Periodic Reporting for period 3 - VESSEL CO-COPTION (Vessel co-option and radioresistance in glioblastoma)
Berichtszeitraum: 2022-08-01 bis 2024-01-31
Glioblastoma (GB) is one of the deadliest types of human cancer. Despite a very aggressive treatment regime – including resection of the tumor, radiation and chemotherapy – its estimated recurrence rate is more than 90%. Recurrence is mostly caused by the regrowth of highly invasive cells spreading from the tumor bulk, which are not removed by resection. To develop an effective therapeutic approach, we need to better understand the underlying molecular mechanism of chemoradiation resistance and tumor spreading in GB.
GB resistance to therapy is attributed to glioma stem cells (GSCs), a fraction of perivascular, self-renewing, multipotent and tumor-initiating cells. Growing evidence highlights the perivascular space as a niche for GSC survival, resistance to therapy, progression and dissemination. The unknown factor is the dynamics of GSCs, how they end up in the vascular niche and how this impacts on resistance to therapy.
My overall hypothesis is that GSCs reach the perivascular niche through vessel co-option - the directional migration of tumor cells towards vessels - and that targeting vessel co-option has the potential to sensitize GB to therapy.
GB resistance to therapy is attributed to glioma stem cells (GSCs), a fraction of perivascular, self-renewing, multipotent and tumor-initiating cells. Growing evidence highlights the perivascular space as a niche for GSC survival, resistance to therapy, progression and dissemination. The unknown factor is the dynamics of GSCs, how they end up in the vascular niche and how this impacts on resistance to therapy.
My overall hypothesis is that GSCs reach the perivascular niche through vessel co-option - the directional migration of tumor cells towards vessels - and that targeting vessel co-option has the potential to sensitize GB to therapy.
First of all, these initial years have been the setup period for my own new laboratory at Institut Curie (Orsay, France), entitled Tumor Microenvironment Lab.
We dedicated our research on the study of the glioblastoma cells that reside in the perivascular niche and the study of vessel co-option.
In a first paper recently published in collaboration with a team in Barcelona we describe the role of integrin alpha6 in glioblastoma stem cells. Integrin alpha6 is the receptor for laminins, an extracellular matrix present in the perivascular niche. Here, we describe the molecular role of integrin alpha6 in the radioresistance of glioblastoma cells.
On the top of this, my team has put the majority of its energy on another project, the “flagship” for our lab, and we have just submitted a manuscript to a top-level journal. Our results are under review via a rigorous peer-review process, so we still cannot disclose all results. Interestingly, just part of our initial hypotheses was confirmed by our results, while a surprising branch of data has opened an exciting new part of the project. Our results deeply describe the glioblastoma cell plasticity occurring upon therapy and in proximity to brain vasculature. The results from our projects may direct a completely new way of treating glioblastoma, by inhibiting the glioblastoma cell plasticity occurring in perivascular niche.
In parallel, I edited a book on experimental methods to study brain tumors published by Springer-Nature. In this context and in line with the ERC policy for improving reproducibility, we extensively described the method for intravital microscopy, a key experimental strategy used in our project.
We dedicated our research on the study of the glioblastoma cells that reside in the perivascular niche and the study of vessel co-option.
In a first paper recently published in collaboration with a team in Barcelona we describe the role of integrin alpha6 in glioblastoma stem cells. Integrin alpha6 is the receptor for laminins, an extracellular matrix present in the perivascular niche. Here, we describe the molecular role of integrin alpha6 in the radioresistance of glioblastoma cells.
On the top of this, my team has put the majority of its energy on another project, the “flagship” for our lab, and we have just submitted a manuscript to a top-level journal. Our results are under review via a rigorous peer-review process, so we still cannot disclose all results. Interestingly, just part of our initial hypotheses was confirmed by our results, while a surprising branch of data has opened an exciting new part of the project. Our results deeply describe the glioblastoma cell plasticity occurring upon therapy and in proximity to brain vasculature. The results from our projects may direct a completely new way of treating glioblastoma, by inhibiting the glioblastoma cell plasticity occurring in perivascular niche.
In parallel, I edited a book on experimental methods to study brain tumors published by Springer-Nature. In this context and in line with the ERC policy for improving reproducibility, we extensively described the method for intravital microscopy, a key experimental strategy used in our project.
We expect to be able clearly determine if glioblastoma vessel co-option is clinically relevant in treated glioblastoma patients. Moreover, we aim at molecularly describing the changes occurring in glioblastoma cells when vessel co-option occurs. These pathological and molecular insights may allow us to envision completely novel therapeutic strategies that may ultimately provide clinicians with a new tools-kit against this very deadly tumor.