Flash talk - Call for proposal FAC 2014

Personalized breast cancer therapy based on viral functional assays toscore pathway activityHaraldWodrich, University of Bordeaux

State-of-the-art mass sequencingtechnology has paved the road to identify the genetic make-up of tumors on apatient-by-patient basis, allowing targeted and personalized treatment. Whilethis worked in specific cases it remains difficult to translate genetic changesinto causative cancer pathway alterations. For example, in luminal A breast tumours PIK3CA mutations that activatethe kinase do not correlate with phosphorylation of downstream targets orresponse to PI3K inhibitors. An alternative/complementing approach is todirectly test pathway integrity in primary tumor samples. We propose to useadenovirus infection of primary breast cancer samples as such a test.Adenoviruses modulate and depend on several of the pathways frequently mutatedin breast cancer to deliver their genomes into the nucleus. This property isentirely encoded in the virion and does not require viral gene expression. Hence weattempt to score pathways by comparing marker gene expression from wildtype virionswith mutant virions developed in our group that are sensitive to defects in thePI3K/AKT/mTOR/SGK1 pathway and subject to autophagic degradation. Since these events occur so early, they are ideallyplaced to form the basis of rapid functional assays for oncogenic pathwayactivation.

Activation of human gamma-delta T cells by cancer metabolismBenjaminFaustin, University of Bordeaux

Compelling clinical data frompatients treated with immunomodulatory agents indicate that harnessing thepower of the immune system can improve long-term cancer containment and extendoverall survival. Immunotherapies potentiate or reactivate ongoing, inefficientantitumor immune responses and break tumor tolerance, which is one of the majorstrategies used by cancer cells to escape immune recognition. Human γδ T cells contribute to lymphoidstress surveillance against tumors by directly recognizing cancer cells throughunknown mechanisms. This year, we have shown that several types of cancer cellsexpress caspase-1 inflammasomes and release IL-18 to promote T cellcytotoxicity and IFNγproduction. Moreover, we report that triggering the AMP-activated proteinkinase (AMPK)-dependent metabolic reprogramming of cancer cells induces theupregulation of a broad immune signature comprised of T-Cell Receptor antigens,co-stimulatory molecules, adhesion molecule, and the secretion of solublemolecules. These signals merge to enhance γδ T cell response and potentially others immunecells. Hence, AMPK activity in cancer cells improves immune detection by tissueγδ T cells withimplications for cancer immunotherapy. This research is applied to colorectaland lung cancers (which are sites of γδ T cell homing).

Discoidin domain receptors (DDR) involvement in melanoma progression andinvasionFrédéricSaltel, University of Bordeaux

Background:Cutaneous melanoma is an aggressive cancer that forms from melanocytes. Duringmelanoma progression, cells will invade the dermis which is rich in type Icollagen. Linear invadosomes are invasive structures induced by fibrillar typeI 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 cellproliferation and/or invasion. DDR1 is known to mediate cell migration andinvasion in non-small cell lung carcinoma and DDR2 has been shown to facilitatebreast cancer cells migration and metastasis. However there is no solidevidence of DDRs involvement in melanoma. As the melanoma cells will be incontact with type I collagen

fibers duringinvasion into the dermis, our hypothesis is that if melanoma express DDRs,linear invadosomes may be relevant in melanoma progression.

Results: Ourpreliminary data obtained on human melanoma tissue samples demonstrate thatDDR1 and DDR2 are co-overexpressed in this cancer. In vitro, a comparisonbetween primary human melanocytes and a melanoma cell lines shows that DDRs areoverexpressed in A375. Moreover, DDR1 and DDR2 colocalize along collagenfibers. Furthermore, melanoma cell lines are able to form more linearinvadosomes than primary melanocytes. These results prompted us to study theinvolvement of DDR1 and DDR2 in a same cellular model, addressing thecontribution of each member in melanoma progression and linear invadosomesformation. Using an ex vivo model of reconstructed epidermis, we will study theimpact of overexpression or depletion of DDR1 and/or DDR2 on cell invasion. Inparallel, we want to highlight the existence of linear invadosomes in vivousing correlative microscopy. Finally, we want to determine DDRs as potential therapeutictargets to block tumor invasion in melanoma.

Quantitative optical nanoscopy of infrared nano-markers : toward colon cancer tissue microarrays characterizationLaurentCognet, University of Bordeaux

The main objective of this project isthe simultaneous development, implementation and tests of a new imagingmodality, Photothermal Imaging (PhI) that can detect single absorbingnanolabels. Our aim is to supplement IHC and IF in terms of sensitivity, andreproducibility and transfer this approach to the medical world in order to aidcancer diagnosis and to guide therapeutic choices.

In this presentation, I will show that thefirst tests performed on human cancer samples from the tumor bank of Bergoniéindicate that PhI should be operating with near infrared nano-labels. I willthen present our current efforts to produce and characterize such near infrarednano-labels. Those are based on extremely small gold nanorods and ultra-shortnanotubes. Future experiments including nanoparticle bio-functionalization andimaging microarrays of colon tumors will then be discussed.

Ces présentations ont été données dans le cadre du BRIO SIRICscientific day 3 organisé annuellement par le SIRIC BRIO et qui a pour but deréunir tous les acteurs du SIRIC BRIO et plus largement de la cancérologie àBordeaux.