VNTME-GAVARD

Vascular niche and tumor microenvironment

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 Obiettivo del progetto (Objective)

'Cancer progression is a complex process where cells acquire aberrant proliferative, survival and migratory properties, as well as the ability to trigger the formation of a dedicated tumour blood supply. There is now compelling evidence that the bulk of the malignant cells in cancers contained a rare fraction of self-renewing, multi-potent, and tumour-initiating cells, termed stem-like cancer cells (SLCCs), that constitute a reservoir to generate and/or maintain the tumours. Such as developmental or normal stem cells, cancer stem cells reside within a stem cell niche, which heterogeneous composition always contains a vascular structure. Therefore, in addition to the delivery of nutrients and oxygen, and to provide a circulating option for metastatic cells, the tumour blood vessels may also form a specific and confined microenvironment where endothelial cells from the vascular wall and tumour stem cells from the tumour mass may interact. Indeed, these SLCCs reside in close proximity of tumour blood. In line with these recent observations and hypothesis, we propose to explore the nature of the interactions between “cancer” stem cells and brain endothelium, and how this niche may impact both stemness properties and endothelial barrier function. My research program involved 3 major aims: - Influence of the endothelium/cancer stem cell interactions on their transcriptome - Modulation of mTor signalling axis in the tumour vascular niche - Semaphorin signalling in the vascular niche Through the combination of innovative technologies and approaches, such as transcriptome analysis, cell imagery, in vivo model of angiogenesis, we have here a unique opportunity to better understand the basis for molecular and cellular interactions within the tumour microenvironment. Overall, I expect my proposal research to provide the molecular basis for the development of novel therapeutic targets designed to impede on deregulation of the vascular niche or to promote its normalization.'

Introduzione (Teaser)

Cancer stem cells reside in a microenvironment, a niche, which always contains blood vessels. The VNTME-GAVARD project studied the functional interaction between cancer stem cells and endothelial cells of the vasculature.

Descrizione progetto (Article)

During cancer progression, cells acquire proliferative, survival and migratory properties as well as the ability to trigger the formation of a dedicated tumour blood supply. The bulk of the malignant cells in cancers contain a rare fraction of self-renewing, tumour-initiating cells, termed stem-like cancer cells (SLCCs). These cells constitute a reservoir for generation and/or maintenance of the tumours.

As with developmental or normal stem cells, cancer stem cells reside within a stem cell niche, the heterogeneous composition of which always contains a vascular structure. The fact that SLCCs reside in close proximity to tumour blood vessels had led to the hypothesis of bi-directional exchanges between endothelial cells and SLCCs. The EU-funded project 'Vascular niche and tumor microenvironment' (VNTME-GAVARD) explored the nature of the interactions between SLCCs and brain endothelial cells, and how these impacted their functions.

Researchers developed an original in vitro co-culture model between human SLCCs from high-grade glioblastoma and human brain endothelial cells. Using this setting, they demonstrated the importance of secreted endothelial factors in SLCC self-renewal.

Targeting cancer stem cell niches may represent a new opportunity for treating cancer. Comparative analysis will ensure the development of the therapies that selectively target malignant stem cells and their niches.