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Cell migration in tumorigenesis and metastasis

English title Cell migration in tumorigenesis and metastasis
Applicant Rüegg Curzio Roberto
Number 137079
Funding scheme ProDoc
Research institution Unité de Pathologie Faculté de Science et Médecine Université de Fribourg
Institution of higher education University of Fribourg - FR
Main discipline Experimental Cancer Research
Start/End 01.01.2012 - 29.02.2016
Approved amount 532'527.00
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All Disciplines (2)

Discipline
Experimental Cancer Research
Immunology, Immunopathology

Keywords (3)

Migration cellulaire; Metastase; Immunosuppression

Lay Summary (French)

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

Responsible applicant and co-applicants

Employees

Publications

Publication
Angiogenesis and Metastasis
Wyss C.B., Lorusso G., Rüegg C. (2015), Angiogenesis and Metastasis, ESMO, Lugano.
TLR and RLR Signaling Are Reprogrammed in Opposite Directions after Detection of Viral Infection
Hotz C, Roetzer LC, Huber T, Sailer A, Oberson A, Treinies M, Heidegger S, Herbst T, Endres S, Bourquin C (2015), TLR and RLR Signaling Are Reprogrammed in Opposite Directions after Detection of Viral Infection, in J Immunol, 195(9), 4387-4395.

Collaboration

Group / person Country
Types of collaboration
Research Training Group 1202 of the German Research Foundation (DFG) Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
CCRP/Oncosuisse consortium (UNIBAS-UNIGE) Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Eric Alléman, UNIGE Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
BayImmuNet Immunotherapy Network Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. A. Bikfalvi, University of Bordeaux France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Joshua Weiner United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
FP 7 JUSTBRAIN Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Ulrich Pohl, LMU, München Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
FP7 - European Stroke Network Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
AACR meeting The Function of Tumor Microenvironment in Cancer Progression Poster Transcriptional activation of HIF-1 and loss of miRNA let-7 in breast cancer cells induces Pdgfb-mediated metastatic colonization of the brain 07.01.2016 San Diego, United States of America Wyss Christof;
ProDoc Retreat Talk given at a conference The Transcription Factor HIF-1 induces Pdgfb-mediated colonisation of breast cancer metastasis in the brain 18.11.2015 Bern, Switzerland Wyss Christof;
CIMT Annual Meeting 2015 Poster The role of MDA-5-mediated immune activation for T cell recruitment into tumors 11.05.2015 Mainz, Germany Fertig Treinies Marina;
WIRM Immune Regulation Meeting Poster The role of TLR9-mediated activation of myeloid-derived suppressor cells (MDSC) on their ability to migrate into tumors 18.03.2015 Davos, Switzerland Spinetti Thibaud;
ProDoc Retreat Talk given at a conference he Transcription Factors NF-kB1 and HIF-1 as molecular mediators of breast cancer metastasis to the brain 09.02.2015 Weggiy, Switzerland Wyss Christof;
Brupbacher Symposium Poster A regulatory motif analysis implicates NF-kB1 and HIF-1 transcription factors as molecular mediators of breast cancer metastasis to the brain 28.01.2015 Zürich, Switzerland Wyss Christof;
International Biennial Congress of the Metastasis Research Society Talk given at a conference Mechanisms of therapy-induced metastasis and dormancy 28.06.2014 Heildelberg, Germany Rüegg Curzio Roberto;
Research day in medicine, Fribourg Poster Mechanism of brain metastasis 21.05.2014 Fribourg, Switzerland Wyss Christof;
12th CIMT Annual Meeting in Mainz, Germany Poster A TLR agonist–based treatment enhances T cell recruitment into gastric tumors 06.05.2014 Mainz, Germany Fertig Treinies Marina;
World immune Regulation Meeting VIII in Davos, Switzeralnd Poster A TLR agonist–based treatment enhances T cell recruitment into gastric tumors 19.03.2014 Davos, Switzerland Fertig Treinies Marina;
Tumor Invasion and Metastasis Special Conference by AACR, Poster Breast cancer cell migration across the blood-brain barrier (BBB) 20.01.2013 San Diego, United States of America Wyss Christof;


Self-organised

Title Date Place
European Cytoskeletal Forum 01.09.2013 Fribourg, Switzerland

Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Metastasen: Entstehung und Wanderung der Krebszellen Western Switzerland 2014
Talks/events/exhibitions WIE WIRD EIN MEDIKAMENT ENTDECKT? Western Switzerland 2014

Associated projects

Number Title Start Funding scheme
143718 Impact of Synergy-inducing Molecules on Chemokine Activities 01.01.2013 Project funding (Div. I-III)
141773 ProDoc Cell Migration Research Module 3: Soluble factors in Cell Migration 01.10.2012 ProDoc
157752 Microchip-based flow cell sorting in biomedicine and material sciences 01.05.2015 R'EQUIP
138284 Immunotherapy of gastric cancer: Enhancing T cell recruitment into tumors 01.01.2012 Project funding (Div. I-III)
157658 High frequency, high resolution Ultrasound imaging platform (Vevo2100) for preclinical imaging 01.12.2014 R'EQUIP
159824 Mechanisms of therapeutic control and escape of breast cancer metastasis 01.05.2015 Project funding (Div. I-III)

Abstract

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.
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