Description of the PhD thesis project
The major goal of our research is to gain a
better understanding of the biogenesis and functions of extracellular vesicles
(RVs). They originate from the endosomal network (exosomes) or from the plasma
membrane (microvesicles). Carrying a defined but mixed cargo of biomolecules,
EVs possess versatile biological activities with the ability to modulate the
molecular configuration and behavior of target cells, while they can also be
involved in disease states.
We use several model systems, like Drosophila,
primary and transformed cells in culture, and human tissues. These different in
vivo and in vitro model systems are combined cell biological molecular and
biochemical to powerful multiscale imaging methods and electron microscopy
The spread of cancer cells from the primary
tumor into surrounding tissues and metastasis to distant organs is the primary
cause of cancer morbidity and mortality. Recent data suggest that EVs released
by cancer cells may stimulate tissue invasion and dissemination of tumor cells
to target tissues. The CD133/Prominin protein, prominently associated to EVs,
is a prognostic marker in different cancer types: high levels of CD133 having been correlated
with adverse outcome in colorectal, pancreas and brain tumors and favor
chemotherapy resistance. We have recently shown that CD133/Prominin promotes
the generation EVs and their secretion from epithelial cells.
The main aim of the project is to unravel the
nature and role of EVs bearing CD133/Prominin, and other components modulating
cell signaling and iron metabolism at inducing invasion, metastasis, and
ferroptosis resistance in cancer. The project combines cell biology with
state-of-the-art imaging at different resolution levels, biochemistry,
molecular biology, chemistry, and in vivo translational research. This work
should provide evidence for the development of new therapeutic tools that could
interfere with EV production and prevent invasion and metastasis in most cancer
International, interdisciplinary & intersectoral aspects of the project
The project is at the interface between cell
biology, cancer, and anti-cancer therapy.
The student will visit and/or interact with
the lab of H. Peinado (Spanish National Cancer Research Center), who has,
together with D. Leyden, evidenced the metastatic capacities of EVs and is
currently developing new and more effective approaches to understand how the
tumor microenvironment influences metastasis, and to prevent their spread.
Their expertise and knowledge will be crucial to accompany and to advise the
The PhD student will also collaborate with V.
Agache, Physicist (CEA/LETI Grenoble, France) for isolation of EVs by
microfluidics. V. Agache is deeply versed in-flow microfluidic sorting device
coupled to high precision sensors to isolate cells and EVs.
1. Hurbain I, Macé AS, Romao M, Sengmanivong
L, Ruel L, Basto R, Therond P, Raposo G, D’Angelo
G. Microvilli-derived extracellular vesicles govern morphogenesis in
Drosophila wing epithelium bioRxiv. 2020. DOI: 10.1101/2020.11.01.363697
2. Adams SD, Csere J, D’Angelo G, Carter E, Arnandis T, Kocher H, Grose R, Raposo G,
Mardakheh F, Godinho SA. Centrosome amplification mediates small extracellular
vesicles secretion via lysosome disruption bioRxiv. 2020. DOI:
Niel G, D'Angelo G, Raposo G.
Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell
Biol. 2018 Apr; 19(4): 213-228: DOI: 10.1038/nrm.2017.125
S, de la Fouchardière C, Kim S, Cohen R, Bachet JB, Tournigand C, Ferraz
JM, Lefevre M, Colin D, Svrcek M, Meurisse
A and Louvet C. Oxaliplatin, 5-FU and Nab-Paclitaxel as perioperative
regimen in patients with resectable gastric adenocarcinoma: a GERCOR phase II
study (FOXAGAST) European Journal of Cancer, 2019 Jan; 107: 46-52.
S, Perrin V, Guillemot D, Reynaud S, Coindre JM, Karanian M, Guinebretière
JM, Freneaux P, Le Loarer F, Bouvet M, Galmiche-Rolland L, Larousserie F,
Longchampt E, Ranchere-Vince D, Pierron G, Delattre O, Tirode F. Transcriptomic
definition of molecular subgroups of small round cell sarcoma Journal of
pathology 2018 May; 245(1): 29-40.