Poster Presentation 14th International Biennial Conference on Metastasis Research 2012

Microenvironmental regulation of kinase signalling dynamics as a critical mediator of tumour metastasis (#154)

Thomas R Cox 1 , Erwin M Schoof 2 , Rune Linding 2 , Janine T Erler 1
  1. Biotech Research & Innovation Centre, University of Copenhagen, Copenhagen, Denmark
  2. Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark

Tumour metastasis is a highly complex, dynamic and inefficient process involving multiple steps, yet it accounts for over 90% of cancer patient deaths. The tumour microenvironment and in particular the extracellular matrix is a key component in driving this process at multiple stages. In order to respond to changes in the environment, a cell has to integrate multiple input-cues and modulate its signalling networks accordingly. Both the biochemical and biomechanical properties of tumour extracellular matrix (ECM) are important in determining cell behaviour, and phosphorylation events play a major role in translating these environmental cues into cellular messages.

Metastatic tumours often show elevated ECM remodelling and increased stiffness in comparison to their non-metastatic counterparts and these changes in stiffness are known to drive metastatic cell behaviour although the underlying molecular mechanisms remain elusive. Utilising multiple approaches we evaluate both the molecular and behavioural changes occurring in tumour cells leading to metastasis, focussing on the phosphorylation dynamics behind metastatic phenotypes. By computationally integrating molecular and phenotypic data, we elucidate the molecular networks associated with tumour progression and identify key enablers of kinase signalling leading to metastatic progression. 

Using breast and colorectal cancer models, we show that metastatic tumours are stiffer than matched non-metastatic tumours, and that increased ECM stiffness can drive the invasive behaviour of non-metastatic cancer cells. We observe changes in both dynamic cell signalling events and gene expression, leading to global shifts in molecular networks associated with enhanced metastasis in response to environmental cues.

Our ultimate goal is to predict and test novel network-based therapeutic strategies for the treatment of metastatic disease.