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David Brindley

Brindley70.jpg 

Professor
Ph.D, D.Sc., University of Birmingham
Department of Biochemistry
Faculty of Medicine & Dentistry
University of Alberta
357 Heritage Medical Research Center
Edmonton, Alberta, Canada  T6G 2S2

Tel: 780.492.2078
Lab Tel: 780.492.4613
Fax:  780.492.3383
david.brindley@ualberta.ca

 
Research:

Our work focuses on understanding how changes in signal transduction processes lead to increased progression of tumours, their spread (metastasis) and the development of resistance to chemotherapy and radiotherapy.  These are some of the most outstanding problems in successfully treating most types of cancer.  
Our group focuses on messengers, which are produced by agonists that activate cell surface receptors. For example, we have a major interest in the enzyme, autotaxin, which is an important component in wound healing.  This is because autotaxin produces a bioactive compound called lysophosphatidate (LPA), which activates six G-protein coupled receptors. These receptors stimulate the migration, proliferation and survival of cells in the wounded area and they increase the development of a new blood supply1.  These functions of autotaxin and LPA are hijacked by tumours, which are likened to “wounds that do not heal”.  We showed that LPA signalling is part of a vicious cycle of inflammation in cancer in which LPA stimulus the production of at least 20 inflammatory cytokines and chemokines2-4.  These inflammatory mediators stimulate further autotaxin secretion and perpetuate the vicious cycle. This inflammatory milieu stimulates the tumour growth and metastasis.
We also discovered that LPA increases resistance to cancer treatment by decreasing the effectiveness of various chemotherapeutic agents (Taxol, doxorubicin, tamoxifen), which normally kill cancer cells. This is partly explained since we showed that LPA increases the stability of the transcription factor, Nrf25. This activates the anti-oxidant response element, which increases the expression of proteins that protect cancer cells from oxidative damage caused chemotherapeutic agents. In addition, Nrf2 increase the transcription of the multidrug resistance proteins, which export both toxic oxidation products and chemotherapeutic drugs from cancer cells5.
Our work concentrates on blocking the autotaxin-LPA-inflammatory axis as a new strategy to improve cancer treatment. Most of our work so far has been with a long acting autotaxin inhibitor, which decreases LPA production and signalling. It also has a potent anti-inflammatory effect. Autotaxin inhibition decreases tumor growth, metastasis and it synergistic improves the efficacy of doxorubicin treatment5,6.
 Another part of our work focuses on a family of three lipid phosphate phosphatases (LPPs), which destroy extracellular LPA and block its effects on cell signalling.  Expressions of LPP1 and LPP3 are decreased in many cancer cells and this amplifies the effects of LPA. We showed that restoring the low activity of LPP1 in cancer cells decreases tumour growth and metastasis by about 80%.  Conversely, the activity of LPP2 is increased in cancer cells and this is part of the transformed phenotype. Our work is now directed to devising strategies for increasing the expression of LPP1 and LPP3 relative to LPP2 as a new paradigm for blocking tumour growth and metastasis. 
Our research group is integrated with that of Dr. Todd McMullen who is an Endocrine Surgeon in the Department of Surgery at the University of Alberta. We are now working jointly to translate our work on blocking the autotaxin-LPA-inflammatory axis into clinical practice as a new paradigm to improve the effectiveness of chemotherapy and radiotherapy. 
 
Lab Members
 
Xiaoyun Tang, Research Associate
Zelei Yang, Graduate Student
 
Selected Publications
 
1. Autotaxin in the crosshairs: Taking aim at cancer and other inflammatory conditions. MGK Benesch, YM Ko, TPW McMullen and DN Brindley.  FEBS Lett. 588 (2014) 2712-2727.
2. Regulation of autotaxin expression and secretion by lysophosphatidate and sphingosine1-phosphate. MGK Benesch, YY Zhao, JM Curtis, TPW McMullen and DN Brindley J Lipid Res. J Lipid Res. in press, 2015, doi:10.1194/jlr.M057661.
3. Tumor-induced inflammation in mammary adipose tissue stimulates a vicious cycle of autotaxin expression and breast cancer progression. MGK Benesch, X Tang, J Dewald, W-F Dong, JR Mackey, DG Hemmings, TPW McMullen and DN Brindley. FASEB J, in press.
4. Autotaxin is an inflammatory mediator and therapeutic target in thyroid cancer. MGK Benesch, YM Ko, X Tang, J Dewald, A Lopez-Campistrous, YY Zhao, R Lai, JM Curtis, DN Brindley1 and TPW McMullen. Endocrine-Related Cancer, in press
5. Inhibition of autotaxin delays breast tumor growth and lung metastasis in mice. M Benesch, X Tang, T Maeda, A Ohata, Y Zhao, B Kok, J Dewald, M Hitt, J Curtis, T McMullen and DN Brindley, FASEB J. 28 (2014) 2655-2666.
6. Lysophosphatidate signaling stabilizes Nrf2 and increases the expression of genes involved in drug resistance and oxidative stress responses: Implications for cancer treatment. G Venkatraman, MGK Benesch, X Tang, J Dewald, TPW McMullen & DN Brindley.  FASEB J. 29 (2015) 772-785.
7. Lipid phosphate phosphatase-1 expression in cancer cells attenuates tumor growth and metastasis in mice. X Tang, MGK Benesch, J Dewald, YY Zhao, N Patwardhan, WL Santos, JM Curtis, TPW and DN Brindley. J Lipid Res. 55 (2014) 2389-2400.