Final Report Summary - VNTME-GAVARD (Vascular niche and tumor microenvironment)
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.
In addition to the delivery of nutrients and oxygen, and to provide a circulating option for metastatic and inflammatory cells, the tumour blood vessels may therefore also form a specific and confined micro-environment where endothelial cells from the vascular wall and tumour stem cells from the tumour mass may interact. Indeed, the fact that stem-like cancer cells (SLCC) reside in close proximity of tumour blood vessels had led to the hypothesis of bidirectional exchanges between endothelial cells and SLCCs.
In line with these recent observations, we propose to explore the nature of the interactions between stem-like cancer cells and brain endothelium, and how this niche may impact both stemness properties and endothelial barrier function. My research programme will involve to study the following:
- Aim 1: Influence of the endothelium / stem-like cancer cell interactions on their transcriptome
- Aim 2: Modulation of mTor signalling axis in the tumour vascular niche
- Aim 3: Semaphorin signalling in the vascular niche.
To achieve such aims, we have developed an original in vitro co-culture model between human cancer stem-like cells from high-grade glioblastoma and human brain endothelial cells. Using this setting, we have been able to demonstrate the importance of secreted endothelial factors in SLCC self-renewal. We have then pursued the study of the molecular mechanisms involved in the bidirectional exchanges.
Targeting cancer stem cell niches may represent new opportunity for treating cancer. Comparative analysis of normal and malignant stem cell biology within their niches will be central to advance on this treatment approach, ensuring that we develop therapies that selectively target malignant stem cells and their niches. In addition, elucidating the mechanisms underlying normal and abnormal vascular function is an exciting and important area of current investigation as it may provide new targets for the treatment of many disease conditions, including cancer, ocular and inflammatory disorders, asthma, diabetes, acquired immunodeficiency syndrome, and bacterial infections.
In addition to the delivery of nutrients and oxygen, and to provide a circulating option for metastatic and inflammatory cells, the tumour blood vessels may therefore also form a specific and confined micro-environment where endothelial cells from the vascular wall and tumour stem cells from the tumour mass may interact. Indeed, the fact that stem-like cancer cells (SLCC) reside in close proximity of tumour blood vessels had led to the hypothesis of bidirectional exchanges between endothelial cells and SLCCs.
In line with these recent observations, we propose to explore the nature of the interactions between stem-like cancer cells and brain endothelium, and how this niche may impact both stemness properties and endothelial barrier function. My research programme will involve to study the following:
- Aim 1: Influence of the endothelium / stem-like cancer cell interactions on their transcriptome
- Aim 2: Modulation of mTor signalling axis in the tumour vascular niche
- Aim 3: Semaphorin signalling in the vascular niche.
To achieve such aims, we have developed an original in vitro co-culture model between human cancer stem-like cells from high-grade glioblastoma and human brain endothelial cells. Using this setting, we have been able to demonstrate the importance of secreted endothelial factors in SLCC self-renewal. We have then pursued the study of the molecular mechanisms involved in the bidirectional exchanges.
Targeting cancer stem cell niches may represent new opportunity for treating cancer. Comparative analysis of normal and malignant stem cell biology within their niches will be central to advance on this treatment approach, ensuring that we develop therapies that selectively target malignant stem cells and their niches. In addition, elucidating the mechanisms underlying normal and abnormal vascular function is an exciting and important area of current investigation as it may provide new targets for the treatment of many disease conditions, including cancer, ocular and inflammatory disorders, asthma, diabetes, acquired immunodeficiency syndrome, and bacterial infections.