Interactions between mesencyhmal stromal cells and macrophages in the progression of cancer.

Identification of novel interactions between the Mesenchymal stromal cells (MSCs) and tumour associated macrophages (TAMs) which facilitate cancer progression.
This project aims to study the interactions between MSCs and TAMs to understand the specific pathways, receptors and molecules through which they communicate to influence each other's actions. The aim is that through furthering our understanding of the crosstalk between MSCs and TAMs that we might identify novel targets for therapeutic intervention which disrupt the interaction, and resulting phenotypes, to prevent tumour progression.
This project aims to incorporate both in vivo and ex vivo models of cancer to explore the interactions between TAMs and MSCs in the tumour microenvironment. Both MSCs and TAMs have very specific signatures of gene expression in the tumour microenvironment, these will be resolved using microarray analysis in the polyoma middle T antigen (PyMT) mouse mammary tumour virus (MMTV) spontaneous model of breast cancer. This data will permit us, for the first time, to fully dissect the contribution of each of these cells in a single model and tumour to the microenvironment. The potential interactions between MSCs and TAMs which are identified using microarray analysis will be tested for functionality using small molecule inhibitors or antibodies in vivo and in co-culture assays. The effects of these interactions and changes in cell phenotype will be established mechanistically using flow cytometry, confocal microscopy
Tumour growth and progression is aided by a collection of normal cells which get recruited to the tumour. These cells are collectively termed the 'stroma'. MSCs and TAMs are two highly represented stromal cell types within the tumour microenvironment. These cells both have been demonstrated to contribute to tumour progression through facilitating immune suppression, the formation of new vessels, and metastases of the tumour cells to distant sites. However, very little is currently known about the pathways through which these cells communicate with each other to orchestrate progression of the disease. In Arnold et al., 2014, we conditionally ablated (using transgenic models) either a subpopulation of TAMs or MSC like cells from the tumour microenvironment of an immunogenic tumour. We found that when either population was respectively ablated, tumour control was achieved. One possibility to explain this observation is that the two cells are in close communication within the tumour microenvironment and removal of either one breaks a fundamental pathway required for tumour progression. This project aims to investigate and resolve this possibility.