A Quorum Sensing Regulated Small Volatile Molecule Reduces Acute Virulence and Promotes Chronic Infection Phenotypes

A significant number of environmental microorganisms can cause serious, even fatal, acute and chronic infections in humans. The severity and outcome of each type of infection depends on the expression of specific bacterial phenotypes controlled by complex regulatory networks that sense and respond to the host environment. Although bacterial signals that contribute to a successful acute infection have been identified in a number of pathogens, the signals that mediate the onset and establishment of chronic infections have yet to be discovered. We identified a volatile, low molecular weight molecule, 2-amino acetophenone (2-AA), produced by the opportunistic human pathogen Pseudomonas aeruginosa that reduces bacterial virulence in vivo in flies and in an acute mouse infection model. 2-AA modulates the activity of the virulence regulator MvfR (multiple virulence factor regulator) via a negative feedback loop and it promotes the emergence of P. aeruginosa phenotypes that likely promote chronic lung infections, including accumulation of lasR mutants, long-term survival at stationary phase, and persistence in a Drosophila infection model. We report for the first time the existence of a quorum sensing (QS) regulated volatile molecule that induces bistability phenotype by stochastically silencing acute virulence functions in P. aeruginosa. We propose that 2-AA mediates changes in a subpopulation of cells that facilitate the exploitation of dynamic host environments and promote gene expression changes that favor chronic infections

Telomere profiling : toward glioblastoma medicine : application to carbon ion hadrontherapy

Le glioblastome, tumeur maligne des tissus astrocytaires, est de mauvais pronostic. Malgré un traitement standard invasif (chirurgie, radiochimiothérapie), la médiane de survie des patients n’excède pas 14 mois, essentiellement due à la récidive tumorale (radiorésistance des cellules résiduelles). L’hadronthérapie par ion carbone offre des atouts radiobiologiques importants : i) Balistique très précise (épargne les tissus sains), ii) Efficacité Biologique Relative (EBR) supérieure à la radiothérapie conventionnelle (augmentation de la dose possible), iii) Réponse indépendante de l’effet oxygène (tumeurs hypoxiques). L’hadronthérapie a montré des résultats prometteurs en traitement du glioblastome. Cependant, la rareté des centres offrant cette thérapeutique oblige les cliniciens à utiliser des marqueurs prédictifs de réponse à la radiothérapie conventionnelle afin de mieux orienter les patients diagnostiqués mauvais répondeur. L’homéostasie télomérique est connue pour moduler la radiosensibilité de différents types de cancer. Aussi, ce travail présente deux axes. D’une part, nous avons déterminé que la taille des télomères et l’expression de POT-1 (Protection Of Telomere1) peuvent être utilisées par les cliniciens pour diagnostiquer les patients mauvais répondeurs au traitement standard et ainsi les orienter vers l’hadronthérapie où leurs pronostics seraient meilleurs. D’autre part, nous avons montré qu’un traitement pharmacologique dirigé contre la télomérase (GRN163L, Geron Corp) pouvait améliorer les résultats de la radiothérapie conventionnelle sur un modèle in vivo de glioblastome humain chez la sourisGlioblastoma, high grade tumor of neuroepithelial tissue, is poor prognosis cancer. Despite an invasive standard treatment (surgery, radiochemotherapy), the overall survival of patients does not exceed 15 months, largely due to aggressive recurrence (radioresistance of residual cells). Hadrontherapy with Carbon ion beam have strong radiobiological arguments: i) high ballistic precision (save healthy tissues), ii) Relative Biological Efficiency (RBE) above conventional radiotherapy (dose escalation), iii) independent response of oxygen enhancement ratio (hypoxic tumors). Hadrontherapy have shown promising preliminary results in treatment of brain tumors. However, the rareness of health centers which purposed Handrontheray necessitates the use of predictive markers of resistance to conventional radiotherapy to address bad responder patient. Telomere homeostasis is also known to modulate radiosensitivity of different types of cancer. Thus, this work has two arms. On the one hand, we have shown that telomere length and POT1 (Protection Of Telomere1) level (RNA and protein) can be used by clinicians to diagnose bad responder of standard treatment and towards the hadrontherapy. On the other hand, we have shown that pharmacological treatment inhibitory of telomerase (GRN163L, Geron Corp) can improve the radiationinduced responses to conventional radiotherapy on human glioblastoma mice mode

Carbon ions Versus γ-Irradiation: The Telomeric Effect in Cancer Cells

International audienceThe higher biological effect of Carbon ions hadrontherapy (C+) is explained by the nature of the DNA damages. It is known that cell response to γ-irradiation (γ-IR), but not to C+, is correlated with telomere length in different type of cancer cells. Here, we propose that this " telomeric effect " must result from an effect of ROS in γ-IR compared to C+

Cellular and molecular portrait of eleven human glioblastoma cell lines irradiated with photons or carbon ions

International audienceThe multiform glioblastoma (GBM) is a heterogeneous and highly invasive entity, making it the most aggressive brain tumor. The standard-of-care for glioblastoma consists of surgical resection, radiotherapy and chemotherapy, but despite the recent improvement of therapeutic protocols, the recurrence seems inevitable. Due to a better dose localization in the tumor volume and a greater Relative Biological Efficiency (RBE), carbon ion therapy seems to be a promising alternative to conventional radiotherapy. However, to optimize individual treatment by hadrontherapy the exact carbon equivalent dose needs to be determined from data obtained after photon irradiation. Therefore, molecular and cellular investigations of GBM are required in order to improve the prediction and treatment of brain tumors. In this study, we have examined the radiobiological features of 11 human glioma cell lines displaying gradual radiosensitivity, following photon- or carbon-therapy in order to optimize and secure antiglioma strategies. Independent of p53 or O6-methylguanine-DNA methyltransferase (MGMT) status, all cell lines respond to both types of radiation by a G2/M phase arrest followed by the appearance of mitotic catastrophe, which is concluded by a ceramide-dependent-apoptotic cell death. Statistical analyses demonstrate that: (i) the surviving fraction at 2Gy (SF2) and the dose for 10% survival (D10) photon values are correlated with that obtained in response to carbon ions; (ii) regardless of p53, MGMT status, and radiosensitivity, the release of ceramide is associated with the induction of late apoptosis; (iii) the appearance of polyploid cells after photon irradiation could predict the RBE to carbon ions.The present study clearly provides a consistent database of the cellular and molecular response of glioblastoma cell lines to photon irradiation, and to the best of our knowledge represents the largest archive for carbon ion hadrontherapy response of glioblastoma cells. This type of archive is intended to customize the treatment of patients by allowing the development of new predictive mathematical models for the response of tumors to radiation, and ultimately could improve hadrontherapy treatment plans

MiR-422a promotes loco-regional recurrence by targeting NT5E/CD73 in head and neck squamous cell carcinoma

International audienc