Team 8: Integrated CAncer GENomics (ICAGEN)

Team Leaders: Stéphane Minvielle & Eric Letouzé

Research Program

Multiple myeloma is a complex and heterogeneous cancer that develops from plasma cells in the bone marrow. Despite tremendous advances in drug development, multiple myeloma remains incurable as tumor cells evolve and adapt to treatment. As a result, patients usually develop several relapses requiring new therapeutic strategies.

Our team (ICAGEN) aims at dissecting the genetic and epigenetic mechanisms that underpin cancer development and therapeutic resistance, with a particular focus on immunotherapies (CAR-T cells and bispecific antibodies) that show great promise in myeloma. To that aim, we integrate genomic, epigenomic and transcriptomic data, and we develop innovative single-cell technologies and computational approaches to characterize the evolution of myeloma cells and their interactions with immune cells during treatment. In collaboration with the Hematology department of Nantes CHU and the Intergroupe Francophone du Myélome, we apply this strategy to reconstruct the molecular histories of myeloma patients treated in Nantes or enrolled in multi-centric clinical trials.

Our project is organized in two research axes.

1) Integrated epigenomics of multiple myeloma  (PI: Stéphane Minvielle)

Aberrant DNA methylation is associated with a redistribution of histone modifications, a disruption of 3D compartment as well as a rewiring of 3D chromatin contacts. These cancer mechanisms destabilize gene expression and cellular states and provide intra et inter phenotypic heterogeneity which paves the way to cell-to-cell diversity in transcriptional programs and the opening of multiple trajectories in response to therapy.
In this context, our project is to apply epigenomic technologies to characterize epigenetic reprogramming events that occur in cancer cells of myeloma patients in order to better understand myeloma development and evolution, as well as response to environmental changes and therapeutic resistance.

2) Molecular evolution and drug resistance (PI: Eric Letouzé)

Drug resistance can be due to acquired genomic alterations, epigenetic plasticity or perturbed interaction of tumor cells with their microenvironment. These parameters have rarely been analyzed together and their relative contribution to myeloma resistance is unknown. Besides, new treatments emerge quickly and each myeloma finds its own resistance path across multiple and heterogenous treatment lines. Here, we aim at reconstructing the complete molecular evolution of myelomas by integrating whole genome sequencing, single-cell transcriptomic and epigenetic profiles of cancer cells and surrounding immune cells. We develop innovative computational strategies to integrate the genetic lineage with phenotypic changes. This approach is applied to patients treated at Nantes CHU and receiving new treatments in the context of clinical trials.

Researchers

Stéphane Minvielle, Research Director
Eric Letouzé, Research Director
Florence Magrangeas, Researcher
Marie Denoulet, Postdoc
Nils Giordano, Postdoc

Clinicians

Philippe Moreau, Professor
Loïc Campion, Physician

Technical team

Jennifer Derrien, Research Engineer
Victor Bessonneau-Gaborit, Engineer
Catherine Guérin-Charbonnel, Engineer
Mia Cherkaoui, Engineer
Magali Devic, Technician
Elise Douillard, Technician

Students

Stanislas Riescher-Tuczkiewicz, Intern

stephane.minvielle@univ-nantes.fr
eric.letouze@inserm.fr

Institut de Recherche en Santé de l'Université de Nantes
8 quai Moncousu - BP 70721
44007 Nantes cedex 1

 

Mechanisms of resistance to bispecific T-cell engagers in multiple myeloma and their clinical implications
Letouzé E, Moreau P, Munshi N, Samur M, Minvielle S, Touzeau C
Blood Advances 2024. Jun 11;2952‑59

Acquired resistance to a GPRC5D-directed T-cell engager in multiple myeloma is mediated by genetic or epigenetic target inactivation
Derrien J, Gastineau, S, Frigout A, Giordano N, Cherkaoui M, Gaborit V, Boinon R, Douillard E, Devic M, Magrangeas F, Moreau P, Minvielle S, Touzeau C, Letouzé E
Nat Cancer 2023. Aug 31;1-8

Exploring the Impact of Dexamethasone on Gene Regulation in Myeloma Cells
Bessonneau-Gaborit V, Cruard J, Guérin-Charbonnel C, Derrien J, Alberge JB, Douillard E, Devic M, Roi N, Campion L, Westermann F, Moreau P, Herrmann C, Bourdon J, Magrangeas F, Minvielle S
Life Science Alliance 2023 Jul 30;6(9) e202302195

Structure, Dynamics, and Impact of Replication Stress-Induced Structural Variants in Hepatocellular Carcinoma
Bayard Q, Cordier P, Péneau C, Imbeaud S, Hirsch TZ, Renault V, Nault JC, Blanc JF, Calderaro J, Desdouets C, Zucman-Rossi J**, Letouzé E**
Cancer Res 2022 Apr 15;82(8):1470-1481

Molecular signature of FDG-PET biomarkers in newly diagnosed multiple myeloma patients: a genome-wide transcriptome analysis from the CASSIOPET study
Alberge JB, Kraeber-Bodere F, Jamet B, Touzeau C, Caillon H, Wuilleme S, Bene MC, Kampfenkel T, Sonneveld P, Van Duin M, Avet-Loiseau H, Corre J, Magrangeas F, Carlier T, Bodet-Milin C, Cherel M, Moreau P, Minvielle S, Bailly C
J Nucl Med 2022 Jan 27;jnumed.121.262884

Integrated Genomic Analysis Identifies Driver Genes and Cisplatin-Resistant Progenitor Phenotype in Pediatric Liver Cancer
Hirsch TZ*, Pilet J*, Morcrette G*, Roehrig A, Monteiro BJE, Molina L, Bayard Q, Trépo E, Meunier L, Caruso S, Renault V, Deleuze JF, Fresneau B, Chardot C, Gonzales E, Jacquemin E, Guerin F, Fabre M, Aerts I, Taque S, Laithier V, Branchereau S, Guettier C, Brugières L, Rebouissou S, Letouzé E**, Zucman-Rossi J**
Cancer Discov. 2021 Oct;11(10):2524-2543

The DNA methylation landscape of multiple myeloma shows extensive inter- and intrapatient heterogeneity that fuels transcriptomic variability
Derrien J, Guérin-Charbonnel C, Gaborit V, Campion L, Douillard E, Devic M, Roi N, Avet-Loiseau H, Decaux O, Facon T, Mallm J-P, Eils R, Munshi NC, Moreau P, Herrmann C, Magrangeas F and Minvielle S
Genome Med 2021 Aug 9;13(1):127.

DNA hydroxymethylation is associated with disease severity and persists at enhancers of oncogenic regions in multiple myeloma
Alberge JB, Magrangeas F, Wagner M, Denié S, Guérin-Charbonnel C, Campion L, Attal M, Avet-Loiseau H, Carell T, Moreau P, Minvielle S, Sérandour AA
Clin Epigenetics. 2020 Nov 2;12(1):163
 

• No specific announcement at the moment.

If you are interested in joining the team, please feel free to submit your spontaneous application to us.