Team 08 - Biotherapies Genetics and Oncology (BioGO)

Équipe 08 – Biotherapies Génétique et Oncologie (BioGO)

The BioGO team gathers strong expertise in gene therapy, fundamental and practical aspects of genome editing, genetic-related cancer initiation and predisposition and protein and nucleic acid-derived circulating cancer biomarkers. Technically, in addition to routinely used mouse-based in vivo experimental models, the team also possesses state-of-the-art molecular and cellular tools, such as induced pluripotent stem cells (human iPSCs), CRISPR-Cas technology, high throughput gene analysis and vectorology. Our cell and gene therapy knowledge from non-cancer hereditary diseases is used to propose innovative patient management with porphyria and to create tumor genetic vulnerabilities by cancer gene therapy or with naturally occurring molecules to render tumor cells sensitive to conventional treatments. We also explore CRISPR-CAS genotoxicity, focusing on the oncologic risk, and work on CRISPR-Cas gene therapy safety. Our translational program focused on identifying constitutive mutations leading to cancer susceptibility and detecting circulating cancer elements by liquid biopsy.


Keywords

Gene therapy, crispr-cas, genetic vulnerability, genome editing, pancreatic cancer, rectal cancer, prostate cancer, phototherapy, radiotherapy, bioactive food components

News


Projects

Cancer liquid biopsy

Liquid biopsy is a promising tool to help therapeutic decision-making. Our research program on liquid biopsy is the result of tight interactions between the research unit and the clinicians of the team. A multimodal liquid biopsy can improve the sensitivity of pancreatic ductal adenocarcinoma (PANC-CTC, clinical trial # NCT03032913), for which we are testing the highly sensitive CRISPR-Cas tool. We are also assessing resectable tumor aggressiveness by high scale proteomic analysis. We are developing the extracellular vesicle-based liquid biopsy of rectum cancer response assessment (RECC-EV, clinical trial # NCT04852653).


Project members

Noteworthy publications
KRAS gene mutation quantification in the resection or venous margins of pancreatic ductal adenocarcinoma is not predictive of disease recurrence.
Amintas S, Fernandez B, Chauvet A, Chiche L, Laurent C, Belleannée G, Marty M, Buscail E, Dabernat S
Scientific reports ; 2022 Feb 22
Next-Generation Cancer Biomarkers: Extracellular Vesicle DNA as a Circulating Surrogate of Tumor DNA.
Amintas S, Vendrely V, Dupin C, Buscail L, Laurent C, Bournet B, Merlio JP, Bedel A, Moreau-Gaudry F, Boutin J, Dabernat S, Buscail E
Frontiers in cell and developmental biology ; 2021 Feb 02
Circulating Tumor Cell Clusters: United We Stand Divided We Fall.
Amintas S, Bedel A, Moreau-Gaudry F, Boutin J, Buscail L, Merlio JP, Vendrely V, Dabernat S, Buscail E
International journal of molecular sciences ; 2020 Apr 10
High Clinical Value of Liquid Biopsy to Detect Circulating Tumor Cells and Tumor Exosomes in Pancreatic Ductal Adenocarcinoma Patients Eligible for Up-Front Surgery.
Buscail E, Alix-Panabières C, Quincy P, Cauvin T, Chauvet A, Degrandi O, Caumont C, Verdon S, Lamrissi I, Moranvillier I, Buscail C, Marty M, Laurent C, Vendrely V, Moreau-Gaudry F, Bedel A, Dabernat S, Chiche L
Cancers ; 2019 Oct 26
CD63-GPC1-Positive Exosomes Coupled with CA19-9 Offer Good Diagnostic Potential for Resectable Pancreatic Ductal Adenocarcinoma.
Buscail E, Chauvet A, Quincy P, Degrandi O, Buscail C, Lamrissi I, Moranvillier I, Caumont C, Verdon S, Brisson A, Marty M, Chiche L, Laurent C, Vendrely V, Moreau-Gaudry F, Bedel A, Dabernat S
Translational oncology ; 2019 Nov 01

