The laboratory studies the cellular mechanisms and genetic alterations involved in human cancer to better understand cancer, establish better classifications, identify stem cells and mutated genes, and identify diagnostic and prognostic markers that can be transferred into routine use. We study various types of human tumors.
In breast cancers, the teams of François Bertucci, Max Chaffanet/Anne Letessier, Emmanuelle Charafe-Jauffret/Christophe Ginestier, and Marc Lopez work at identifying cancer stem cells, genomic alterations specific of molecular subtypes and histoclinical forms, prognostic and predictive markers, and to characterize the role and function of mutated genes. In vivo models such as transgenic and xenografted mice allow pre-clinic studies.
The team of Palma Rocchi develops new therapeutic drugs against prostate cancer.
Identification of mutated genes in chronic and acute myeloid hematopoietic diseases is done by the team of Marie-Joelle Mozziconacci, Anne Murati and Véronique Gelsi-Boyer.
Finally, Emilie Mamessier and Claire Acquaviva's team explores circulating tumor cell (CTCs) heterogeneity to identify cells at high risk of seeding metastases.
- A new oncogene in breast cancer : The ZNF703 oncogene at 8p12 is amplified in luminal B breast cancers. ZNF703 plays a role in stem cell biology.
- One of the most frequently mutated gene in malignant myeloid blood diseases : ASXL1 is frequently mutated in myeloid diseases and encodes a regulator of polycomb genes.
- Mutations of SWI/SNF component ARID1A in pancreatic and breast cancers.
Prostate cancer (PC) represents one of the most common cancers in industrialized countries.
Patients with localized disease may be treated with surgery or radiation, while androgen ablation is used as first- line therapy in patients with metastatic disease. While most patients initially respond well to this hormonal therapy, they most ultimately become unresponsive and recur within 2 years as castration- resistant prostate cancer (CRPC).
Recently, docetaxel-based regimens have demonstrated improved survival in men with CRPC in two different, large, phase III studies. However, the median overall survival was prolonged for only 2-3 months. Castration Resistant (CR) progression involves variable combinations of clonal selection, ligand-independent androgen receptor (AR) activation and alternative growth factor pathways and dative up-regulation of anti-apoptotic genes. Additional therapeutic strategies targeting molecular mechanisms mediating resistance must be developed.
One strategy to improve therapies in advanced PC involves targeting genes that are activated by androgen withdrawal, either to delay or prevent the emergence of the CR phenotype. Recently, we identified Hsp27 as a highly over-expressed gene in CRPC.
Hsp27 knockdown using antisens oligonucleotides (ASO) and small interference RNA (siRNA) increased apoptotic rates and enhanced hormone- and chemo- therapy in PC.We developed and patented a second generation ASO targeting Hsp27 that has been licensed (OGX-427) and clinical trials phase II is currently in process in PC (http://oncogenex.ca/). Despite OGX-427 efficiency, the functional role of stress induced Hsp27 in castration or chemotherapy-induced apoptosis remains undefined.
Our purpose now is to elucidate the pathways leading to Hsp27 action in CRPC in order to 1/ Increase the pharmacological safety of OGX-427 and obtain the FDA approval 2/find new specific therapeutic targets and treatment strategy for CRPC that would have no toxicity for normal tissues.
Palma Rocchi, CR1 Inserm, Responsable
David Taïeb, MCU-PH, Médecine Nucléaire
Sophie Giusiano-Courcambeck, MCU-PH, Anatomo-Pathologiste
Raquel Mejias-Laguna, Dr. Sciences, Jeune Chercheur, Contrat SATT Sud-Est
Sarah Karaki, Thèse Oncologie, 3ème année, Contrat Amidex
Hajer Ziouziou, Thèse Oncologie, 4ème année, Bourse Alternance Tunisienne
Chayma Cherif, Thèse Oncologie, 1ère année, Bourse Alternance Tunisienne
Tan-Nguyen Dang, Thèse Oncologie, 1ère année, Bourse du Gouv Vietnamien
Nicolas Branger, Interne en Urologie, M2 Onco, Bourse de l'Ass Franç d'Urologie
Aurélien Archier, Assistant en Médecine Nucléaire, M2 Oncologie
Mona Ouled Dhaou, M2 Oncologie, Gratification
- Financement Inserm Transfert « Proof of Concept of Projects with high economical Potential ».
- Financement Amidex. Novel UltraSonic Biomarkers of Tumor response
- Financement cancéropole PACA*. Nanodevice for targeted imaging in prostate cancer.
- Financement Inserm Transfert « Proof of Concept of Projects with high economical Potential »
- Financement ITMO Cancer « Biologie des Systèmes »
- Financement CNRS « PEPS : innovation thérapeutique »
- Financement ANR « Programme Emergence »
- Financement INCa-ARC-Ligue « Programme d'Action Intégrée sur le cancer de la prostate »
- Financement Européen « EuroNanoMed »
The laboratory analyses the molecular alterations of myeloid hemopathies, myelodysplastic and myloproliferative syndromes and chronic myelomonocytic leukemia. We were the first to report mutations of the ASXL1 gene in these hemopathies.
