Team 02 - Reprograming tumor activitY and associaTed MicroenvironmEnt (Rytme).

Équipe 02 – Reprogrammation de l’activité tumorale et du microenvironnement associé (Rytme).

The research of the team is mainly dealing with the role of the secretory pathway during tumour initiation and progression, and tumour cells interaction with their microenvironment. Our main objective is to evaluate the potential use of the tumour secretory pathway signalling and associated tumour microenvironment molecules as cancer prognostic markers and/or therapeutic targets.   See interview TV FR3 2021: Subconazol, la molécule anti-Covid-19 transfrontalière du Pays basque

Keywords

AGRs, furin, convertases, Apelin, Elabela, tumoral miroenvironnement, organoids, zebrafish

News

Events

Projects

AGR, ProTeostasis & Cellular plaSticity - ARTiSt Lab

The ARTiSt (AGR, ProTeostasis & Cellular plaSticity) Lab primarily focuses on investigating the responses to endoplasmic reticulum (ER) stress in cancer development. Specifically, the lab aims to understand how ER stress responses, particularly those related to proteostasis and cell plasticity, can be exploited to identify new biomarkers, new therapeutic targets, and ultimately new therapeutic strategies.

The Lab consists of two research groups, each led by Dr. Delphine Fessart (Researcher, UB) and Dr. Frederic Delom (MCF, UB). It comprises about ten members, including clinicians, technical staff, students and post-doctoral fellows.

 

Research Project: Cancer progression involves the adaptation of tumour cells to a multitude of both intrinsic and extrinsic factors. Some of these adaptations are, in part, driven by ER stress responses to control proteostasis and cellular plasticity. We have demonstrated an interaction between ER stress with both proteostasis and cell plasticity through the Anterior Gradient (AGR) family. AGR proteins belong to the ER-resident PDI family, essential for ER homeostasis. Moreover, they can relocate to the cytosol or extracellular microenvironment, to gain pro-oncogenic functions.

The aims of our research project are as follows:

  1. Investigate mechanisms by which proteostasis reprogramming, induced by ER stress, signalled throughout the cell and its microenvironment (F Delom).
  2. Investigate the role of ER stress in the reprogramming of tumour cell plasticity, in particular epithelial-mesenchymal transition (EMT) and senescence, within the framework of therapy resistance (D Fessart).

 

Academic Funding:

Institut Bergonié, Inserm, National Cancer Institute (PLBio), French League Against Cancer, MyTIGER, Nouvelle Aquitaine Region.

 

Collaborative network: 

National – D Bernard (Lyon), F Carreiras (Orsay), C Chaveroux (Lyon), E Chevet (Rennes), S Croce (Bordeaux), L Poulain (Caen). The team is affiliated with the GDR Organoïdes network (https://gdr-organoides.cnrs.fr/) and the ARCAGY-GINECO network (https://arcagy.org/).

International – A Chatziioannou (Greece), KP Janssen (Germany), MA Mohtar (Malaysia), A Igbaria (Israel). The team is part of the COST network Proteocure (https://proteocure.eu/).

 

Project members
Noteworthy publications
Secretion of protein disulphide isomerase AGR2 confers tumorigenic properties.
Fessart D, Domblides C, Avril T, Eriksson LA, Begueret H, Pineau R, Malrieux C, Dugot-Senant N, Lucchesi C, Chevet E, Delom F
eLife ; 2016 May 30
The role of protein disulphide isomerase AGR2 in the tumour niche.
Delom F, Nazaraliyev A, Fessart D
Biology of the cell ; 2018 Dec 01
Extracellular AGR2 triggers lung tumour cell proliferation through repression of p21CIP1.
Fessart D, de Barbeyrac C, Boutin I, Grenier T, Richard E, Begueret H, Bernard D, Chevet E, Robert J, Delom F
Biochimica et biophysica acta. Molecular cell research ; 2021 Mar 01
Integrative analysis of genomic and transcriptomic alterations of AGR2 and AGR3 in cancer.
Fessart D, Villamor I, Chevet E, Delom F, Robert J
Open biology ; 2022 Jul 01
AGR2 protein expression in colorectal tumour epithelialcompartment.
Chevet E, Bassal F, Beq S, Bonhomme B, Boisteau E, Calloch J, Cazals-Hatem D, Delom F, Fessart D, Evrard S, Hrstka R, Hupp T, Lièvre A, Louis E, Mariau J, Meuwis MA, Ogier-Denis E, Paradis V, Pernot S, Pineau R, Treton X, Velasco V, Vieujean S
Gut ; 2022 Dec 09

