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Flash talk - Call for proposal FAC 2014
Personalized breast cancer therapy based on viral functional assays to
score pathway activity
Harald Wodrich, University of Bordeaux
State-of-the-art mass sequencing technology has paved the road to identify the genetic make-up of tumors on a patient-by-patient basis, allowing targeted and personalized treatment. While this worked in specific cases it remains difficult to translate genetic changes into causative cancer pathway alterations. For example, in luminal A breast tumours PIK3CA mutations that activate the kinase do not correlate with phosphorylation of downstream targets or response to PI3K inhibitors. An alternative/complementing approach is to directly test pathway integrity in primary tumor samples. We propose to use adenovirus infection of primary breast cancer samples as such a test. Adenoviruses modulate and depend on several of the pathways frequently mutated in breast cancer to deliver their genomes into the nucleus. This property is entirely encoded in the virion and does not require viral gene expression. Hence we attempt to score pathways by comparing marker gene expression from wildtype virions with mutant virions developed in our group that are sensitive to defects in the PI3K/AKT/mTOR/SGK1 pathway and subject to autophagic degradation. Since these events occur so early, they are ideally placed to form the basis of rapid functional assays for oncogenic pathway activation.
Activation of human gamma-delta T cells by cancer metabolism
Benjamin Faustin, University of Bordeaux
Compelling clinical data from patients treated with immunomodulatory agents indicate that harnessing the power of the immune system can improve long-term cancer containment and extend overall survival. Immunotherapies potentiate or reactivate ongoing, inefficient antitumor immune responses and break tumor tolerance, which is one of the major strategies used by cancer cells to escape immune recognition. Human γδ T cells contribute to lymphoid stress surveillance against tumors by directly recognizing cancer cells through unknown mechanisms. This year, we have shown that several types of cancer cells express caspase-1 inflammasomes and release IL-18 to promote T cell cytotoxicity and IFNγ production. Moreover, we report that triggering the AMP-activated protein kinase (AMPK)-dependent metabolic reprogramming of cancer cells induces the upregulation of a broad immune signature comprised of T-Cell Receptor antigens, co-stimulatory molecules, adhesion molecule, and the secretion of soluble molecules. These signals merge to enhance γδ T cell response and potentially others immune cells. Hence, AMPK activity in cancer cells improves immune detection by tissue γδ T cells with implications for cancer immunotherapy. This research is applied to colorectal and lung cancers (which are sites of γδ T cell homing).
Discoidin domain receptors (DDR) involvement in melanoma progression and
Frédéric Saltel, University of Bordeaux
Background: Cutaneous melanoma is an aggressive cancer that forms from melanocytes. During melanoma progression, cells will invade the dermis which is rich in type I collagen. Linear invadosomes are invasive structures induced by fibrillar type I collagen, able to degrade the matrix. The discoidin domain receptor 1 (DDR1) was shown to be necessary for linear invadosomes formation and functionality. DDR1 and DDR2 are overexpressed or mutated in various tumors, mediating cell proliferation and/or invasion. DDR1 is known to mediate cell migration and invasion in non-small cell lung carcinoma and DDR2 has been shown to facilitate breast cancer cells migration and metastasis. However there is no solid evidence of DDRs involvement in melanoma. As the melanoma cells will be in contact with type I collagen
fibers during invasion into the dermis, our hypothesis is that if melanoma express DDRs, linear invadosomes may be relevant in melanoma progression.
Results: Our preliminary data obtained on human melanoma tissue samples demonstrate that DDR1 and DDR2 are co-overexpressed in this cancer. In vitro, a comparison between primary human melanocytes and a melanoma cell lines shows that DDRs are overexpressed in A375. Moreover, DDR1 and DDR2 colocalize along collagen fibers. Furthermore, melanoma cell lines are able to form more linear invadosomes than primary melanocytes. These results prompted us to study the involvement of DDR1 and DDR2 in a same cellular model, addressing the contribution of each member in melanoma progression and linear invadosomes formation. Using an ex vivo model of reconstructed epidermis, we will study the impact of overexpression or depletion of DDR1 and/or DDR2 on cell invasion. In parallel, we want to highlight the existence of linear invadosomes in vivo using correlative microscopy. Finally, we want to determine DDRs as potential therapeutic targets to block tumor invasion in melanoma.
Quantitative optical nanoscopy of infrared nano-markers : toward colon cancer tissue microarrays characterization
Laurent Cognet, University of Bordeaux
The main objective of this project is the simultaneous development, implementation and tests of a new imaging modality, Photothermal Imaging (PhI) that can detect single absorbing nanolabels. Our aim is to supplement IHC and IF in terms of sensitivity, and reproducibility and transfer this approach to the medical world in order to aid cancer diagnosis and to guide therapeutic choices.
In this presentation, I will show that the first tests performed on human cancer samples from the tumor bank of Bergonié indicate that PhI should be operating with near infrared nano-labels. I will then present our current efforts to produce and characterize such near infrared nano-labels. Those are based on extremely small gold nanorods and ultra-short nanotubes. Future experiments including nanoparticle bio-functionalization and imaging microarrays of colon tumors will then be discussed.
Ces présentations ont été données dans le cadre du BRIO SIRIC scientific day 3 organisé annuellement par le SIRIC BRIO et qui a pour but de réunir tous les acteurs du SIRIC BRIO et plus largement de la cancérologie à Bordeaux.
- Date de réalisation : 10 Novembre 2015
- Durée du programme : 63 min
- Classification Dewey : Cancer
- Auteur(s) : ELUSTONDO Frédéric, WODRICH Harald, FAUSTIN Benjamin, SALTEL Frédéric, COGNET Laurent
- producteur : Université de Bordeaux - Service Audiovisuel et Multimédia
- Réalisateur(s) : Université de Bordeaux - Service Audiovisuel et Multimédia
- Editeur : Université de Bordeaux - Service Audiovisuel et Multimédia