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

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

Les recherches de l’équipe Rytme portent sur le rôle de la sécrétion et la maturation des protéines dans le microenvironnement tumoral (cellules tumorales et immunitaires, fibroblastes, etc..) au cours de la progression tumorale et de la métastase. Notre objectif principal est d’évaluer l’utilisation potentielle des voies de sécrétion protéique du microenvironnement tumoral comme marqueurs pronostiques et/ou cibles thérapeutiques.   Voir interview TV FR3 2021 : Subconazol, la molécule anti-Covid-19 transfrontalière du Pays basque.


Mots-clés

AGRs, furine, convertases, Apeline, Elabela, miroenvironement tumoral, organoïdes, poisson zèbre

Actualités


Projets

AGR, Tumour Niche and Secretome – ARTiSt

The project “AGR, Tumor Niche & Secretome” (ARTiSt) aims at understanding how tumour cells initiate and maintain a tumour niche which favors tumour development. Through the release of specific extracellular signals, cancer cells recruit/activate non-transformed host cells such as immune or endothelial cells (Fig.1). Then the material (proteins, lipids…) secreted by both cancer and stromal cells, shapes the extracellular proteome which in turn plays a critical role in controlling the establishment of a protumoral tumour niche (Fig.1). In particular, our work as brought us to focus on the Anterior GRadient (AGR) family of proteins which act on the tumour niche through 2 different modes, including intracellular and extracellular functions. This occurs either intracellularly via the control of Endoplasmic Reticulum (ER) proteostasis, by affecting tumour or stromal cells secretomes, or extracellularly, when AGR proteins are secreted and act as pro-oncogenic factors. The objectives of our research group are to explore: 1 – How intracellular AGR (iAGR) proteins in tumour cells can impact on the tumour niche: We investigate how iAGR proteins, by regulating ER proteostasis capacity, could have an impact on the nature of the tumour cell secretome, and consequently contributing to the initiation and development of tumour niche. 2 – How extracellular AGR (eAGR) proteins signal towards tumour and stromal cells: We investigate how eAGR proteins, as microenvironmental factors, could have an impact on cancer and stromal cells in tumour-associated processes.


Membres du projet

Publications remarquables
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
The Anterior GRadient (AGR) family proteins in epithelial ovarian cancer.
Fessart D, Robert J, Hartog C, Chevet E, Delom F, Babin G
Journal of experimental & clinical cancer research : CR ; 2021 Aug 27
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
Extracellular AGR3 regulates breast cancer cells migration via Src signaling.
Obacz J, Sommerova L, Sicari D, Durech M, Avril T, Iuliano F, Pastorekova S, Hrstka R, Chevet E, Delom F, Fessart D
Oncology letters ; 2019 Nov 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

Plateforme POETIC

La plateforme PhenOtypic scrEening TechnICal (POETIC) permet l’automatisation d’essais miniaturisés de criblage phénotypique, pour comprendre les mécanismes moléculaires qui régulent la transformation cellulaire et la croissance tumorale. La directrice scientifique de la plateforme est Delphine Fessart.

A ce jour, POETIC a réalisé avec succès un certain nombre de tests de dépistage phénotypique :

4 – Reprogrammation directe des cellules épithéliales humaines en organoïdes par miR-106a-3p. BioRxiv. (doi : https://doi.org/10.1101/314658)

3 – L’AGR2 extracellulaire déclenche la prolifération des cellules tumorales pulmonaires par la répression de p21CIP1. BBA Recherche sur les cellules moléculaires. (2021)

2 – Patients Lung Derived Tumoroids (PLDTs) pour modéliser la réponse thérapeutique. BBA Recherche sur les cellules moléculaires. (2020)

1 – Le contrôle de la dimérisation du GRadient antérieur 2 (AGR2) relie la protéostase du réticulum endoplasmique à l’inflammation. EMBO Mol Med.(2019)


Membres du projet

Publications remarquables
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
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
Control of anterior GRadient 2 (AGR2) dimerization links endoplasmic reticulum proteostasis to inflammation.
Maurel M, Obacz J, Avril T, Ding YP, Papadodima O, Treton X, Daniel F, Pilalis E, Hörberg J, Hou W, Beauchamp MC, Tourneur-Marsille J, Cazals-Hatem D, Sommerova L, Samali A, Tavernier J, Hrstka R, Dupont A, Fessart D, Delom F, Fernandez-Zapico ME, Jansen G, Eriksson LA, Thomas DY, Jerome-Majewska L, Hupp T, Chatziioannou A, Chevet E, Ogier-Denis E
EMBO molecular medicine ; 2019 Jun 01

Protein Maturation by PCSKs and Onco-Immunology


Membres du projet

Publications remarquables
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

Offres d’emploi


Publications remarquables de l’équipe

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


Partenaires

Chef(s) d’équipe

A.Majid KHATIB
Research Director / DR

Frederic DELOM
Lecturer / MCU


Toute l’équipe

Guillaume BABIN
Clinician / PH

Frederic DELOM
Lecturer / MCU

Delphine FESSART
Researcher / CR

Marianne GUILBARD
PhD Student / Doc

Cecile HARTOG
Clinician / PH

A.Majid KHATIB
Research Director / DR

Coriolan LEBRETON
Clinician / PH

Jacques ROBERT
Professor Emeritus / PU émérite

Saïd TAOUJI
Engineer / IE

Ines VILLAMOR
Technician / Tech