Ph.D, D.Sc., University of Birmingham
Our work focuses on understanding how changes in signal transduction lead to increased progression of tumours, their spread (metastasis) and the development of therapy resistance. We concentrate on the enzyme, autotaxin, which is an important component in wound healing. This is because autotaxin produces a 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 breast cancer where the tumours secrete inflammatory cytokines, which stimulate autotaxin production by surrounding adipose tissue. The LPA, which is formed by autotaxin, then stimulates more inflammation. Inhibiting autotaxin activity decreases the production of >20 inflammatory cytokines and chemokines 2,3 and this decreases tumor growth and metastasis4.
We also discovered that LPA increases decreases the effectiveness of taxanes, doxorubicin, and tamoxifen, which are used to treat breast cancer5,6. This is partly because 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 increases the transcription of the multidrug resistance transporters, which export toxic oxidation products and chemotherapeutic drugs from cancer cells5.
Our future work on autotaxin will study how LPA signalling can decrease the efficacy of radiotherapy. Breast cancer is routinely treated by irradiating of the whole breast with ~25 daily fractions of radiation. We showed that irradiating human breast adipose tissue with therapeutic doses of radiation increases the expression of autotaxin, LPA receptors, multiple inflammatory cytokines and cycolooxygenase-2. We are now studying if blocking these effects with a clinically approved autotaxin inhibitor increases the effectiveness of subsequent fractions of radiotherapy in destroying breast cancer cells in vivo.
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 cancers and this amplifies the effects of LPA. We showed that restoring the low activity of LPP1 in cancer cells decreases breast tumour growth and metastasis by about 80%8. We discovered that tetracyclines increase LPA degradation by the LPPs and this decreases inflammation in breast tumours and tumour growth9. 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, an Endocrine Surgeon. We are now working to translate our work on blocking the autotaxin-LPA-inflammatory axis into clinical practice as a new paradigm to improve the efficacies of chemotherapy and radiotherapy. The development of resistance to existing therapies represents a major obstacle to successfully treating most types of cancer.
1. Autotaxin in the crosshairs: Taking aim at cancer and other inflammatory conditions.
Benesch MGK, Ko YM, McMullen TPW, Brindley DN.
FEBS Lett. 588 (2014) 2712-2727.
2. Regulation of autotaxin expression and secretion by lysophosphatidate and sphingosine1-phosphate.
Benesch MGK, Zhao YY, Curtis JM, McMullen TPW and Brindley DN.
J Lipid Res. J Lipid Res. 56 (2015) 1134-44.
3. Tumor-induced inflammation in mammary adipose tissue stimulates a vicious cycle of autotaxin expression and breast cancer progression.
Benesch MG, Tang X, Dewald J, Dong WF, Mackey JR, Hemmings DG, McMullen TP, Brindley DN.
FASEB J 29 (2015) 3990-4000
4. Inhibition of autotaxin delays breast tumor growth and lung metastasis in mice.
Benesch MG, Tang X, Maeda T, Ohhata A, Zhao YY, Kok BP, Dewald J, Hitt M, Curtis JM, McMullen TP, Brindley DN.
FASEB J. 28 (2014) 2655-2666.
5. Lysophosphatidate signaling stabilizes Nrf2 and increases the expression of genes involved in drug resistance and oxidative stress responses: Implications for cancer treatment.
Venkatraman G, Benesch MG, Tang X, Dewald J, McMullen TP, Brindley DN.
FASEB J. 29 (2015) 772-785.
6. Oxidative stress contributes to the tamoxifen-induced killing of breast cancer cells: implications for tamoxifen therapy and resistance.
Bekele RT, Venkatraman G, Liu RZ, Tang X, Mi S, Benesch MG, Mackey JR, Godbout R, Curtis JM, McMullen TP, Brindley DN.
Sci Rep. (2016) Feb 17;6:21164
7. Implications for breast cancer treatment from increased autotaxin production in adipose tissue after radiotherapy.
Meng G, Tang X, Yang Z, Benesch MGK, Marshall A, Murray D, Hemmings DG, Wuest F, McMullen TPW, Brindley DN.
FASEB J. (2017) Sep;31(9):4064-4077.
8. Lipid phosphate phosphatase-1 expression in cancer cells attenuates tumor growth and metastasis in mice.
Tang X, Benesch MG, Dewald J, Zhao YY, Patwardhan N, Santos WL, Curtis JM, McMullen TP, Brindley DN.
J Lipid Res. 55 (2014) 2389-2400.
9. Doxycycline attenuates breast cancer related inflammation by decreasing plasma lysophosphatidate concentrations and inhibiting NF-kB activation.
Tang X, Wang X, Zhao YY, Curtis JM, Brindley DN.
Molecular Cancer. (2017) Feb 8;16(1):36.