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Mechanisms of therapeutic control and escape of breast cancer metastasis

English title Mechanisms of therapeutic control and escape of breast cancer metastasis
Applicant Rüegg Curzio Roberto
Number 159824
Funding scheme Project funding (Div. I-III)
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 01.05.2015 - 30.04.2018
Approved amount 600'000.00
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Keywords (5)

Inflammation; Translational study; Radiotherapy; Metastasis; Cancer

Lay Summary (French)

Lead
La radiothérapie adjuvante est un traitement courant dans le cancer du sein et améliore la survie globale d’environ 30%. ll a été longtemps considérée que la radiothérapie agit uniquement en tuant les cellules tumorales. D’autres groupes et notre laboratoire ont cependant démontré que les modifications du microenvironnement tumoral contribuent également aux effets thérapeutiques de la radiothérapie. Plus spécifiquement, nous avons observé que des événements inflammatoires et immunitaires systémiques induites par la radiothérapie contribuent à son effet adjuvant souhaité mais pourraient également promouvoir la métastase lors de rechutes. Dans ce projet, nous poursuivrons la caractérisation des effets systémique de la radiothérapie afin de améliorer nos connaissances sur les mécanismes de réponse et de résistance à la radiothérapie. Les résultats obtenus pourraient servir pour le développement de nouvelles thérapies ou pour améliorer le suivit des patients après radiothérapie.
Lay summary

Les traitements adjuvants associés à la chirurgie ont contribué de manière significative à la diminution de la mortalité due au cancer du sein. En dépit de ce succès, le cancer du sein reste la première cause de mortalité liée au cancer pour les femmes. La mortalité est due à la formation de métastases et à l'émergence de résistance à la thérapie.

La radiothérapie adjuvante est couramment utilisée dans le cancer du sein localisé et améliore la survie globale d’environ 30%. Bien qu’il aie été longtemps considérée que la radiothérapie agit uniquement en tuant les cellules tumorales, on sait aujourd’hui que des modifications du microenvironnement tumoral contribuent également aux effets thérapeutiques. Nous avons démontré que des événements inflammatoires et immunitaires systémiques induites par la radiothérapie contribuent à son effet adjuvant (effets abscopale) où a certains de ses effets indésirables. .

Dans ce projet, nous proposons de continuer dans ces études en combinant des expériences de biologie cellulaire et moléculaire, des modèles de traitement du cancer du sein par radiothérapie, de l’analyse d’expression génique et des études cliniques, afin de répondre aux questions suivantes:

1) Quelles sont les effets à distance et systémiques (abscopal) qui contribuent aux effets thérapeutiques de la radiothérapie?

2) Quel est le mécanisme de CYR61, une protéine exprimée dans les tumeurs récurrentes après la radiothérapie, dans la formation des métastases et à la résistance à la radiothérapie ?

3) Comment la radiothérapie modifie l’expression des gènes de cellules inflammatoires chez les patients avec cancers du sein?

Les résultats obtenus fourniront des connaissances importantes sur les mécanismes de réponse et de résistance à la radiothérapie et les mécanismes de métastases et pourraient servir pour le développement de nouvelles thérapies ou pour améliorer le suivit des patients.
Direct link to Lay Summary Last update: 29.03.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Consensus guidelines for the use and interpretation of angiogenesis assays
Nowak-Sliwinska Patrycja, Alitalo Kari, Allen Elizabeth, Anisimov Andrey, Aplin Alfred C., Auerbach Robert, Augustin Hellmut G., Bates David O., van Beijnum Judy R., Bender R. Hugh F., Bergers Gabriele, Bikfalvi Andreas, Bischoff Joyce, Böck Barbara C., Brooks Peter C., Bussolino Federico, Cakir Bertan, Carmeliet Peter, Castranova Daniel, Cimpean Anca M., Cleaver Ondine, Coukos George, Davis George E., De Palma Michele, et al. (2018), Consensus guidelines for the use and interpretation of angiogenesis assays, in Angiogenesis, 1-118.
Arginase inhibition suppresses lung metastasis in the 4T1 breast cancer model independently of the immunomodulatory and anti-metastatic effects of VEGFR-2 blockade
Secondini Chiara, Coquoz Oriana, Spagnuolo Lorenzo, Spinetti Thibaud, Peyvandi Sanam, Ciarloni Laura, Botta Francesca, Bourquin Carole, Rüegg Curzio (2017), Arginase inhibition suppresses lung metastasis in the 4T1 breast cancer model independently of the immunomodulatory and anti-metastatic effects of VEGFR-2 blockade, in OncoImmunology, 6(6), e1316437-e1316437.
The matricellular protein CYR61 promotes breast cancer lung metastasis by facilitating tumor cell extravasation and suppressing anoikis
Huang Yu-Ting, Lan Qiang, Lorusso Girieca, Duffey Nathalie, Rüegg Curzio (2017), The matricellular protein CYR61 promotes breast cancer lung metastasis by facilitating tumor cell extravasation and suppressing anoikis, in Oncotarget, 8(6), 9200-9215.
TLR7-based cancer immunotherapy decreases intratumoral myeloid-derived suppressor cells and blocks their immunosuppressive function
Spinetti Thibaud, Spagnuolo Lorenzo, Mottas Inès, Secondini Chiara, Treinies Marina, Rüegg Curzio, Hotz Christian, Bourquin Carole (2016), TLR7-based cancer immunotherapy decreases intratumoral myeloid-derived suppressor cells and blocks their immunosuppressive function, in OncoImmunology, 5(11), e1230578-e1230578.

