutos,S, Rodriguez-Puyol,M. Integrin-Linked Kinase regulkates tubular aquaporin-2 content and intracellular localization in vivo and in vitro: a link between extracellular matrix and water reabsorption. FASEB J. 28, 3654-3659, 2014
  16. Peng,H, Farrooji,MTZ, 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, Corolin,AS, Speicher,DW, Skordalakes,E, Huang,Q, Dedhar, S, Borden,KLB, Rauscher,III, FJ. LIMD2 is a small LIM-only protein overexpressed in metastatic lesions which regulates cell motility and tumor progression by directly binding to and activating integrin-linked kinase. Cancer Res. 74, 1390-1402, 2014
  17. Teo ZL, McQueen-Miscamble L, Turner K, Martinez G, Madakashira B, Dedhar S, Robinson ML, de Iongh RU. Integrin linked kinase (ILK) is required for lens epithelial cell survival, proliferation and differentiation. Exp Eye Res. 121C, 130-142, 2014
  18. Serrano,I, McDonald,PC, Lock,F, Muller,W, and Dedhar, S. Inactivation of the Hippo tumor suppressor pathway by Integrin-Linked Kinase (ILK)  Nature Communications. 4, 2976, 2013
  19. Dai J, Matsui T, Abel ED, Dedhar S, Gerszten RE, Seidman CE, Seidman JG, Rosenzweig A.DSAGE Identifies Osteopontin as a Downstream Effector of Integrin-Linked Kinase (ILK) in Cardiac-Specific ILK Knockout Mice. Circ Heart Fail. 7, 184-193, 2014
  20. McDonald PC, Dedhar S.Carbonic Anhydrase IX (CAIX) as a Mediator of Hypoxia-Induced Stress Response in Cancer Cells. Subcell Biochem. 75:255-69, 2014
  21. El-Hoss J, Arabian A, Dedhar S, St-Arnaud R. Inactivation of the Integrin-Linked Kinase (ILK) in osteoblasts increases mineralization. Gene.533, 246-252, 2014.
  22. Kawamura E, Fielding AB, Kannan N, Balgi A, Eaves CJ, Roberge Michel, Dedhar, S. Identification of novel small molecule inhibitors of centrosome clustering in cancer cells. Oncotarget.4, 1763-1776, 2013
  23. Barakat B, Liang Y, De Luca E, Lo C, Cain J, Martelotto L, Dedhar S, Wang D, Sadler A, Vu D, Watkins D and Hannigan GE. Interaction of Smoothened with Integrin-Linked Kinase in the primary cilium mediates Hedgehog signaling. EMBO Rep., 14, 837-844, 2013
  24. Serrano I, Frutos S, Griera M, Mediano D, Rodriguez-Puyol M, Dedhar S, Ruiz-Torres MP, and Rodriguez-Puyol D. ILK conditional deletion in adult animals increases cyclic GMP-dependent vasorelaxation. Cardiovasc. Res. 99, 535-544, 2013
  25. Pan J, Pourghiasian W, Hundai N, lau J, Benard F, Dedhar S and Lin KS. 2-[18-F] fluoroethanol and 3[18-F]fluoropropanol: facile preparation, biodistribution in mice and application as nucleophiles in the synthesis of [18F] fluoroalkyl ester and ether PET tracers. Nucl.Med. Biol. E.Pub June 13 2013
  26. Pan J, lau J, Mesah F, Hundai N, Pourghiasian W, Liu Z, Benard F, Dedhar S, Supuran CT, Lin KS. Synthesis and evaluation of F18-labeled carbonic anhydrase inhibitors for imaging with positron emission tomography. J Enzyme Inhib.Med. Chem. E Pub, March 7th 2013
  27. Lim S, Kawamura E, Fielding AB, Maydan M, and Dedhar S. Integrin-Linked Kinase regulates interphase and mitotic microtubule dynamics. PLoS One. 8, e57702, 2013
  28. Lock FE, McDonald PC, Lou Y, Serrano I, Chafe SC, Ostlund C, Aparicio S, Winum JY, Supuran CT, and Dedhar S. Targeting Carbonic Anhydrase IX depletes breast cancer stem cells within the hypoxic niche. Oncogene, 32, 5210-5219, 2013