Heme biosynthesis deficiency in genetic diseases and cancers: therapeutic approaches and implication in oncogenesis

Porphyrias are inherited metabolic diseases of heme biosynthesis characterized by the toxic overproduction and clearance of porphyrins and/or their precursors ALA and PBG. The team develops new concepts of therapeutic approaches based on the identification of enzymes and/or metabolic pathways that could be targeted by pharmacological molecules using high-throughput screening strategies (chemical and CRISPR lentiviral libraries). The candidates will be evaluated in new cellular models of porphyria available in the laboratory as well as in murine models of the disease. The team is also interested by the role of heme and biosynthesis in oncogenesis. Team members lead both diagnostic laboratory and clinical reference centers for porphyrias at the Bordeaux University Teaching Hospital of Bordeaux and are involved in national and international networks for heme synthesis disorders.


Project members

Noteworthy publications
Iron chelation rescues hemolytic anemia and skin photosensitivity in congenital erythropoietic porphyria.
Blouin JM, Ged C, Lalanne M, Lamrissi-Garcia I, Morice-Picard F, Costet P, Daher R, Moreau-Gaudry F, Bedel A, Puy H, Gouya L, Karim Z, Richard E
Blood ; 2020 Nov 19
Repurposing ciclopirox as a pharmacological chaperone in a model of congenital erythropoietic porphyria.
Urquiza P, Laín A, Sanz-Parra A, Moreno J, Bernardo-Seisdedos G, Dubus P, González E, Gutiérrez-de-Juan V, García S, Eraña H, San Juan I, Macías I, Ben Bdira F, Pluta P, Ortega G, Oyarzábal J, González-Muñiz R, Rodríguez-Cuesta J, Anguita J, Díez E, Blouin JM, de Verneuil H, Mato JM, Richard E, Falcón-Pérez JM, Castilla J, Millet O
Science translational medicine ; 2018 Sep 19
Phlebotomy as an efficient long-term treatment of congenital erythropoietic porphyria.
Mirmiran A, Poli A, Ged C, Schmitt C, Lefebvre T, Manceau H, Daher R, Moulouel B, Peoc'h K, Simonin S, Blouin JM, Deybach JC, Nicolas G, Puy H, Richard E, Gouya L
Haematologica ; 2021 Mar 01
Missense UROS mutations causing congenital erythropoietic porphyria reduce UROS homeostasis that can be rescued by proteasome inhibition.
Blouin JM, Bernardo-Seisdedos G, Sasso E, Esteve J, Ged C, Lalanne M, Sanz-Parra A, Urquiza P, de Verneuil H, Millet O, Richard E
Human molecular genetics ; 2017 Apr 15
Therapeutic potential of proteasome inhibitors in congenital erythropoietic porphyria.
Blouin JM, Duchartre Y, Costet P, Lalanne M, Ged C, Lain A, Millet O, de Verneuil H, Richard E
Proceedings of the National Academy of Sciences of the United States of America ; 2013 Nov 05

CRISPR-Cas9 genotoxicity: detect, understand, prevent

CRISPR-Cas9 nuclease is a very promising technology for gene therapy. The first clinical trials have started. However, genome editing, to be safe, must be precise and reliable. Genotoxicity at the targeted locus (ON-target) is little studied. Unexpectedly, we observed megabase-scale loss-of heterozygoties, following the use of Cas9 nuclease to edit the genome at the UROS (Chr10) and the globin (Chr11) loci in cell lines and primary cells. These results raise a potential new worrisome safety issue for CRISPR use in clinic. Indeed, theses undesired outcomes can lead to impact cell behavior. This nuclease side-effect was recently confirmed in human embryos. This project measures their functional impact, and reveals the molecular mechanism(s) to find solutions to secure CRISPR-Cas9 technology.


