TGF-ß signaling in cell plasticity and cancer

Céline Prunier
Team leader(s) : Céline Prunier
Administrative contact : Sandrine Gromat

Saint-Antoine Hospital - Kourilsky Building – 4th floor
184, rue du Faubourg Saint-Antoine - 75012 Paris - France

Professors, Lecturers, Researchers, Clinicians
Post-docs, Contract researchers, Emeritus, Volunteering
Engineers, Technicians
PhD candidates, MSc students

Our laboratory is focused on the fundamental aspects of cancer cell biology and cell signaling induced by TGF-β. Alterations that inactivate TGF-β signaling are known to trigger early tumorigenesis events by abolishing TGF-β anti-proliferative and pro-apoptotic effects, while excessive presence of TGF-β in the tumor microenvironment at later stages of the tumorigenesis promotes tumor aggressiveness by increasing epithelial-mesenchymal transition (EMT), invasion, metastasis, and immunosuppression. Our research projects aim at understanding this dual and intricate role of TGF-β in cancer development through diverse approaches and methodologies. TGF-β’s biological effects are determined by key successive events including TGFβ ligand bioavailability, binding to receptors and downstream intracellular signaling. Our vision is to conduct an integrated research spanning from ligand presentation to cellular responses. In particular, we aim (1) to investigate the newly discovered role of exosomes in TGF-β presentation, (2) to deepen the investigation of the E3 ubiquitin ligases in TGF-β downstream signaling and understand their involvement in tumor formation and metastasis, (3) to understand the mechanisms involved in TGF-β induced cellular responses during late stages of cancer progression including EMT, cell invasion, and chemoresistance.


Team 1 : Role of exosome-bound TGF-β in TGF-β signaling and cancer (lead I. Petit & O. Ferrigno)

Exosomes are extracellular vesicles secreted by tumor cells that carry a myriad of bioactive molecules that influence the tumor, its microenvironment and the immune system. These biological messengers favor aggressiveness and mediate therapy resistance. The utility of exosomes in predictive oncology is promising because of their presence in all biological fluids and their potential for multiplexed biomarker analyses. Thus, they could offer great opportunities for easy detection of tumor material by liquid biopsy. Our team investigates the role of exosomes in cytokine functions. Our data suggest a new function for exosomes as a major component of cytokine signaling by binding growth factors on their surface. We aim to further investigate the interplay between exosomes and cytokines during tumor progression by focusing on: 1/ understanding the molecular mechanism of TGF-β presentation on exosomes, 2/ identifying in vivo such interactions in plasma of cancer patients.

Team members : I. Petit (CRCN INSERM), O. Ferrigno (CRCN INSERM)

Main publications :
Fibroblast growth factor-2 bound to specific dermal fibroblast-derived extracellular vesicles is protected from degradation. Petit I, Levy A, Estrach S, Féral CC, Trentin AG, Dingli F, Loew D, Qu J, Zhou H, Théry C, Prunier C, Aberdam D, Ferrigno O. Sci Rep. 2022 Dec 22;12(1):22131. doi: 10.1038/s41598-022-26217-8

Purification of Extracellular Microvesicles Secreted by Dermal Fibroblasts. Petit I, Levy A, Aberdam D. Methods Mol Biol. 2020;2154:63-72. doi: 10.1007/978-1-0716-0648-3_6.


Team 2 : Mechanism of action and regulation of E3 ubiquitin ligases in TGF-β downstream signaling (lead L. Levy & C. Prunier)

Our laboratory studies the mechanisms by which ubiquitination and ubiquitination-like modifications affect TGF-β signaling during tumor and metastatic progression. More specifically, we have characterized different E3 ubiquitin ligases including Arkadia/RNF111 and WWP1 that are deregulated in cancers and modulate TGF-β signaling. We are currently searching for new substrates and modulators of these E3 ubiquitin ligases to better understand their involvement in tumor formation and metastasis and focus our efforts towards the diagnostic and therapeutic exploitation of our findings.

Team members : L. Levy (CRCN INSERM). C Prunier (CRCN INSERM), T. Perron (PhD student), S. Colasse (IE)

Main publications :
The UAS thioredoxin-like domain of UBXN7 regulates E3 ubiquitin ligase activity of RNF111/Arkadia. Amhaz S, Boëda B, Chouchène M, Colasse S, Dingli F, Loew D, Henri J, Prunier C, Levy L. BMC Biol. 2023 Apr 7;21(1):73. doi: 10.1186/s12915-023-01576-4. PMID: 37024974

