S100A4 and its role in metastasis – simulations of knockout and amplification of epithelial growth factor receptor and matrix metalloproteinases

Abstract

The calcium-binding signalling protein S100A4 enhances metastasis in a variety of cancers. Despite a wealth of data available, the molecular mechanism by which S100A4 drives metastasis is unknown. Integration of the current knowledge defies straightforward intuitive interpretation and requires computer-aided approaches to represent the complexity emerging from cross-regulating species. Here we carried out a systematic sensitivity analysis of the S100A4 signalling network in order to identify key control parameters for efficient therapeutic intervention. Our approach only requires limited details of the molecular interactions and permits a straightforward integration of the available experimental information. By integrating the available knowledge, we investigated the effects of combined inhibition of signalling pathways. Through selective knockout or inhibition of the network components, we show that the interaction between epidermal growth factor receptor (EGFR) and S100A4 modulates the sensitivity of angiogenesis development to matrix metalloproteinases (MMPs) activity. We also show that, in cells that express high EGFR, MMP inhibitors are not expected to be useful in tumours if high activity of S100A4 is present.

Increased S100A15 expression and decreased DNA methylation of its gene promoter are involved in high metastasis potential and poor outcome of lung adenocarcinoma

“…The lack of clinical association with S100A15 in the other two pathological types (squamous cell and small cell carcinoma) of lung cancer in the present study could be attributed to several reasons. First, the interaction between epidermal growth factor receptor and S100A family can promote angiogenesis and metastasis in a variety of cancers, whereas the percentage of EGFR mutations is relatively small in these 2 types of lung cancers [ 19 , 20 ]. Second, some S100A family members contribute to progression of squamous cell carcinomas, while others maintain the differentiated state of epithelium and contribute to a less invasive tumor type [ 21 – 24 ].…”

Sensitivity Analysis of the NPM-ALK Signalling Network Reveals Important Pathways for Anaplastic Large Cell Lymphoma Combination Therapy

“… Sensitivity of the endpoints (“Cell Survival” and “Proliferation”, encircled in the network representation Fig 1 in red and black, respectively) is calculated according to [ 38 , 39 ] and represented in red and black data points in the central plot. Each point in the central plot corresponds to one of states that differ from each other in exactly one node (recall that each node may assume a value of low or high activity).…”

“…, [ 29 , 32 , 37 , 58 , 59 ] and references therein). This information is analysed altogether as a single system and the factors that exert nonlinear control on the endpoints are studied with our network analysis program [ 38 , 39 ]. Several oncogenic proteins interact with NPM-ALK.…”

“…Simulations have been performed according to the framework developed by us before [ 38 , 39 ]. Briefly, the NPM-ALK network was built and analysed with a quantitative phenomenological modelling framework which relied on empirical Hill-type transfer functions as interaction links between nodes.…”

New Insights into the Occurrence of Matrix Metalloproteases -2 and -9 in a Cohort of Breast Cancer Patients and Proteomic Correlations

“…In particular, the S100A4 protein is known to be secreted by tumor and/or stromal cells and to support tumorigenesis by stimulating angiogenesis and promoting endothelial cell migration [26]. In addition it has been reported that S100A4 may support MMP-9 and MMP-13 gene expression [27] and also that it may enhance the activity of some MMPs, causing higher cell dissociation and cancer metastasis [28,29]. Vimentin, VIME (VIM).…”