Project members

Noteworthy publications
ON-Target Adverse Events of CRISPR-Cas9 Nuclease: More Chaotic than Expected.
Boutin J, Cappellen D, Rosier J, Amintas S, Dabernat S, Bedel A, Moreau-Gaudry F
The CRISPR journal ; 2022 Feb 01
CRISPR-Cas9 globin editing can induce megabase-scale copy-neutral losses of heterozygosity in hematopoietic cells.
Boutin J, Rosier J, Cappellen D, Prat F, Toutain J, Pennamen P, Bouron J, Rooryck C, Merlio JP, Lamrissi-Garcia I, Cullot G, Amintas S, Guyonnet-Duperat V, Ged C, Blouin JM, Richard E, Dabernat S, Moreau-Gaudry F, Bedel A
Nature communications ; 2021 Aug 13
Mutation-Specific Guide RNA for Compound Heterozygous Porphyria On-target Scarless Correction by CRISPR/Cas9 in Stem Cells.
Prat F, Toutain J, Boutin J, Amintas S, Cullot G, Lalanne M, Lamrissi-Garcia I, Moranvillier I, Richard E, Blouin JM, Dabernat S, Moreau-Gaudry F, Bedel A
Stem cell reports ; 2020 Sep 08
ON-Target Adverse Events of CRISPR-Cas9 Nuclease: More Chaotic than Expected.
Boutin J, Cappellen D, Rosier J, Amintas S, Dabernat S, Bedel A, Moreau-Gaudry F
The CRISPR journal ; 2022 Feb 01
Metabolic correction of congenital erythropoietic porphyria with iPSCs free of reprogramming factors.
Bedel A, Taillepierre M, Guyonnet-Duperat V, Lippert E, Dubus P, Dabernat S, Mautuit T, Cardinaud B, Pain C, Rousseau B, Lalanne M, Ged C, Duchartre Y, Richard E, de Verneuil H, Moreau-Gaudry F
American journal of human genetics ; 2012 Jul 13

Modelling and study of pathogenic consequences of genetic alterations linked to oncogenesis

Oncogenesis is a multistep process due to cumulative molecular alterations. For certain genomic regions known to be altered in cancers, the target genes have still not been identified. Uncovering these genes and their biological functions is essential for understanding the carcinogenic process and for better cancer patients’ management. The absence of relevant cell lines carrying the genetic alterations of interest, but also the fact that, when such cell lines are available, they exhibit many other molecular alterations, is a major limitation to study the pathogenic contribution of individual genomic hits. The genetic engineering approaches that we master in our team (CRISPR-Cas9, expression and RNA interference lentiviral vectors) allow us to model alterations of genes or chromosomal regions (gene overexpression or silencing, mutations, deletions, translocations and copy neutral losses of heterozygosity). Modelling these molecular events, alone or in combination, in cellular and animal models and characterization of the molecular (epigenetic status and gene expression) and cellular consequences (proliferation, survival, clonogenicity and tumorigenicity, invasion and metastasis) allow us to study their contribution and cooperation in oncogenesis.


Project members

Noteworthy publications
Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas.
Cappellen D, De Oliveira C, Ricol D, de Medina S, Bourdin J, Sastre-Garau X, Chopin D, Thiery JP, Radvanyi F
Nature genetics ; 1999 Sep 01
Novel c-MYC target genes mediate differential effects on cell proliferation and migration.
Cappellen D, Schlange T, Bauer M, Maurer F, Hynes NE
EMBO reports ; 2007 Jan 01
p73alpha isoforms drive opposite transcriptional and post-transcriptional regulation of MYCN expression in neuroblastoma cells.
Horvilleur E, Bauer M, Goldschneider D, Mergui X, de la Motte A, Bénard J, Douc-Rasy S, Cappellen D
Nucleic acids research ; 2008 Aug 01
Molecular alterations and tumor suppressive function of the DUSP22 (Dual Specificity Phosphatase 22) gene in peripheral T-cell lymphoma subtypes.
Mélard P, Idrissi Y, Andrique L, Poglio S, Prochazkova-Carlotti M, Berhouet S, Boucher C, Laharanne E, Chevret E, Pham-Ledard A, De Souza Góes AC, Guyonnet-Duperat V, Bibeyran A, Moreau-Gaudry F, Vergier B, Beylot-Barry M, Merlio JP, Cappellen D
Oncotarget ; 2016 Oct 18
CRISPR-Cas9 globin editing can induce megabase-scale copy-neutral losses of heterozygosity in hematopoietic cells.
Boutin J, Rosier J, Cappellen D, Prat F, Toutain J, Pennamen P, Bouron J, Rooryck C, Merlio JP, Lamrissi-Garcia I, Cullot G, Amintas S, Guyonnet-Duperat V, Ged C, Blouin JM, Richard E, Dabernat S, Moreau-Gaudry F, Bedel A
Nature communications ; 2021 Aug 13

