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Unraveling mechanisms of brest cancer metastasis

English title Unraveling mechanisms of brest cancer metastasis
Applicant Rüegg Curzio Roberto
Number 135738
Funding scheme Project funding (Div. I-III)
Research institution Département de Médecine Université de Fribourg
Institution of higher education University of Fribourg - FR
Main discipline Experimental Cancer Research
Start/End 01.03.2012 - 28.02.2015
Approved amount 468'000.00
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Keywords (3)

Cancer; Metastasis; Radiotehrapy

Lay Summary (French)

Lead
Lay summary

L’invasion et la formation de métastases sont deux évènements biologiques de grande relevance clinique car ils sont associés à un mauvais pronostique. Cependant, les mécanismes cellulaires et moléculaires qui régissent la formation de métastases ne sont pas pleinement compris. La capacité à détecter et à interférer avec les étapes initiales de l'invasion et de la métastase pourrait ouvrir de nouvelles thérapies. La radiothérapie est utilisée avec succès pour traiter le cancer, y compris le cancer du sein. Par contre, les récidives après radiothérapie sont associées à une augmentation du risque de métastase et à un mauvais pronostic.

Dans notre laboratoire nous étudions les mécanismes de la formation des métastase, et aussi les effets de la radiothérapie sur la progression du cancer. Nous avons démontré que l'irradiation du lit tumorale favorise la formation de métastases (« effet du lit tumoral »). Un fois irradié, le tissu sain qui entoure la tumeur, inhibe la formation de nouveaux vaisseaux tumoraux créant ainsi une hypoxie tumorale. L’hypoxie en suite stimule la production des protéines qui favorisent l’invasion cellulaire et la formation de métastase. En suite nous avons découvert que l'hypoxie tumorale mobilise des globules blancs (leucocytes) de la moelle osseuse à migrer vers la tumeur et que les globules blancs qui expriment le récepteur cKit, favorise la métastatisation tumorale.

Dans ce projet, nous allons utiliser des techniques de biologie cellulaire et moléculaire, de biochimie, et des modèles in vivo pour analyser les effets de la radiothérapie sur le stroma tumorale et les mécanismes de métastatisation pulmonaire et ganglionnaire. Nous voulons mieux comprendre comment des leucocytes exprimant le récepteur cKit favorisent la métastatisation pulmonaire. Nous nous attendons à ce que les résultats obtenus à partir de ce projet permettront d'obtenir des informations importantes à la compréhension des mécanismes de métastase suite à radiothérapie et à identifier les événements cellulaires et moléculaires responsables de l'effet du lit tumoral.

Compte tenu de la pertinence clinique des questions abordées, nous nous attendons à ce que ces résultats ouvrent de nouvelles perspectives pour le suivi des patients à haut risque de progression métastatique après la radiothérapie.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Fibroblast surface-associated FGF-2 promotes contact-dependent colorectal cancer cell migration and invasion through FGFR-SRC signaling and integrin αvβ5-mediated adhesion
Sarah Knuchel Pascale Anderle Patricia Werfelli Eva Diamantis and Curzio Rüegg, Fibroblast surface-associated FGF-2 promotes contact-dependent colorectal cancer cell migration and invasion through FGFR-SRC signaling and integrin αvβ5-mediated adhesion, in Oncotargets, Manuscript.
Mechanism of irradiation-induced mammary cancer metastasis: A role for SAP-dependent Mkl1 signaling
Maria B. Asparuhovaa Chiara Secondini Curzio Ruegg and Ruth Chiquet-Ehrismann, Mechanism of irradiation-induced mammary cancer metastasis: A role for SAP-dependent Mkl1 signaling, in Molecular Cancer, MOLONC-D-1.

Collaboration

Group / person Country
Types of collaboration
Dr Eva Diamantis Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof Ruth Chiquet, FMI, Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
FP7-TUMIC consortium Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
CCRP/Oncosuisse consortium (UNIBAS-UNIGE) Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Mathematical modeling and experimental models in vascular biology Talk given at a conference Anti-angiogenesis therapy affects mobilization of inflammatory cells and modulates metastatic development 02.02.2015 Fribourg, Switzerland Secondini Chiara;
Biology and Treatment of Metastatic Cancers Talk given at a conference Contact dependent fibroblast contribution to colorectal canecr invasion 23.09.2014 El Jadida, Morocco Knuchel Sarah;
15th International Biennial Congress of the Metastasis Research Society Talk given at a conference Mechanisms of therapy-induced metastasis and dormancy 28.06.2014 Heidelberg, Germany Rüegg Curzio Roberto;
Research Days in Medicine, University of Fribourg Poster Impact of Bevacizumab on chemotherapy-induced mobilisation of endothelial progenitor cells in breast cancer 21.05.2014 Fribourg, Switzerland Knuchel Sarah;
Mathematical modeling and experimental models in vascular biology Individual talk Tumro angiogenesis 25.04.2014 Fribourg, Switzerland Rüegg Curzio Roberto;
Annual meeting of the Swiss Society of Pharmacology and Toxicology Individual talk Inhibition de l’angiogenese : principes et problemes 30.01.2014 Berne, Switzerland Rüegg Curzio Roberto;
9 Journees Canceropole Grand Sud-Ouest Talk given at a conference Tumor host interaction in cancer progression and treatment 16.10.2013 Limoges, France Rüegg Curzio Roberto;
5th International Conference on Tumor-Host Interaction and Angiogenesis Talk given at a conference Chemotherapy- induces tumor metastasis and dormancy 02.06.2013 Ascona, Switzerland Rüegg Curzio Roberto;
5th International Conference on Tumor-Host Interaction and Angiogenesis Poster Role of fibroblast in promoting colon cancer cell invasion 02.06.2013 Ascona, Switzerland Secondini Chiara;
Research Days in Medicine, University of Fribourg Poster Inhibition of the Kit ligand/c-Kit axis attenuates metastasis in a mouse model mimicking local breast cancer relapse after radiotherapy 10.05.2012 Fribourg, Switzerland Secondini Chiara;
ICTR-PHE 2012 Talk given at a conference Tumor microenvironmental reactions influencing response to radiotherapy 01.03.2012 Geneve, Switzerland Rüegg Curzio Roberto;


