Cancer & Neural-Immune Regulation

Project areas

Research focus

Left: Histological staining of a pancreatic tumour. Right: Image of mouse with a bioluminescent tumour.

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.

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Neural regulation of metastasis

Top: LYVE-1 staining of lymphatic vessels in a tumour. Bottom: Tumour cells invading through extracellular matrix.

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

locomotor trace test
Trace from locomotor activity test used to assess anxiety-like behaviour in mice.

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 in association with our 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.

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Key publications

Research papers

  1. Carvalheira Alcobia D, Kondrashov, A., Comeo, E, Mistry, S., Kellam, B, Chang, A., Zeigler, A.I. Woolard, J., Hill, S.J., Sloan, E.K. 2018 Visualising Ligand-binding to a GPCR in vivo using NanoBRET. iScience. 6:280-288
  2. Walker, A.K., Chang, A., Ziegler, A.I., Dhillon, H.M., Vardy, J.L., Sloan, E.K. 2018. Low dose aspirin blocks breast-cancer induced cognitive impairment in mice. PlosOne. 99:191
  3. Nissen, M.D., Sloan, E.K., Mattarollo, S.R. 2017. Beta-adrenergic signaling impairs antitumor CD8+ T cell responses to B-cell lymphoma immunotherapy.  Cancer Immunology Research. 6(1)98-109.
  4. Knight, J.M., Kerswill, S.A., Hari, P., Cole, S.W., Logan, B.R., D’Souza, A., Shah, N.N., Horowitz, M.M., Stolley, M.R., Sloan, E.K., Giles, K.E., Costanzo, E.S., Hamadani, M., Chhabra, S., Dhakal, B., and Rizzo, J.D. 2018. Repurposing existing medications as cancer therapy: Design and feasibility of a randomized pilot investigating propranolol administration in patients receiving hematopoietic cell transplantation. BMC Cancer. 18(1):593
  5. Yap, A., Lopez-Olivo, M.A., Dubowitz, J., Pratt, G., Hiller, J., Gottumukkala, V., Sloan, E.K., Riedel, B., Schier, R. 2018. Effect of Beta-Blockers on Cancer Recurrence and Survival: A Meta-Analysis of Epidemiological and Perioperative Studies. British Journal of Anaesthesia. 121(1):45-57.
  6. Chang, A., Le, C.P., Pon, C.K. Albold, S.A., Carroll, D., Walker, A., Halls, M.L., Lane, R.J. Riedel, B., Ferrari, D., Sloan, E.K. 2016. β2-adrenoceptors on tumor cells play a critical role in stress-enhanced metastasis in a mouse model of breast cancer. Brain Behavior and Immunity. 57:106.
  7. 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. 2016. Chronic stress in mice remodels lymph vasculature for metastatic dissemination. Nature Communications, 7: 10634
  8. Kim-Fuchs, C, Le, CP., Pimentel, MA, Shackleford, D., Ferrari, D., Angst, E., Hollande F., Sloan, EK. 2014. Chronic stress accelerates pancreatic cancer growth and invasion: A critical role for beta-adrenergic signaling in the pancreatic environment.  Brain Behavior and Immunity. 40:40-47

Reviews

  1. Hiller, J.G., Perry, N.J., Poulogiannis, G., Riedel, B., Sloan, E.K. 2018. Perioperative events influence cancer recurrence risk after surgery.  Nature Reviews Clinical Oncology. 15(4):205-218.
  2. Riedel, B., Sloan, E., Forget, P. 2016. Long-term consequences of the acute neural-inflammatory stress response in the cancer surgical patient: new findings and perspectives. International Anesthesiology Clinics 54(4): 58-71.

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Collaborations

  • Prof Bernhard Riedel, Peter MacCallum Cancer Centre
  • A/Prof Scott Mueller, University of Melbourne
  • Dr Stephen Mattarollo, University of Queensland
  • A/Prof Amy Rowat, University of California Los Angeles
  • Prof Steve Cole, University of California Los Angeles
  • Dr Edoardo Botteri, Norwegian Cancer Registry
  • Prof Stephen Hill, University of Nottingham

Lab members

 

A/Prof Bernhard Riedel
Clinical Associate
Researcher

 

Dr Adam Walker
NBCF Postdoctoral Fellow

Associate Researcher

 

Dr Alexandra Ziegler
Research Officer

 

Dr Julia Dubowitz
PhD Student

 

Dr Jonathan Hiller
PhD Student

 

Mr Aeson Chang
PhD student

 

Ms Amanda Peterson
PhD student

 

Mr Ryan Gillis
Honours student

 

Ms Ni-chun Chung
PhD student

Funding

  • 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