Team 01 - Tumor and vascular biology laboratory.

Équipe 01 – Laboratoire de biologie tumorale et vasculaire.

Our team (exUMR1029 LAMC) is primarily focused on malignant brain tumours especially in relationship with the tumour microenvironment. The aims of our research project are:

  1. to understand how brain tumours acquire the capacity to spread and invade the brain tissue and to evade anticancer therapies
  2. to elucidate intracellular and intercellular communications in brain tumours
  3. to understand the regulation of vascular development under normal and malignant conditions
  4. to build 3D models for vascular biology and brain tumours as tools to understand the molecular regulations in these tissues.

Several of these projects have also a translational aspect and include the discovery of new biomarkers and therapeutic targets.


Keywords

Cancer Biology, Vascular Biology, brain tumor models, invasion, secretome, cell communication, phosphatase, metabolism, autophagy

News


Projects

Vascular biology

1- Role of Phosphatases in Normal and Tumor Angiogenesis

This project is a collaboration between the Tremblay Laboratory (Goodman Cancer Center, Mc Gill University), the team of Barbara Garmy-Susini (Institute of Metabolic and Cardiovascular Diseases, UMR 1297 University Toulouse III – Paul Sabatier) and our team.

Protein tyrosine phosphatases are essential modulators of angiogenesis and have been identified as new therapeutic targets in cancer and angiogenesis. We have demonstrated that the expression of the atypical Phosphatase of Regenerative Liver 2 (PRL2) in endothelial promotes angiogenesis by increasing endothelial cell migration and the VEGF-A, DLL-4/NOTCH-1 signaling pathway (Poulet et al., 2020).

Our current project aims to fully elucidate the role of PRLs in both neo-angiogenesis, lymphangiogenesis and tumor development. We will focus our attention on the signaling pathways controlled by PRLs in blood and lymphatic endothelial cells and whether the interaction with the metal transporter CNNM3 is involved, since PRLs act as a magnesium sensor. We will also investigate the role of stroma derived-PRL on tumor development and metastatic spread through both the blood and the lymphatic vasculature.

Fundings: INCA, Ligue contre le cancer Nouvelle Aquitaine

2- 3D models of functional vessels: vesseloïd

We have, in collaboration with the BioImaging & OptoFluidics Lab (UMR CNRS 5298 Institut d’Optique d’Aquitaine), develop a one-step strategy using a microfluidic coextrusion device to produce mature functional blood vessels. This “vesseloids” is created with alginate hydrogel tube internally coated with extracellular matrix to direct the self-assembly of a mixture of endothelial cells (ECs) and smooth muscle cells (SMCs). The resulting structure, with a lumen formed by ECs surrounded by layers of SMCs, shows properties of functional vessels like quiescence, perfusability, and contractility in response to vasoconstrictor agents (Andrique et al., 2019).

We will further develop and use this original model to understand the complexity of blood and lymphatic vessels. Since blood vessels are in first line when an inflammatory process, due to infection, injury, or auto-immune disease, is triggered, we will focus on the development of an inflamed 3D vessel model used to explore vessel inflammation and test the effect of pharmacological modulators and drugs. This project include the investigation of the effect of COVID-19 on blood vessels.


Project members

Noteworthy publications
PRL-2 phosphatase is required for vascular morphogenesis and angiogenic signaling.
Poulet M, Sirois J, Boyé K, Uetani N, Hardy S, Daubon T, Dubrac A, Tremblay ML, Bikfalvi A
Communications biology ; 2020 Oct 23
A model of guided cell self-organization for rapid and spontaneous formation of functional vessels.
Andrique L, Recher G, Alessandri K, Pujol N, Feyeux M, Bon P, Cognet L, Nassoy P, Bikfalvi A
Science advances ; 2019 Jun 12
Mechanisms of invasion in glioblastoma.
Chouleur T, Tremblay ML, Bikfalvi A
Current opinion in oncology ; 2020 Nov 01
Regulation of the Src kinase-associated phosphoprotein 55 homologue by the protein tyrosine phosphatase PTP-PEST in the control of cell motility.
Ayoub E, Hall A, Scott AM, Chagnon MJ, Miquel G, Hallé M, Noda M, Bikfalvi A, Tremblay ML
The Journal of biological chemistry ; 2013 Sep 06

Brain tumour signalling

Glioblastomas (GBM) are the most frequent and aggressive primary brain tumors with a high invasive capacity and low sensitivity to anticancer treatments.