Self-organised

Title Date Place
Mathematical modeling and experimental models in vascular biology 02.02.2015 Fibourg, Switzerland
Mathematical modeling and experimental models in vascular biology 25.04.2014 Fribourg, Switzerland
5th International Conference on Tumor-Host Interaction and Angiogenesis 02.06.2013 Ascona, Switzerland

Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Etude des interaction entre le cancer et l’organisme pour améliorer e diagnostique et le traitemen Western Switzerland 2014

Associated projects

Number Title Start Funding scheme
157658 High frequency, high resolution Ultrasound imaging platform (Vevo2100) for preclinical imaging 01.12.2014 R'EQUIP
179248 Unravelling mechanisms of metastatic dormancy and colonization in breast cancer 01.05.2018 Project funding (Div. I-III)
157752 Microchip-based flow cell sorting in biomedicine and material sciences 01.05.2015 R'EQUIP
118079 Role of endothelial cell PKB/Akt in controlling the metastatic switch (tumor dormancy vs progression) 01.01.2008 Project funding (Div. I-III)
120473 Characterisation of the signalling mechanisms in Tie2-expressing monocytes promoting breast tumor angiogenesis 01.04.2009 Project funding (Div. I-III)
118079 Role of endothelial cell PKB/Akt in controlling the metastatic switch (tumor dormancy vs progression) 01.01.2008 Project funding (Div. I-III)
154499 Investigating the Role of Class-1 PI3K signaling in Obesity-Mediated Tumor Promotion: the interplay between fat metabolism, inflammatory cells and angiogenesis 01.06.2015 Sinergia
159824 Mechanisms of therapeutic control and escape of breast cancer metastasis 01.05.2015 Project funding (Div. I-III)
133864 Fluorescence-Mediated Tomography (FMT) to study cellular and molecular events in physiology and pathology: application to cancer, cardiovascular and circadian biology 01.02.2011 R'EQUIP
139226 IncuCyte-based high throughput imaging-based platform for determination of cellular and molecular events in real time in cultured cells in vitro: application to nanomaterial studies, cancer and cardiovascular research 01.12.2011 R'EQUIP

Abstract

Of all the processes promoting tumor progression, local invasion and metastasis formation are the most clinically relevant ones as they are associated with poor patient survival. Despite its clinical relevance, however, the cellular and molecular mechanisms governing the formation of metastases are not fully understood. The ability to detect and interfere with the initial steps of invasion and metastasis may open new diagnostic, prognostic and therapeutic opportunities. Radiotherapy is successfully used to treat cancer, including breast cancer, but emerging evidence, however, indicates that recurrences after radiotherapy are associated with increased metastatic spreading and poor prognosis. Radiation-induced modifications of the tumor microenvironment have been proposed to contribute to increased tumor aggressiveness, an effect also referred to as ‘tumor bed effect’, but the putative mechanisms involved have remained largely elusive. We are actively working on the study of the tumor bed effect, and we have recently demonstrated that irradiation impairs de novo angiogenesis thereby creating a highly hypoxic tumor bed. We demonstrated that hypoxia-mediated selection of tumor cells expressing high levels of he matricellular protein CYR61 and integrin aVß5 and that these molecules cooperate in mediating metastasis. More recently, we have observed that hypoxia mobilizes CD11b+cKit+ myelomonocytic cells though hypoxia-mediated KITL expression and that CD11b+cKit+ recruit to primary tumors and premetastatic lungs and promote metastasis, but not primary tumor growth, in an orthotopic immunocompetent model of breast cancer. These observations have raised many important questions. In this application we will combine cellular, biochemical, molecular and in vivo experimental approaches to address some of the outstanding issues:1. Does the irradiated tumor bed actively promote tumor cell invasion and intravasation ? 2. How do CD11b+cKit+ cells promote lung metastasis ?3. Does tumor irradiation, and not just tumor bed irradiation, also promote metastasis ? 4. Which events are associated with lymph node metastasis? We anticipate that results obtained from this project will deliver important insights to unravel general mechanisms of metastasis formation and more specifically to identify cellular events and molecular pathways mediating the ‘tumor bed effect’. Considering the clinical relevance of the addressed question, we expect that these results will also have direct clinical relevance. On the one side they are likely to identify novel approaches to the prevention or treatment of complications of cancer relapsing locally after radiotherapy, while on the other they will open new perspectives to the monitoring of patients at high risk for progression after radiotherapy. Clinical studies aimed at validating preclinical observations in patients are being planned as a complement to the present proposal.
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