Project

Discipline

Migration cellulaire; Metastase; Immunosuppression

Lead
Lay summary
Le cancer est le résultat de l'accumulation de multiples mutations menant à une prolifération cellulaire incontrôlée et illimitée. Les cellules cancéreuses, cependant, interagissent avec le tissu environnant normal (appelé aussi le microenvironnement tumoral) afin de progresser vers la formation des métastases. Les cellules cancéreuses elle mêmes, ainsi que nombreuses cellules du microenvironnement tumoral, telles que les fibroblastes, les cellules des vaisseaux tumoraux et les cellules du système immunitaire et inflammatoire, acquièrent des capacités migratoires et invasives lors de la croissance tumorale et de la dissémination métastatique. Dans ce module de recherche nous aborderons la question de la migration cellulaire dans le cancer dans deux projets. Dans un premier projet nous allons étudier les mécanismes de migration et invasion des cellules du cancer du sein lors de la formation de métastases dans le cerveau. Pour cela nous utiliserons un modèle récemment développé dans le laboratoire. Nous allons étudier comment les cellules métastatiques du cancer du sein migrent à travers la barrière hémato-encéphalique, comment elles envahissent le cerveau sain une fois qu'elles ont passé la barrière. Aussi nous étudierons le rôle des cellules inflammatoires (leucocytes) dans l'entrée des cellules cancéreuses dans le cerveau. Dan un deuxième projet nous étudierons le rôle de récepteur TLR9 dans l’activation d’une population de cellules immunosuppressives (MDSC) et dans leur capacité à migrer vers les tumeurs. Nous pensons que l'activation des MDSC par TLR9 puisse modifier leurs propriétés migratoires à intérieur de l'hôte. Une diminution du recrutement des MDSC dans la tumeur et les ganglions lymphatiques drainant pourrait avoir un impact positif sur la réponse immunitaire anti-tumorale. Le résultats issus de ces projets devraient nous permettre de mieux comprendre les mécanismes de migration des cellules tumorales et du système immunitaire relevant pour la progression de la tumeur. En vu de la pertinence clinique et biomédicale des projets poursuivis, nous allons tenter, autant que possible, de valider rapidement les résultats expérimentaux par des observations sur du tissus humain.

Direct link to Lay Summary

Last update: 21.02.2013

Active participation

Self-organised

Communication	Title	Media	Place	Year

Number	Title	Start	Funding scheme

Malignant cell transformation is the result of the accumulation of multiple genetic and epigenetic cell-autonomous events leading to uncontrolled cell proliferation and survival. Transformed cells, however, require support from the surrounding normal tissue (i.e. the tumor microenvironment) in order to progress to life-threatening invasive and metastatic cancers. Compared to normal quiescent tissue, the tumor microenvironment is characterized by profound changes in cellular composition, such as the appearance of cancer-associated fibroblasts, angiogenic blood and lymphatic endothelial cells, and the accumulation of many immune, inflammatory and bone marrow-derived cells (BMDC). Collectively these cells cooperate to promote tumor growth, invasion and metastatic spreading. Cell migration is key to many events of cancer progression: tumor cells acquire migratory and invasive capacities during transformation, migration is necessary for metastatic spreading, angiogenic endothelial cells migrate toward the growing tumors, and immune, inflammatory and BMD-cells migrate to primary tumors and metastatic sites. In this ProDoc research module we will address complementary topics of cancer research involving cell migration. With ProDoc Student 3 we will investigate mechanisms of breast cancer metastasis to the brain. We have recently established a model of spontaneous breast cancer metastasis to the brain in immunocompetent mice and identified clinically relevant genes that are functionally involved in this process. We will use this model to investigate how brain metastatic cells migrate across the blood-brain barrier, how the brain parenchyma modulates their invasive capacities once they have passed the blood-brain barrier, and whether BMDC contribute to breast cancer cell entry into the brain. A main focus of this module concerns the role of immune, inflammatory and BMDC in tumor progression. With ProDoc Student 4 we will study the role of TLR9-mediated activation of myeloid-derived suppressor cells (MDSC) on their ability to migrate into tumors. By analogy with dendritic cells, we are proposing that activation-induced maturation of MDSC may lead to changes in their homing and recirculation properties within the tumor-bearing host. A reduced recruitment of MDSC to the tumor microenvironment and draining lymph nodes is expected to impact on the anti-tumor immune response. This thesis will also investigate whether immune activation of MDSC might impinge on tumor metastasis. ProDoc Student 5 will investigate the role of endothelial Angiopoietin-2 (Ang-2) on the recruitment of BMDC into primary tumors and premetastatic niches. This project is based on the use of a transgenic mouse model for endothelial cell-specific Tetracycline-regulatable expression of human Ang-2 that we have recently established and characterized. In particular, we will characterize the effect of continuous and moderate increase of Ang-2 expression in endothelial cells on tumor vessel morphology and function, on the recruitment of BMDC and Tie-2 expressing monocytes (TEM) to primary and metastatic sites and on their contribution to tumor angiogenesis and metastasis. ProDoc Student 13 will investigate the role of endothelial cell-derived factors in promoting migration and invasion of adjacent tumor cells. We have previously observed that endothelial cell activation induces tumor cell motility, and by genome wide screenings we have identified candidate molecules promoting tumor cell migration. Here we will characterize the effect of some of these factors and their receptors. With ProDoc Student 14 we will use an orthotopic model for pancreas cancer to study the effect of innate immune activation on the migration of tumor-specific effector CD8 T cells to tumors and to identify strategies to enhance their recruitment in order to improve the efficacy of immunotherapy. Taken together, in this ProDoc module we will address important aspects of tumor cell, BMDC, immune, and inflammatory cell migration in cancer progression through five coordinated and integrated projects. Interactions across all partner laboratories are essential for each of these projects and are naturally based on the specific backgrounds and expertises of the collaborating groups. Interactions include the shared use of unique experimental models, the investigation of similar or related phenomena in different models and the integration of results across projects to generate novel hypotheses. Considering the important biomedical and clinical relevance of the projects pursued in this module, we will attempt, whenever possible, to rapidly validate experimental results with observations on human material.