Quantitative Ubiquitylome Analysis Reveals the Specificity of RNF111/Arkadia E3 Ubiquitin Ligase for its Degradative Substrates SKI and SKIL/SnoN in TGF-β Signaling Pathway. Laigle V, Dingli F, Amhaz S, Perron T, Chouchène M, Colasse S, Petit I, Poullet P, Loew D, Prunier C, Levy L. Mol Cell Proteomics. 2021;20:100173. doi: 10.1016/j.mcpro.2021.100173. Epub 2021 Nov 3. PMID: 34740826

Functional Characterization of a WWP1/Tiul1 Tumor-derived Mutant Reveals a Paradigm of Its Constitutive Activation in Human Cancer. Courivaud T, Ferrand N, Elkhattouti A, Kumar S, Levy L, Ferrigno O, Atfi A, Prunier C. J Biol Chem. 2015 Aug 21;290(34):21007-21018. doi: 10.1074/jbc.M115.642314. Epub 2015 Jul 7. PMID: 26152726

Disruption of the PHRF1 Tumor Suppressor Network by PML-RARα Drives Acute Promyelocytic Leukemia Pathogenesis. Prunier C, Zhang MZ, Kumar S, Levy L, Ferrigno O, Tzivion G, Atfi A. Cell Rep. 2015 Feb 17;10(6):883-890. doi: 10.1016/j.celrep.2015.01.024. Epub 2015 Feb 12. PMID: 25683711

Arkadia, a novel SUMO-targeted ubiquitin ligase involved in PML degradation. Erker Y, Neyret-Kahn H, Seeler JS, Dejean A, Atfi A, Levy L. Mol Cell Biol. 2013 Jun;33(11):2163-77. doi: 10.1128/MCB.01019-12. Epub 2013 Mar 25. PMID: 23530056


Team 3 : Metastatic dissemination: TGF-β-induced epithelial-mesenchymal transition, senescence, invasion, and chemoresistance (lead M. Boissan, A. Karaiskou & J. Sobczak)

Our research focuses on cellular aspects of late stages of cancer progression, when TGF-β promotes tumor aggressiveness by inducing EMT, associated with the acquisition of migratory and invasive properties, and chemoresistance.

• Emerging links between cellular senescence, epithelial-mesenchymal transition and early tumor cell invasion (lead M. Boissan)

We currently work on the role of nucleoside diphosphate kinases, which are nucleotide metabolism enzymes involved in membrane remodeling, in metastasis dissemination and local invasion as the first member NME1 has been identified as the first metastasis suppressor gene. We are deciphering the mechanisms by which these enzymes exert their antimetastatic activity.
The senescence process is associated with a stable proliferation arrest and a particular secretome, which contains multiple factors including matrix metalloproteases and extracellular matrix components. Epithelial-mesenchymal transition (EMT) process during tumorigenesis is impacting extracellular matrix deposition and cell migration and invasion and is often associated to a proliferation arrest. Some previous results link these two cellular programs. For instance, senescent cells are proposed to promote EMT in a paracrine manner to the neighboring cells through their secretome. Our project aims to demonstrate that cell senescence and EMT can occur in the same tumor cells and to dissect the common molecular drivers between these two phenotypes, and to investigate whether preventing senescence or eliminating senescent cells will impact tumor cell invasion. In long term, it could help identifying tools targeting senescent cells to block tumor cell invasion and thus metastasis dissemination.

Team members: M. Boissan (MCU-PH), H. Debost (IE), C. Monraz (PhD student)

Main publications :
Membrane trafficking. Nucleoside diphosphate kinases fuel dynamin superfamily proteins with GTP for membrane remodeling. Boissan M, Montagnac G, Shen Q, Griparic L, Guitton J, Romao M, Sauvonnet N, Lagache T, Lascu I, Raposo G, Desbourdes C, Schlattner U, Lacombe ML, Polo S, van der Bliek AM, Roux A, Chavrier P. Science. 2014 Jun 27;344(6191):1510-5. doi: 10.1126/science.1253768. PMID: 24970086

NDPK-D (NM23-H4)-mediated externalization of cardiolipin enables elimination of depolarized mitochondria by mitophagy. Kagan VE, Jiang J, Huang Z, Tyurina YY, Desbourdes C, Cottet-Rousselle C, Dar HH, Verma M, Tyurin VA, Kapralov AA, Cheikhi A, Mao G, Stolz D, St Croix CM, Watkins S, Shen Z, Li Y, Greenberg ML, Tokarska-Schlattner M, Boissan M, Lacombe ML, Epand RM, Chu CT, Mallampalli RK, Bayır H, Schlattner U. Cell Death Differ. 2016 Jul;23(7):1140-51. doi: 10.1038/cdd.2015.160. Epub 2016 Jan 8. PMID: 26742431

