Cancer & Neural-Immune Research Laboratory
Cancer diagnosis is a difficult journey that significantly impacts an individual's physical and emotional wellbeing. Challenging circumstances can activate our body's fight-or-flight stress response. While this allows us to respond quickly in times of threat, if activated chronically, stress can have detrimental effects on our health.
Our laboratory investigates the bi-directional interaction between the brain (or nervous system) and the tumour microenvironment. We use advanced imaging technology in animal models of cancer to investigate how stress signaling affects the progression of cancer and its response to therapy. Our research examines the impact of stress signaling that is initiated in the brain on cancer progression. We also investigate how the tumour talks to the brain to disrupt memory and learning, which in turn increases stress.
The goal of these studies is identify the molecular and cellular impact of activating the sympathetic nervous system (SNS or fight-or-flight response) on cancer spread, and to understand the adverse side-effects of current treatments. These studies are helping us design better treatments to improve outcomes for cancer patients.
Neural regulation of metastasis
Metastasis, or cancer spread, is the leading cause of morbidity and mortality of cancer, but little is known about physiological factors that regulate this process. Our studies have shown that chronic stress acts through the SNS to accelerate metastasis of breast and pancreatic cancer.
We have shown that when stress is transmitted through the body via beta-adrenergic signalling pathways it helps tumour cells to move out of the primary tumour and spread to distant sites. We have shown that chronic stress signaling recruits immune cells to the primary tumour. In their intended role, these cells help our immune system fight off disease. However, cancer hijacks the immune system to assist tumour cells disperse throughout the body to colonise vital organs.
Results of these studies are guiding a clinical study of beta-blockers in cancer patients and are aiding the development of novel therapeutic strategies that target this beta-adrenergic regulation of metastasis.
Cancer treatment and cognitive impairment
Chemotherapy has revolutionised treatment of cancer patients, but it often results in long-term neurological and cognitive side-effects (known as 'chemobrain'). While chemotherapy kills the cancer, patients can suffer from learning and memory problems, fatigue and depression that can remain long after treatment has stopped. The severity of chemobrain can significantly impact the quality of life of cancer survivors or even lead to changes in a patient's treatment plan. Little is known about what causes these adverse effects of cancer treatment.
Dr Adam Walker leads a research program within the lab that investigates how cancer, surgery and chemotherapy induce negative effects on the brain. Using preclinical models of cancer and ageing brains, his results so far are demonstrating how cheap and readily available drugs such as aspirin could prevent these debilitating side-effects of chemotherapy and improve the quality of life of cancer survivors.
Targeting perioperative stress to improve cancer outcomes
Surgery is critical to the management of cancer. However, factors associated with surgery including physiological stress and immunosuppression may amplify the risk of cancer recurrence. This identifies the perioperative period as a unique therapeutic window for additional intervention. Importantly, the choice of medications that patients receive during surgery may provide a way intervene in surgical stress and improve long term outcomes. While anaesthetic techniques have the common goal of blocking pain and sensation, some anaesthetic agents may protect against inflammation and surgical stress. Our lab is investigating the impact of anaesthetic agents and adjuncts on long-term cancer outcomes including recurrence and metastasis. These studies will be valuable to inform the design of large, prospective, multi-centre clinical studies looking into the use of anaesthetic agents to improve cancer outcome.
Le, C.P., Nowell, C.J., Kim-Fuchs, C., Hiller, J.G., Ismail, H., Botteri, E., Pimentel, M.A., Chai, M.G., Karnezis, T., Rotmensz, N., Renne, G., Gandini, S., Ferrari, D., Möller, A., Pouton, C.W., Stacker, S.A., Sloan, E.K. Chronic stress remodels lymph vasculature for metastatic dissemination. Nature Communications, 2016; in press.
Le, C.P., Nowell, C.J., Kim-Fuchs, C.,Creed, S.J., Le, C.P., Hassan, M., Pon, C.K., Albold, S., Chan, K.T., Berginski, M.E., Huang, Z., Bear, J.E., Lane, J.R., Halls, M.L., Ferrari, D., Nowell, C.J., Sloan, E.K. β2-adrenoceptor signaling induces invadopodia for breast cancer cell invasion. Breast Cancer Research, 2015; 25;17(1):145.