Protein Maturation by PCSKs and Onco-Immunology

PCSK family consists of 7 members, namely, furin, PC1, PC2, PC4, PACE4, PC5 and PC7 that convert their unprocessed substrates into functional molecules by cleaving their basic amino acid motifs (K/R)-(X)n-(K/R)↓, where n is 0, 2, 4, or 6 and X is any amino acid. These enzymes play an influential role in maintaining homeostasis but also are involved in various pathological conditions. Various PCSKs activate proteins involved in malignant transformation and progression including cell surface-expressed receptors (e.g., integrins, matrix metalloproteinases (MMPs), and growth factors and receptor required for tumor angiogenesis, including VEGF-C and IGF-1 Receptor.

Recently, we revealed the first direct evidence for the critical importance of PCSK activity in the regulation of the immune checkpoint inhibitors, particularly PD-1 on T cells and their importance in TILs infiltration in developed tumors.

In the current project using various in vitro and in vivo assays we will characterize the importance of PCSK in immune checkpoints, and tumorigenesis. The results that will be obtained will shed more light on how blocking PCSK activity and signaling might open doors to a new class of anti-tumorigenic and immune checkpoints regulators.

Project members
Noteworthy publications
Inactivation of Proprotein Convertases in T Cells Inhibits PD-1 Expression and Creates a Favorable Immune Microenvironment in Colorectal Cancer.
Tomé M, Pappalardo A, Soulet F, López JJ, Olaizola J, Leger Y, Dubreuil M, Mouchard A, Fessart D, Delom F, Pitard V, Bechade D, Fonck M, Rosado JA, Ghiringhelli F, Déchanet-Merville J, Soubeyran I, Siegfried G, Evrard S, Khatib AM
Cancer research ; 2019 Oct 01
Loss of the proprotein convertase Furin in T cells represses mammary tumorigenesis in oncogene-driven triple negative breast cancer.
He Z, Khatib AM, Creemers JWM
Cancer letters ; 2020 Aug 01

Jobs offers

Team’s noteworthy publications

Patients Lung Derived Tumoroids (PLDTs) to model therapeutic response.
Delom F, Begiristain I, Grenier T, Begueret H, Soulet F, Siegfried G, Khatib AM, Robert J, Fessart D
Biochimica et biophysica acta. Molecular cell research ; 2020 Nov 01
Inactivation of Proprotein Convertases in T Cells Inhibits PD-1 Expression and Creates a Favorable Immune Microenvironment in Colorectal Cancer.
Tomé M, Pappalardo A, Soulet F, López JJ, Olaizola J, Leger Y, Dubreuil M, Mouchard A, Fessart D, Delom F, Pitard V, Bechade D, Fonck M, Rosado JA, Ghiringhelli F, Déchanet-Merville J, Soubeyran I, Siegfried G, Evrard S, Khatib AM
Cancer research ; 2019 Oct 01
Secretion of protein disulphide isomerase AGR2 confers tumorigenic properties.
Fessart D, Domblides C, Avril T, Eriksson LA, Begueret H, Pineau R, Malrieux C, Dugot-Senant N, Lucchesi C, Chevet E, Delom F
eLife ; 2016 May 30
AGR2 protein expression in colorectal tumour epithelialcompartment.
Chevet E, Bassal F, Beq S, Bonhomme B, Boisteau E, Calloch J, Cazals-Hatem D, Delom F, Fessart D, Evrard S, Hrstka R, Hupp T, Lièvre A, Louis E, Mariau J, Meuwis MA, Ogier-Denis E, Paradis V, Pernot S, Pineau R, Treton X, Velasco V, Vieujean S
Gut ; 2022 Dec 09

Partners

Team leaders

A.Majid KHATIB
Research Director / DR

Frederic DELOM
Lecturer / MCU

Team members

Guillaume BABIN
Clinician / PH

Frederic DELOM
Lecturer / MCU

Sandrine FEDOU
Engineer Assistant / AI

Delphine FESSART
Researcher / CR

Marianne GUILBARD
PhD Student / Doc

Frédéric GUYON
Clinician / PH

Cecile HARTOG
Clinician / PH

A.Majid KHATIB
Research Director / DR

Coriolan LEBRETON
Clinician / PH

Jacques ROBERT
Professor Emeritus / PU émérite

Saïd TAOUJI
Engineer / IE