Genetic susceptibility of breast cancer

The Cowden’s disease shows constitutional deleterious variants of PTEN. But some patients present a Cowden-like disease without an identifiable mutation of PTEN. It is possible that intergenic variants may create susceptibility to the disease. We hypothesize that (i) the activation of the PTEN promoter may be dependent on regulatory regions distant from the gene in topologically associated chromatin domains, TAD, (ii) constitutional genetic alterations in PTEN TADs could impair PTEN expression, related to a Cowden’s disease phenotype, (iii) the removal of the regulatory cis regions by chromatin breaks with the destruction of a PTEN TAD, is a mechanism of PTEN gene downregulation. We map and functionally characterize the chromosomal locus of PTEN and neighboring gene regions, in healthy cells expressing PTEN and in a tumor model PTEN-less. Genetic alterations specifically localized in functional PTEN TADs are being identified in patients with a phenotype Cowden’s disease-like.


Project members

Noteworthy publications
PTEN alterations in sporadic and BRCA1-associated triple negative breast carcinomas.
Jones N, Gros A, Velasco V, Dapremont V, Brouste V, Gastaldello B, Debled M, Tunon de Lara C, Bonnet F, Barouk-Simonet E, Bubien V, Venat L, MacGrogan G, Longy M, Sevenet N
Cancer genetics ; 2022 Jun 01
Increased incidence of pathogenic variants in ATM in the context of testing for breast and ovarian cancer predisposition.
Macquere P, Orazio S, Bonnet F, Jones N, Bubien V, Chiron J, Lafon D, Barouk-Simonet E, Tinat J, Venat-Bouvet L, Gesta P, Longy M, Sevenet N
Journal of human genetics ; 2022 Jan 12
Combined tumor genomic profiling and exome sequencing in a breast cancer family implicates ATM in tumorigenesis: A proof of principle study.
Bubien V, Bonnet F, Dupiot-Chiron J, Barouk-Simonet E, Jones N, de Reynies A, MacGrogan G, Sevenet N, Letouzé E, Longy M
Genes, chromosomes & cancer ; 2017 Nov 01
Insertion of Alu elements at a PTEN hotspot in Cowden syndrome.
Crivelli L, Bubien V, Jones N, Chiron J, Bonnet F, Barouk-Simonet E, Couzigou P, Sevenet N, Caux F, Longy M
European journal of human genetics : EJHG ; 2017 Sep 01

Tumor sensitization to treatments by gene therapy

Using our knowledge on deleterious inherited genetic disease, we target tumor cell metabolism or genetic events occurring in early oncogenesis to propose innovative therapeutics, especially cancer-specific gene therapy. One of the outcomes should be the sensitization to conventional treatments such as dynamic phototherapy and radiotherapy. For example, we want to create in vivo porphyric tumors by inducing an enzymatic deficiency in heme biosynthesis. We use genome-editing and develop oncotropic viral delivery vector.


