The seminar will take place at 14h00, the 26th of March 2015, in the ENSCBP Amphitheater (Bldg B, Allée Geoffroy Saint Hilaire, Pessac).
To date, the emergence of drug resistance is never dealt with until it occurs, and constitutes a genuine daily challenge for patients and oncologists. Our research fits with the field of clonal heterogeneity, which has emerged as a key mechanism that underlies resistance in experimental and clinical oncology . Indeed, a complex pattern of low frequency mutations in oncogenes exists at diagnosis, and influence treatment response. Being able to decipher the relationship between sensitive and resistant cancer cell subpopulations, and characterize the impact of intratumor heterogeneity on treatment efficacy, is essential to understand tumor biology and design new therapeutic strategies to overcome cancer resistance.
We developed 2D models to analyze over time the expansion of A549 cells (DsRed expressing) and A549 EpoB40 (GFP expressing) cells, which are lung carcinoma sensitive and resistant cells to various chemotherapy agents respectively. The fluorescent signal of each tumor subpopulation was daily recorded (PolarStar, well-scanning mode). We also developed spheroid co-culture models that, by recapitulating the 3D organization of a microtumor, are of tremendous interest in that context. We showed that an unexpected suppressive effect on the resistant cell growth was exerted by the sensitive cells, which consequently constitute the predominant subpopulation in the absence of any chemotherapeutic treatment. Similar results were obtained with oxaliplatine-sensitive and resistant colon cancer cells (HT29 and HT29 Rox). By using cell-free supernatants and Transwell co-culture systems, this inhibition was characterized as independent of cell-to-cell interactions. We are currently analyzing this communication (extracellular vesicles versus secreted factors), as well as the potential metabolic competition between clones, to identify the molecular mechanisms responsible for the repressive effect of sensitive cells over resistant ones.
In addition, we showed that a treatment schedule that drastically reduced the number of sensitive cells (cytotoxic dose, once a week) irremediably resulted in the selection of the resistant subpopulation in the different co-culture models. Conversely, a metronomic treatment schedule (i.e. frequent administration of pro-tracted low doses of drugs) was an effective strategy both to suppress sensitive cell growth and to prevent selection of resistant cells by preserving intratumor heterogeneity. Our results thus support the fact that daily low doses of drugs would lead to better long-term results than high cytotoxic doses, to overcome problems of drug resistant cell selection that underlies many cases of cancer recurrence. The mathematical modeling of cell expansion and response to treatment is in progress to further define situations of tumor heterogeneity where resistant cells could be controlled by the metronomic-based treatment schedules, to achieve a stable or reduced global tumor population.
Leading-edge technologies, especially in 3D imaging and high sensitivity genomic fields, will also be required to (i) better understand the complex interactions among the subpopulations of cancer cells, which may regulate critical aspects of tumor biology, and (ii) increase the knowledge of the influence of intra-tumor heterogeneity on response to treatment, which may affect clinical outcome.
Since 2006 : Associate Professor
- Centre de Recherche en Oncologie biologique et Oncopharmacologie (CRO2), INSERM
- Département Bioingénierie Pharmaceutique, Université Aix-Marseille
Adress : Faculté de Pharmacie, Campus Santé Timone, 27 Bd Jean Moulin, 13005 Marseille
2005-2006 ATER in biophysics & pharmaceutical sciences– Aix Marseille Université, CNRS, UMR 2737, Marseille, France
2004-2005 Marie-Curie European program fellow - Biochemistry and Molecular Biology Department, Odense, Denmark
2001-2004 Ph.D. student in Health and Life Sciences, specialty Oncology - Pharmacy Faculty, Université de la Méditerranée, Marseille, France
2000-2001 Master Sc. in Oncology - Medicine Faculty, Université de la Méditerranée, Marseille
SUPERVISION OF GRADUATE STUDENTS AND POSTDOCTORAL FELLOWS
2006-2015 Supervision of 3 Postdocs / 7 Ph.D. / 10 Master students / 2 technicians
CNRS UMR 2737 & INSERM UMR 911, Aix-Marseille University, France
25 publications (impact factors from 3.5 to 15); 48 oral & poster communications
Reviewer for peer-reviewed journals, editorial board member of “Dataset Papers in Science”