1- Glioblastoma extracellular microenvironment

The extracellular microenvironment components are central actors in the establishment of GBM cell invasion. We have demonstrated using RNA sequencing of patient-derived xenograft tissue from laser capture micro-dissected peripheral and central tumour areas that the matricellular protein Thrombospondin-1 (THBS1) is one of the gene with the highest connectivity at the tumour borders. Furthermore, THBS1 expression was found to be increased with glioma grades. Mechanistically, we show that TGFβ1 induces THBS1 expression via Smad3 which contributes to the invasive behaviour during GBM expansion (Daubon et al., 2019).

Our current project aims to understand the complex interaction of tumour cells with the extracellular matrix, tumour vasculature, and the normal stromal compartment and their roles in tumour progression. Specifically, cell-surface transmembrane proteins occupy a strategic location between the cell and its microenvironment and can propagate signals from both extracellular and cytoplasmic ends of the membrane. Furthermore, accumulating evidence suggests that glioblastoma specific secretory proteins released into the tumour microenvironment represent the core mediators of communication between glioblastoma and the tumour-associated stroma and may have a major impact on tumour aggressiveness. Therefore, a detailed characterization will be undertaken. This will lead to the identification of novel druggable targets and can pave the way for future effective therapeutic strategies.

 2-IDH mutated gliomas

 IDH-1 mutated gliomas are characterized by a less aggressive biological behaviour, a clinical prognosis less influenced by tumor grade, and include diffuse low grade and intermediate grade gliomas, recently defined as Lower Grade Gliomas (LGGs). This project focuses on LGGs and how to integrate imaging and molecular heterogeneity into a tool to be used in the routine clinical practice for easily predicting LGGs progression. Predicting the prognosis using such high dimensional and heterogeneous data required specific approaches. A predictive model for patient stratification and prediction at onset of diagnosis is the ultimate deliverable that should improve the clinical management of patients. Additional results should be provided by the multilevel approach leading to a better understanding of the disease.

 3-Glioblastoma adaptation to the tumor microenvironment

Major characteristics of glioblastoma are their high intra-tumor heterogeneity and their ability to adapt to harsh conditions found in the tumor microenvironment. Among the cellular processes used by cancer cells, autophagy may play an important role in the adaptation to the stress conditions found in the tumor microenvironment. In addition to the non-selective autophagy, specific forms of autophagy can selectively degrade intracellular components linked with cellular metabolism such as mitochondria and lipid droplets and participates to metabolic adaptation. We have demonstrated, in other cancer models, that autophagy is highly regulated by the presence or absence of metabolic substrates (lactate, fatty acids) in the microenvironment and by non-cancer cells found in the tumor microenvironment (adipocytes) (Brisson et al., 2016, Fontaine et al., 2021 et Bellanger et al., 2021).

Therefore, selective, and non-selective forms of autophagy might be central cellular mechanisms of the interactions between cancer cells and the surrounding microenvironment and thus participate in cancer progression. We will investigate the role of different forms of autophagy is glioblastoma, in the context of intra-tumor heterogeneity and metabolic adaptation.

 

Besides our work on malignant brain tumors, our team is also also involved in a project of systems biology of renal cell carcinoma. Using functional genomics, imaging, clinical data and computational approaches we discovered molecular pathways and players in renal cancer development and metastasis (Cooley et al., 2021).