Pon, C.K., Lane, J.R., Sloan, E.K., Halls, M.L. The β2-adrenoceptor activates a postivie cAMP-calcium feedforward loop to drive breast cancer cell invasion. FASEB J, 2015; Epub. doi:10.1096/fj.15-277798.
Lamkin, D.L., Sung, H.Y., Yang, G.S., David, J.M., Ma, J.C.Y., Cole, S.W., Sloan, E.K. The alpha-adrenergic blocker phentolamine mimics the enhancing effects of chronic stress on breast cancer progression. Psychoneuroendocrinology, 2015; 51:262-270.
Kim-Fuchs, C, Le, C.P., Pimentel, M.A., Shackleford, D., Ferrari, D., Angst, E., Hollande F., Sloan, EK. Chronic stress accelerates pancreatic cancer growth and invasion: A critical role for beta-adrenergic signaling in the pancreatic environment. Brain Behavior and Immunity,2014; 40:40-47.
Chai, M.G., Kim-Fuchs, C, Angst, E, and Sloan, E.K. Bioluminescent orthotopic model of pancreatic cancer progression. Journal of Visualized Experiments, 2013; (76) doi: 10.3791/50395.
Powell, N.D., Sloan, E.K., Bailey, M.T., Arevalo, J.M., Miller, G.E., Chen, E., Kobor, M.S., Reader, B.F., Sheridan, J.F. and Cole, S.W. Social Regulation of the Monocyte Transcriptome: Glucocortcoid Resistance and Cellular Differentiation of Ly-6chigh Monocytes. PNAS, 2013; 110: 16574.
Sloan, E.K.,Priceman, S.J., Cox, B.F., Yu, S., Pimentel, M.A., Tangkanangnukul, V., Arevalo, J.M., Morizono, K., Karanikolas, B.D., Wu, L., Sood, A.K., Cole, S.W. The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Research, 2010; 70(18):7042-52.
Chang, A., Kim-Fuchs, C., Le, C.P., Hollande, F., Sloan, E.K. Neural regulation of pancreatic cancer: A novel target for intervention. Cancers, 2015; 7(3):1292-312.
Le, C.P., Karnezis, T., Achen, M.G., Stacker, S.A., Sloan, E.K. Vascular and neural regulation of metastasis: Shared tumor signaling pathways and novel therapeutic approaches. Best Practice and Research: Clinical Anaesthesiology, 2013; 27:409-425
Pimentel, M.A., Chai, M.G., Le, C.P., Cole, S.W., and Sloan, E.K. Sympathetic nervous system regulation of metastasis, in Cancer Metastasis: Integrated Organ System and Biological Approach, 2012. Eds. Rahul Jandial and Kent Hunter.
- A/Prof Bernhard Riedel, Peter MacCallum Cancer Centre
- Dr Scott Mueller, University of Melbourne
- Dr Frederic Hollande, University of Melbourne
- Dr Davide Ferrari, University of Melbourne
- Dr Stephen Mattarollo, University of Queensland
- Dr Andreas Moeller, Queensland Institute of Medical Research
- Dr Amy Rowat, University of California Los Angeles
- Dr Steve Cole, University of California Los Angeles
Dr Caroline Le
Dr Adam Walker
NBCF Postdoctoral Fellow
Dr Alexandra Ziegler
Dr Julia Dubowitz
Dr Jonathan Hiller
Dr Corina Kim-Fuchs
Mr Aeson Chang
A/Prof Bernhard Riedel
Ms Amanda Peterson
Mr Daniel Raffoul
- National Health and Medical Research Council
- Australian Research Council
- US National Cancer Institute and NCI Network on Biobehavioral Pathways in Cancer
- Skewes Foundation
- Peter MacCallum Cancer Foundation
- National Breast Cancer Foundation