The University of Southampton
Centre for Human Development, Stem Cells and RegenerationResearch themes

Modelling tumour microenvironment interactions between MSC-derived myofibroblasts and CLL cells

Mesenchymal Stem Cells

 

The last 10 years have seen major advances in our understanding of the role of the tumour microenvironment in modulating the development, progression and therapy resistance in many cancer types. Targeting the microenvironment to deprive malignant cells of supporting interactions is therefore an attractive and novel therapeutic approach to cancer treatment.

 

Chronic Lymphocytic Leukaemia (CLL) is the most common leukaemia in the Western world; in addition to blood involvement, a key microenvironment/niche for CLL cells is the bone marrow (BM), where CLL cells are protected from apoptosis by interactions with supporting stromal cells, primarily mesenchymal stem cells (MSCs), via molecules such as SDF-1 (CXCL12), Fibronectin (Fn), VCAM-1, BAFF/APRIL, MMP-9 and HGF. CLL cells, in turn, activate TGF-β1, which can act as a potent inducer of myofibroblast transdifferentiation of BM-derived MSCs. The stromal myofibroblasts have been recognised as the key component of the tumour microenvironment since they are capable of secreting cytokines, proteases and matrix proteins that promote tumour progression.

 

We therefore propose that bidirectional interactions between CLL cells and MSC-derived myofibroblasts constitute a key ‘vicious cycle' in the BM microenvironment, whereby CLL cells stimulate myofibroblast transdifferentiation of BM-derived MSCs and the resulting myofibroblasts, in turn, promote survival and accumulation of CLL cells within the BM, which acts as a reservoir of proliferating cells that feed the circulating leukaemia cell population.

 

This multidisciplinary project, which is placed at the interface of Stem Cell, Cancer Science and Bioengineering themes, aims to model the bidirectional communication between CLL cells and BM MSC-derived myofibroblasts in 2-D and novel 3-D co-culture systems and, has a clear translational potential in terms of development of a novel therapeutic approach based on depriving malignant cells of the supporting microenvironment interactions.

 

People

Rahul Tare, Graham Packham, Gareth Thomas, Martyn Hill (FEE)

Bidirectional communication between MSC-derived myofibroblasts and CLL cells
Bidirectional communication

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