Project members

Noteworthy publications
Mutation-Specific Guide RNA for Compound Heterozygous Porphyria On-target Scarless Correction by CRISPR/Cas9 in Stem Cells.
Prat F, Toutain J, Boutin J, Amintas S, Cullot G, Lalanne M, Lamrissi-Garcia I, Moranvillier I, Richard E, Blouin JM, Dabernat S, Moreau-Gaudry F, Bedel A
Stem cell reports ; 2020 Sep 08
Iron chelation rescues hemolytic anemia and skin photosensitivity in congenital erythropoietic porphyria.
Blouin JM, Ged C, Lalanne M, Lamrissi-Garcia I, Morice-Picard F, Costet P, Daher R, Moreau-Gaudry F, Bedel A, Puy H, Gouya L, Karim Z, Richard E
Blood ; 2020 Nov 19
Targeted gene therapy in human-induced pluripotent stem cells from a patient with primary hyperoxaluria type 1 using CRISPR/Cas9 technology.
Estève J, Blouin JM, Lalanne M, Azzi-Martin L, Dubus P, Bidet A, Harambat J, Llanas B, Moranvillier I, Bedel A, Moreau-Gaudry F, Richard E
Biochemical and biophysical research communications ; 2019 Oct 01
In vivo gene transfer targeting in pancreatic adenocarcinoma with cell surface antigens.
Lafitte M, Rousseau B, Moranvillier I, Taillepierre M, Peuchant E, Guyonnet-Dupérat V, Bedel A, Dubus P, de Verneuil H, Moreau-Gaudry F, Dabernat S
Molecular cancer ; 2012 Oct 22
Effective gene therapy of mice with congenital erythropoietic porphyria is facilitated by a survival advantage of corrected erythroid cells.
Robert-Richard E, Moreau-Gaudry F, Lalanne M, Lamrissi-Garcia I, Cario-André M, Guyonnet-Dupérat V, Taine L, Ged C, de Verneuil H
American journal of human genetics ; 2008 Jan 01

Tumor sensitization to treatments by bioactive food components

 

Radiosensitization through bioactive food components (BFCs) is approached with orthotopic rectum and pancreatic cancer models. The radiotherapy oncologists apply gamma irradiations protocols, paralleling human management, on the XENX mouse irradiator (University of Bordeaux animal facility). The differential cytotoxic effects of potent stilbenes, including resveratrol, between healthy and tumor cells are mechanistically characterized. They help evidence new actionable tumor vulnerabilities.


Project members

Noteworthy publications
Bioactive food components for colorectal cancer prevention and treatment: A good match.
Amintas S, Dupin C, Boutin J, Beaumont P, Moreau-Gaudry F, Bedel A, Krisa S, Vendrely V, Dabernat S
Critical reviews in food science and nutrition ; 2022 Feb 06
A phase III randomized trial evaluating chemotherapy followed by pelvic reirradiation versus chemotherapy alone as preoperative treatment for locally recurrent rectal cancer - GRECCAR 15 trial protocol.
Denost Q, Frison E, Salut C, Sitta R, Rullier A, Harji D, Maillou-Martinaud H, Rullier E, Smith D, Vendrely V, on behalf the GRECCAR Group.
Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland ; 2021 Jul 01
Organ preservation with chemoradiotherapy plus local excision for rectal cancer: 5-year results of the GRECCAR 2 randomised trial.
Rullier E, Vendrely V, Asselineau J, Rouanet P, Tuech JJ, Valverde A, de Chaisemartin C, Rivoire M, Trilling B, Jafari M, Portier G, Meunier B, Sieleznieff I, Bertrand M, Marchal F, Dubois A, Pocard M, Rullier A, Smith D, Frulio N, Frison E, Denost Q
The lancet. Gastroenterology & hepatology ; 2020 May 01
Combination treatment of resveratrol and capsaicin radiosensitizes pancreatic tumor cells by unbalancing DNA repair response to radiotherapy towards cell death.
Vendrely V, Amintas S, Noel C, Moranvillier I, Lamrissi I, Rousseau B, Coulibaly S, Bedel A, Moreau-Gaudry F, Buscail E, Chiche L, Belleannée G, Dupin C, Dabernat S
Cancer letters ; 2019 Jun 01
Resveratrol and capsaicin used together as food complements reduce tumor growth and rescue full efficiency of low dose gemcitabine in a pancreatic cancer model.
Vendrely V, Peuchant E, Buscail E, Moranvillier I, Rousseau B, Bedel A, Brillac A, de Verneuil H, Moreau-Gaudry F, Dabernat S
Cancer letters ; 2017 Apr 01