Mutations of ASLX1, together with mutations of RUNX1, constitute a poor prognosis; they are frequent in cases with dysplasia and are characteristic of a particular pathway of leukemogenesis, distinct from that associated with mutations in NPM1/DNMT3A.
We have also identified molecular similarities between refractory anemia with ringed sideroblasts and myelomonocytic leukemia with dysplasia.
Circulating tumor cells & cancer metastases
New theme addressed in the Molecular Oncology department
Head D Birnbaum
Alexia Lopresti, PhD Student
Claire Acquaviva, CR1 Inserm
Emilie Mamessier, CR1 Inserm, HDR
Severine Garnier, IR IPC
Colorectal cancer (CRC) is one of the most frequent cancers. Despite recent advances in treatment and surgery, the 10-year survival rate is of 50%. As for all cancers, prognosis is largely dependent on the stage at which the cancer is diagnosed and treated. Metastatic spread is the main mortality cause, and in CRC, liver is the main site of metastasis. About 50% of CRC patients develop liver metastasis (synchronous or metachronous liver metastasis, mCCR). Liver resection is the only treatment associated with long-term survival. However, surgery is only possible for 20 to 30% of these patients. For all the other patients, the important challenges remain the early detection and targeting of metastatic malignant cells and the assessment of treatment efficiency. In all these aspects, Circulating Tumor Cells (CTCs) are relevant as they can serve as real-time liquid tumor biopsy. CTCs are believed to detach from the tumor mass, enter the blood circulation and eventually contribute to distant spread in other organs (Figure 1).
The study of large cohorts of mCCR patients has proved that CTCs detection and abundance are associated with cancer progression, metastases, poor prognosis and risk of relapse (1-3). In this context, CTCs are extremely interesting to study, as models to understand the metastatic process as biomarkers that might guide treatment decisions and as cells to be targeted to avoid metastasis (4,5). However, CTCs represent a heterogeneous population. Only a low percentage has the true potential to grow into solid metastases, whereas most CTCs may just be unable to survive in periphery. Our objective is to characterize such heterogeneity and identify the CTCs with actual metastatic potential. The general lines driving our project are to:
- Compare ex-vivo CTCs (at the single cell level) to the corresponding primary tumor and metastases at the molecular level (using a Biomark/fluidigm approach for transcriptomic analyses and the next generation sequencing for the identification of “druggable” targets by high throughput sequencing),
- Identify new surface CTCs markers (educated guess or issued from the previous analyses), in regards to their metastatic potential, and in the prospect of a specific targeting of these cells (Figure 2),
- Develop an in vitro ecosystem reconstituting interactions between CTCs and their host site. Using 3D liver organoids as the metastatic niche, we would like to build a model predicting which CTCs are more susceptible to seed metastases. Grown CTCs will further be characterized at the molecular levels and compared to the respective patient’s metastases and corresponding xenograft (if available).
Altogether, these approaches will help decipher the mechanisms involved in metastases occurrence and identified adapted targeted therapies, including some that might be useful early during the metastatic process. More specifically, we aim at building a predictive model gathering all the collected information (CTCs counts, phenotype, cluster, mutations, growth and stem cell potential, response to drugs…) able to anticipate metastases occurrences. In the meantime, our approaches will allow the rapid identification of CTCs and a short-term culture to characterize CTCs with a metastatic potential in a time scale compatible with personalized medicine strategies. This project started in 2015. Since, we have launched CTCs description, live CTCs isolation, organotypic cultures and molecular analyses on a first cohort of cancer patients (PERMED study). Shortly, we will be involved in translational projects, such as the follow-up of different cohorts of CRC patients +/- hepatic metastases, in collaboration with clinicians. Other types of cancer will be studied.
1. Ramirez JM, Fehm T, Orsini M, Cayrefourcq L, Maudelonde T, Pantel K, Alix-Panabieres C. Prognostic relevance of viable circulating tumor cells detected by EPISPOT in metastatic breast cancer patients. Clin Chem2014 Jan;60(1):214-21.
2. Deneve E, et al. Capture of viable circulating tumor cells in the liver of colorectal cancer patients. Clin Chem2013 Sep;59(9):1384-92.
3. Bidard FC, et al. Clinical validity of circulating tumour cells in patients with metastatic breast cancer: a pooled analysis of individual patient data. Lancet Oncol2014 Apr;15(4):406-14.
4. Pantel K, Speicher MR. The biology of circulating tumor cells. Oncogene2015 Jun 8.
5. Alix-Panabieres C, Pantel K. Challenges in circulating tumour cell research. Nat Rev Cancer2014 Sep;14(9):623-31.