Collaboration

Group / person Country
Types of collaboration
Albert Santamaria Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Dr. med Alessandra Franzetti Pellanda, Clinica Luganese, Lugano Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Werner Held, LICR, UNIL, Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Christine Desmedt Belgium (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Jonathan Sleeman, University of Heidelberg/Mannheim Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Mauro Delorenzi, SIB, UNIL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Carole Bourquin Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel

Scientific events



Self-organised

Title Date Place
Sixth international conference on tumor-host interaction and Angiogenesis 17.05.2015 Ascona, Monte Vewrita, Switzerland

Knowledge transfer events



Self-organised

Title Date Place
7th Conference on tumor host interaction, 25.06.2017 Ascona Monte Verita, Switzerland

Associated projects

Number Title Start Funding scheme
179248 Unravelling mechanisms of metastatic dormancy and colonization in breast cancer 01.05.2018 Project funding (Div. I-III)
179248 Unravelling mechanisms of metastatic dormancy and colonization in breast cancer 01.05.2018 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
135738 Unraveling mechanisms of brest cancer metastasis 01.03.2012 Project funding (Div. I-III)
137079 Cell migration in tumorigenesis and metastasis 01.01.2012 ProDoc

Abstract

Mammography screening and adjuvant treatments after surgery (i.e. radiotherapy, hormonotherapy, targeted therapies and chemotherapy) significantly contributed to the reduction in breast cancer mortality observed over the past 30 years. In spite of this success, however, breast cancer remains the leading cause of cancer-related mortality for women in Europe. Mortality is due to metastases formation and the concomitant emergence of resistance to therapy. Thus, a significant decrease in breast cancer mortality can only be achieved by improving early detection and metastasis prevention/treatment. Adjuvant radiotherapy is a standard therapeutic modality in localized breast cancer and improves overall survival by approx. 30%. Radiotherapy has been classically considered to exert its effect by directly killing tumor cells. Others and we demonstrated that radiotherapy-induced modifications of the tumor microenvironment and the host also contribute to the outcome of the radiotherapy. Work from our laboratory demonstrated that radiotherapy-induced modifications of the tumor microenvironment and of the host could either promote metastasis of relapsing tumors or inhibit metastasis of tumors resected before radiotherapy (adjuvant setting). Recent results suggest that systemic inflammatory- immune-related host events induced by local radiotherapy contribute to the adjuvant effect of radiotherapy (abscopal effects). In this project we propose to build on these observations by combining in vitro cellular and molecular biology experiments, experimental models of breast cancer radiotherapy treatment, gene expression analyses and clinical studies, to address the following questions: 1) What are the local and systemic host events contributing to the therapeutic effects of adjuvant radiotherapy? 2) What is the mechanism of CYR61, a protein we previously found expressed in tumors recurring after radiotherapy, in mediating resistance to radiotherapy and metastasis?3) Does radiotherapy reprogram gene expression of pro-metastatic myelomonocytic inflammatory cells in breast cancer patients ? We anticipate that the proposed experiments will deliver important insights into mechanisms of response and resistance to radiotherapy and on mechanisms of metastasis. Obtained results may serve as a basis for the development of novel therapies or to improve the monitoring of breast cancer patients after radiotherapy.
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