Breast Cancer Dormancy – Mechanisms and Development of Rational New Therapies.

Supervisor: A/Prof Sarah Ellis and Prof.Robin Anderson

Laboratory: Receptor Biology Laboratory

Olivia Newton-John Cancer Research Institute

School of Cancer Medicine, La Trobe University

In Australia, over 3000 women die from breast cancer each year, and worldwide, over 520,000 women will die. Their cause of death is nearly always uncontrollable secondary tumours, or metastases. Distant metastatic disease is detected in up to 20% of those diagnosed with breast cancer, ultimately resulting in their death. Cancer relapse can occur years or decades after the initial diagnosis and treatment, causing ongoing fear and anxiety for patients.

It is evident that disseminated tumour cells (DTC) can remain in a clinically undetectable dormant state for years before causing a relapse. Since many types of chemotherapy rely on disrupting cell division, tumour cells in a dormant state are resistant to such therapies. To prevent recurrences and reduce breast cancer deaths, we need therapies that can either minimise release from dormancy or completely eradicate dormant cells. Indirect evidence for the existence of residual disease in patients comes from detection of circulating tumour cells (CTCs) or cell-free tumour DNA in blood samples. The difficulty of directly detecting and analysing residual disease in patients, in combination with the challenges of modelling dormancy in the laboratory has resulted in only fragmented knowledge of the establishment of DTCs in distant organs and their outgrowth into metastases.

The aim of this project is to use our preclinical models of breast cancer dormancy to image and isolate cells in the dormant cell niche in bone and lung and to generate transcriptomic profiles of both tumour cells and the surrounding host cells. With this knowledge, we will assess the efficacy of therapies designed to maintain tumour dormancy or target a dormancy-specific vulnerability to eradicate these cells. We will use mouse-based breast cancer models that naturally display dormancy to image and investigate the tumour cell niche in mice using confocal and multiphoton microscopy. Tumour cells will be recovered for transcriptomic profiling as a basis for testing different therapies designed to either maintain dormancy of disseminated tumour cells or to specifically target dormant cells.

Techniques involved:

High power microscopy
Mammalian cell tissue culture
Growth of tumours in mice
Transcriptomic profiling by RNA sequencing