The mitochondrially-localized nucleoside diphosphate kinase D (NME4) is a novel metastasis suppressor. Lacombe ML, Lamarche F, De Wever O, Padilla-Benavides T, Carlson A, Khan I, Huna A, Vacher S, Calmel C, Desbourdes C, Cottet-Rousselle C, Hininger-Favier I, Attia S, Nawrocki-Raby B, Raingeaud J, Machon C, Guitton J, Le Gall M, Clary G, Broussard C, Chafey P, Thérond P, Bernard D, Fontaine E, Tokarska-Schlattner M, Steeg P, Bièche I, Schlattner U, Boissan M. BMC Biol. 2021 Oct 21;19(1):228. doi: 10.1186/s12915-021-01155-5. PMID: 34674701

Metastasis-suppressor NME1 controls the invasive switch of breast cancer by regulating MT1-MMP surface clearance. Lodillinsky C, Fuhrmann L, Irondelle M, Pylypenko O, Li XY, Bonsang-Kitzis H, Reyal F, Vacher S, Calmel C, De Wever O, Bièche I, Lacombe ML, Eiján AM, Houdusse A, Vincent-Salomon A, Weiss SJ, Chavrier P, Boissan M. Oncogene. 2021 Jun;40(23):4019-4032. doi: 10.1038/s41388-021-01826-1. Epub 2021 May 19. PMID: 34012098

Force tuning through regulation of clathrin-dependent integrin endocytosis. Kyumurkov A, Bouin AP, Boissan M, Manet S, Baschieri F, Proponnet-Guerault M, Balland M, Destaing O, Régent-Kloeckner M, Calmel C, Nicolas A, Waharte F, Chavrier P, Montagnac G, Planus E, Albiges-Rizo C. J Cell Biol. 2023 Jan 2;222(1):e202004025. doi: 10.1083/jcb.202004025. Epub 2022 Oct 17. PMID: 36250940

• KIF20A in tumor invasion (lead A. Karaiskou)

The KIF20A kinesin is one of the upregulated hub genes associated with cancer progression (Mushtaq et al., 2022). Although its essential role in cytokinesis has been thoroughly documented, very little is known about its implication in key metastatic steps such as acquisition of motility and invasion. Our project aims at elucidating the molecular mechanism by which KIF20A participates to these EMT-related structural changes, in particular through intracellular trafficking of key adhesion and signaling proteins. KIF20A is also investigated as a new potential anti-cancer therapy target.

Team members : A. Karaiskou (MCU), J. Sobczak (Pr), J. Selot (PhD student), S. Colasse (IE)

Main publication:
KIF20A mRNA and its product MKlp2 are increased during hepatocyte proliferation and hepatocarcinogenesis. Gasnereau I, Boissan M, Margall-Ducos G, Couchy G, Wendum D, Bourgain-Guglielmetti F, Desdouets C, Lacombe ML, Zucman-Rossi J, Sobczak-Thépot J. Am J Pathol. 2012 Jan;180(1):131-40. doi: 10.1016/j.ajpath.2011.09.040. Epub 2011 Nov 1.

• Metallo drugs as new anti-cancer therapies to overcome chemoresistance (lead J. Sobczak)

Chemoresistance is a critical challenge in cancer. Long term activation of the TGF-β pathway leads to cell reprogramming and chemotherapy resistance, providing the rationale to develop innovative chemotherapeutic approaches. Through a collaboration with a team of chemists led by Dr M. Salmain (IPCM, Paris), we are characterizing the mode of action of new metal-based drugs that are able to form adducts with intracellular proteins, to induce a redox imbalance and to trigger cell death. Our current research focuses on the quantification and localization of the drugs, has initiated biochemical analyses to identify and validate their protein targets and the altered signaling pathways, as well as their ability to overcome TGF-β induced chemoresistance.

Team members : J. Sobczak (Pr), A. Karaiskou (MCU), S. Amhaz (Post-doc)

Main publications :
Cytotoxic BODIPY-Appended Half-Sandwich Iridium(III) Complex Forms Protein Adducts and Induces ER Stress. Ramos R, Gilles JF, Morichon R, Przybylski C, Caron B, Botuha C, Karaiskou A, Salmain M, Sobczak-Thépot J. J Med Chem. 2021 Nov 25;64(22):16675-16686. doi: 10.1021/acs.jmedchem.1c01335. Epub 2021 Nov 11.

Insights into the antiproliferative mechanism of (C^N)-chelated half-sandwich iridium complexes. Ramos R , Zimbron JM , Thorimbert S , Chamoreau LM , Munier A , Botuha C , Karaiskou A , Salmain M , Sobczak-Thépot J . Dalton Trans. 2020 Dec 22;49(48):17635-17641. doi: 10.1039/d0dt03414b.

St. Antoine Hospital

Kourilsky Building
34 rue Crozatier - 75012 Paris

Sorbonne Université Medicine
Saint-Antoine Site
27 rue Chaligny - 75012 Paris

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