Jobs offers


Team’s noteworthy publications

Increased incidence of pathogenic variants in ATM in the context of testing for breast and ovarian cancer predisposition.
Macquere P, Orazio S, Bonnet F, Jones N, Bubien V, Chiron J, Lafon D, Barouk-Simonet E, Tinat J, Venat-Bouvet L, Gesta P, Longy M, Sevenet N
Journal of human genetics ; 2022 Jan 12
CRISPR-Cas9 globin editing can induce megabase-scale copy-neutral losses of heterozygosity in hematopoietic cells.
Boutin J, Rosier J, Cappellen D, Prat F, Toutain J, Pennamen P, Bouron J, Rooryck C, Merlio JP, Lamrissi-Garcia I, Cullot G, Amintas S, Guyonnet-Duperat V, Ged C, Blouin JM, Richard E, Dabernat S, Moreau-Gaudry F, Bedel A
Nature communications ; 2021 Aug 13
Iron chelation rescues hemolytic anemia and skin photosensitivity in congenital erythropoietic porphyria.
Blouin JM, Ged C, Lalanne M, Lamrissi-Garcia I, Morice-Picard F, Costet P, Daher R, Moreau-Gaudry F, Bedel A, Puy H, Gouya L, Karim Z, Richard E
Blood ; 2020 Nov 19
High Clinical Value of Liquid Biopsy to Detect Circulating Tumor Cells and Tumor Exosomes in Pancreatic Ductal Adenocarcinoma Patients Eligible for Up-Front Surgery.
Buscail E, Alix-Panabières C, Quincy P, Cauvin T, Chauvet A, Degrandi O, Caumont C, Verdon S, Lamrissi I, Moranvillier I, Buscail C, Marty M, Laurent C, Vendrely V, Moreau-Gaudry F, Bedel A, Dabernat S, Chiche L
Cancers ; 2019 Oct 26
CRISPR-Cas9 genome editing induces megabase-scale chromosomal truncations.
Cullot G, Boutin J, Toutain J, Prat F, Pennamen P, Rooryck C, Teichmann M, Rousseau E, Lamrissi-Garcia I, Guyonnet-Duperat V, Bibeyran A, Lalanne M, Prouzet-Mauléon V, Turcq B, Ged C, Blouin JM, Richard E, Dabernat S, Moreau-Gaudry F, Bedel A
Nature communications ; 2019 Mar 08


Partners

Team leaders

Sandrine DABERNAT
Professor Clinician / PU-PH

François MOREAU-GAUDRY
Professor Clinician / PU-PH


Team members

Samuel AMINTAS
PhD Student-Clin. Assist. / Doc-AHU

Aurélie BEDEL
Lecturer Clinician / MCU-PH

Jean-Marc BLOUIN
Lecturer Clinician / MCU-PH

Corine BOURDIE
Technician / Tech

Julian BOUTIN
Clinician / PH

David CAPPELLEN
Lecturer Clinician / MCU-PH

Sandrine DABERNAT
Professor Clinician / PU-PH

Charles DUPIN
Clinician / PH

Sabrina FAYET
Engineer / IE

Cécile GED
Lecturer Clinician / MCU-PH

Magalie LALANNE
Technician / Tech

Isabelle LAMRISSI
Engineer Assistant / AI

Christophe LAURENT
Professor Clinician / PU-PH

Michel LONGY
Clinician / PH

Jessica MASSIERE
Engineer / IE

Thibaut MATIS
PhD Student-Clin. Assist. / Doc-AHU

Patrick MERCIÉ
Professor Clinician / PU-PH

Isabelle MORANVILLIER
Technician / Tech

François MOREAU-GAUDRY
Professor Clinician / PU-PH

Emmanuel RICHARD
Professor Clinician / PU-PH

Juliette ROSIER
PhD Student / Doc

Eric RULLIER
Professor Clinician / PU-PH

Nicolas SEVENET
Professor Clinician / PU-PH

Jérôme TOUTAIN
Clinician / PH

Véronique VENDRELY
Professor Clinician / PU-PH