Project members

Noteworthy publications
Experimental and computational modeling for signature and biomarker discovery of renal cell carcinoma progression.
Cooley LS, Rudewicz J, Souleyreau W, Emanuelli A, Alvarez-Arenas A, Clarke K, Falciani F, Dufies M, Lambrechts D, Modave E, Chalopin-Fillot D, Pineau R, Ambrosetti D, Bernhard JC, Ravaud A, Négrier S, Ferrero JM, Pagès G, Benzekry S, Nikolski M, Bikfalvi A
Molecular cancer ; 2021 Oct 20
The invasive proteome of glioblastoma revealed by laser-capture microdissection.
Daubon T, Guyon J, Raymond AA, Dartigues B, Rudewicz J, Ezzoukhry Z, Dupuy JW, Herbert JMJ, Saltel F, Bjerkvig R, Nikolski M, Bikfalvi A
Neuro-oncology advances ; 2019 Sep 28
Deciphering the complex role of thrombospondin-1 in glioblastoma development.
Daubon T, Léon C, Clarke K, Andrique L, Salabert L, Darbo E, Pineau R, Guérit S, Maitre M, Dedieu S, Jeanne A, Bailly S, Feige JJ, Miletic H, Rossi M, Bello L, Falciani F, Bjerkvig R, Bikfalvi A
Nature communications ; 2019 Mar 08
Lactate Dehydrogenase B Controls Lysosome Activity and Autophagy in Cancer.
Brisson L, Bański P, Sboarina M, Dethier C, Danhier P, Fontenille MJ, Van Hée VF, Vazeille T, Tardy M, Falces J, Bouzin C, Porporato PE, Frédérick R, Michiels C, Copetti T, Sonveaux P
Cancer cell ; 2016 Sep 12
Lipophagy and prostate cancer: association with disease aggressiveness and proximity to periprostatic adipose tissue.
Fontaine A, Bellanger D, Guibon R, Bruyère F, Brisson L, Fromont G
The Journal of pathology ; 2021 Oct 01

Jobs offers


Team’s noteworthy publications

A model of guided cell self-organization for rapid and spontaneous formation of functional vessels.
Andrique L, Recher G, Alessandri K, Pujol N, Feyeux M, Bon P, Cognet L, Nassoy P, Bikfalvi A
Science advances ; 2019 Jun 12
Deciphering the complex role of thrombospondin-1 in glioblastoma development.
Daubon T, Léon C, Clarke K, Andrique L, Salabert L, Darbo E, Pineau R, Guérit S, Maitre M, Dedieu S, Jeanne A, Bailly S, Feige JJ, Miletic H, Rossi M, Bello L, Falciani F, Bjerkvig R, Bikfalvi A
Nature communications ; 2019 Mar 08
Experimental and computational modeling for signature and biomarker discovery of renal cell carcinoma progression.
Cooley LS, Rudewicz J, Souleyreau W, Emanuelli A, Alvarez-Arenas A, Clarke K, Falciani F, Dufies M, Lambrechts D, Modave E, Chalopin-Fillot D, Pineau R, Ambrosetti D, Bernhard JC, Ravaud A, Négrier S, Ferrero JM, Pagès G, Benzekry S, Nikolski M, Bikfalvi A
Molecular cancer ; 2021 Oct 20
The role of CXCR3/LRP1 cross-talk in the invasion of primary brain tumors.
Boyé K, Pujol N, D Alves I, Chen YP, Daubon T, Lee YZ, Dedieu S, Constantin M, Bello L, Rossi M, Bjerkvig R, Sue SC, Bikfalvi A, Billottet C
Nature communications ; 2017 Nov 17
PRL-2 phosphatase is required for vascular morphogenesis and angiogenic signaling.
Poulet M, Sirois J, Boyé K, Uetani N, Hardy S, Daubon T, Dubrac A, Tremblay ML, Bikfalvi A
Communications biology ; 2020 Oct 23


Partners

Team leaders

Lucie BRISSON
Researcher / CR

Andreas BIKFALVI
Professor / PU


Team members

Jean-Christophe BERNHARD
Professor Clinician / PU-PH

Andreas BIKFALVI
Professor / PU

Lucie BRISSON
Researcher / CR

Charlotte BRONNIMANN
Clinician / PH

Laura CHAILLOT
Engineer / IE

Tiffanie CHOULEUR
PhD Student / Doc

Andrea EMANUELLI
Post PhD Researcher / Post-doc

Julien ENGELHARD
Lecturer Clinician / MCU-PH

Rarahu MAGAUT
PhD Student / Doc

Olivier MOLLIER
Clinician / PH

Kristelle OIZEL
PhD Student / Doc

Ahmad SHARANEK
Post PhD Researcher / Post-doc

Wilfried SOULEYREAU
Engineer Assistant / AI

Maxime TOUJAS
Technician / Tech