"Multi-scale imaging and study of the perivascular niche in glioblastoma (2017-08-SEANO-DUTREIX)" project details

× Help section

To download a PDF version of the PhD thesis project, please click on the PDF document in orange.

General information

Application closed

2017-08-SEANO-DUTREIX

Glioblastoma, Glioma stem cells, Intravital microscopy, Perivascular niche, Tumor microenvironment

Multi-scale imaging and study of the perivascular niche in glioblastoma

Director(s) and team

Giorgio Seano

Junior Group Leader

Abstract

Description of the PhD thesis project
Glioblastoma (GBM) is the deadliest type 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 supposedly mostly caused by the regrowth of highly invasive cells, which are not removed by resection. Chemoradiation is mostly insufficient in preventing tumor regrowth, with the fact that GBM is composed of intrinsically treatment-resistant perivascular glioma stem cells (GSCs) – self-renewing, multipotent and tumor-initiating cells – provides an explanation for this.

To develop an effective therapeutic approach, we need to better understand the underlying molecular mechanism of radioresistance and tumor spreading in GBM. Radiation increases the number of GSCs, as well as GBM invasion and vascular satellitosis, and identifies the vascular niche as a crucial condition to maintain the GSCs’ resistance to therapy. The unknown factor is how GSCs end up in the vascular niche.  We will use state-of-the-art technologies that will allow us to dynamically visualize GSC and differentiated GBM cells with a single-cell resolution. Experimental radiotherapy will be delivered by unique equipment in order to be in line with the most innovative discoveries in the field. We will also extensively use patient material to reconstitute a “patient-in-a-dish” model, by following a “bench-to-bedside and bedside-to-bench” strategy.

Our studies will provide clinically relevant insights into the involvement of GSCs and the vascular niche in the GBM radioresistance. The understanding of these pathological mechanisms may substantially transform our current view of GBM and radiotherapy. Importantly, we expect to propose new therapeutic strategies capable of overcoming GBM radioresistance and validate potential drugs translatable to clinics. Since all GBM patients receive radiotherapy, many would benefit from strategies aimed at improving radiotherapy.

International, interdisciplinary & intersectoral aspects of the project
This project is the result of a close collaboration among research laboratories in Boston and in Paris. We indeed have assembled a network of numerous, highly experienced and supportive collaborators at the Institut Curie, Hôpital Foch, Dana-Farber/Harvard Cancer Center and Massachusetts Institute of Technology (MIT) and Expansion Technologies. Expansion microscopy is believed to be one of the most relevant and innovative inventions in microscopy in the last years. After having learned the imaging basics in our laboratory, the PhD student will have the privileged opportunity to spend time in the pioneer lab for expansion microscopy in MIT. Following the “bench-to-bedside and bedside-to-bench” strategies, the aims are characterized by both preclinical and translational investigations.

Recent publications
1. Seano G. Targeting the perivascular niche in brain tumors. Invited review. Curr Opin Oncol. 2017 Nov 14. doi: 10.1097/CCO.0000000000000417
2. Kloepper J*, Riedemann L*, Amoozgar Z*, Seano G, Susek KH, Yu V, Dalvie N, Amelung RL, Datta M, Song JW, Askoxylakis V, Taylor JW, Lu-Emerson C, Batista A, Kirkpatrick ND, Snuderl M, Muzikansky A, Stubenrauch KG, Wakimoto H, Xu L, Munn LL, Duda DG, Fukumura D, Batchelor TT and Jain RK. Dual Angiopoietin-2/VEGF inhibition in glioblastoma prolongs survival through macrophage reprogramming. Proc Natl Acad Sci USA. 2016 Apr 19;113(16):4476-81.
3. Seano G, Chiaverina G, Gagliardi PA, di Blasio L, Puliafito A, Bouvard C, Sessa R, Tarone G, Sorokin L, Helley D, Jain RK, Serini G, Bussolino F, Primo L. Endothelial podosome rosettes regulate vascular branching in tumour angiogenesis. Nat Cell Biol. 2014 Oct (16) 931–941.
4. Seano G, Chiaverina G, Gagliardi PA, di Blasio L, Sessa R, Bussolino F, Primo L. Modeling human tumor angiogenesis in a three-dimensional culture system. Blood. 2013 May 23;121(21):e129-e137.
5. Primo L*, Seano G*, Roca C, Maione F, Gagliardi PA, Sessa R, Martinelli M, Giraudo E, di Blasio L, Bussolino F. Increased expression of α6 integrin in endothelial cells unveils a proangiogenic role for basement membrane. Cancer Res. 2010 Jul 15;70(14):5759-69.  

Requirements to apply for the PhD thesis project

Applicants should have a strong desire to explore cell biological phenomena in an in vivo context and should show solid capacity for independent and creative thinking.
Background in cell biology and/or stem cell biology is strongly recommended. Background in neurobiology or vascular biology is a plus but not mandatory.  The project highly relies on microscopy and live imaging techniques, for which the applicant should have either experience or a strong motivation to learn.