Interactions between tumour cells and the bone microenvironment

photo2
29 July 2016 - 12:00am to 1:00pm
Samuels 513

Metastatic cancers which primarily target the skeleton, and the predominantly bone residing malignancy multiple myeloma, are largely incurable due to high rates of relapse. This is despite the development of therapies that target tumour cell-intrinsic pathways. Disease relapse is thought to originate from dormant tumour cells, which reside in specialised niches, and resist therapy to re-populate the tumour. However, little is known about the niche, and how it exerts cell-extrinsic control over tumour cell dormancy and re-activation. This is due to the technical challenges of identifying and tracking the fate of these rare dormant cells in the skeleton in vivo. We developed a novel technique to capture the engraftment, dormancy, activation and growth of tumour cells in bone.  We tracked individual myeloma cells by intravital imaging as they colonised the endosteal niche, entered a dormant state, in which they remained, or were subsequently activated to form tumour colonies. We demonstrated that dormancy is a reversible state that can be switched ‘on’ by engagement with bone lining cells or osteoblasts, and switched ‘off’ by osteoclasts remodelling the endosteal niche. Using intravital imaging we captured the cellular dynamics of these pivotal components of the niche. Further, dormant myeloma cells were resistant to chemotherapy, and were re-activated to contribute to relapse.  These advances provide novel approaches to understanding tumour and bone cell interactions, and highlight the potential for targeting cell-extrinsic mechanisms to overcome cell-intrinsic drug resistance and prevent disease relapse in bone resident tumours.

About Michelle McDonald - Dr Michelle McDonald’s research careers spans over 13 years, attaining her PhD in 2008, investigating the impact of bone targeted therapies on fracture repair. Dr McDonald is currently Group Leader of the Bone Microenvironment Group at The Garvan Institute. She has 34 peer reviewed publications including Nature Communications and Nature Reviews Cancer. Her research team aims to develop novel strategies to target the bone microenvironment to prevent initiation and relapse in malignant disease. Using a specialised cell tracking technique and intravital imaging of single tumour cells in real time, her team investigates bone micro-environment regulation of tumour cell, colonisation, dormancy and activation. Dr McDonald and her team also explore improved strategies for treating myeloma induced bone disease utilising agents which target Wnt/β catenin signalling to promote bone formation. This work has recently attracted a number of awards, and competitive grants and spans collaborations with academic and industry partners internationally.

Seminar Coordinators Heba Khamis, Jelena Rnjak-Kovacina