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Unravelling mechanisms of metastatic dormancy and colonization in breast cancer

English title Unravelling mechanisms of metastatic dormancy and colonization in breast cancer
Applicant Rüegg Curzio Roberto
Number 179248
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 01.05.2018 - 30.04.2022
Approved amount 800'000.00
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All Disciplines (2)

Discipline
Experimental Cancer Research
Immunology, Immunopathology

Keywords (5)

Cancer du sein; Dormance; Metastase; Thérapie; Inflmammation

Lay Summary (French)

Lead
Étude des mécanismes de dormance des métastases dans le cancer du sein
Lay summary

Le cancer du sein demeure la principale cause de mortalité liée au cancer chez les femmes en Suisse. Environ un tiers des patientes meurent en raison de rechutes sous forme de métastases. Afin de diminuer la mortalité, il est essentiel de prévenir ou de traiter efficacement les métastases. Les rechutes se produisent avec des pics à 1-2 ans et 4-5 ans après thérapie, suggérant une période de dormance avant la reprise de la croissance rapide.

Dans ce projet, nous proposons d'étudier les mécanismes de dormance des métastases du cancer du sein. Nous avons récemment démontré que la chimiothérapie peut induire une dormance immunologique. Nous avons identifié les cellules inflammatoires de type monocytaire (globules blancs) en tant que régulateurs de la dormance. Cependant, leur fonction exacte et leur contrôle restent insaisissable. Dans ce projet nous allons étudier la fonction de ces cellules dans la dormance, comment elles sont affectées par les thérapies, et comment les utiliser à des fins thérapeutiques. Pour atteindre ces objectifs, nous utiliserons des modèles expérimentaux associés à des études clinique et des analyses de données cliniques et épidémiologiques, en collaboration avec des cliniciens et des biostatisticiens.

Les résultats obtenus fourniront d’une part des informations importantes sur les mécanismes de la dormance des métastases, et d’autre part pourraient ouvrir de nouvelles pistes thérapeutiques. Le but de ces recherches est de développer des nouvelles stratégies pour maintenir les cellules disséminées dans un état de dormance prolongée, en alternative aux thérapies cytotoxiques actuelles, ceci afin d’améliorer la qualité de vie et la survie des patientes atteinte de cancer du sein.

Direct link to Lay Summary Last update: 30.04.2018

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Associated projects

Number Title Start Funding scheme
118079 Role of endothelial cell PKB/Akt in controlling the metastatic switch (tumor dormancy vs progression) 01.01.2008 Project funding (Div. I-III)
135738 Unraveling mechanisms of brest cancer metastasis 01.03.2012 Project funding (Div. I-III)
208136 Myeloid-derived cells in breast cancer dormancy and metastasis 01.05.2022 Project funding (Div. I-III)
159824 Mechanisms of therapeutic control and escape of breast cancer metastasis 01.05.2015 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)
205916 Full spectrum cytometry: the next generation cytometry for high-dimensional single cell analysis 01.01.2022 R'EQUIP
208136 Myeloid-derived cells in breast cancer dormancy and metastasis 01.05.2022 Project funding (Div. I-III)

Abstract

In spite of a decrease in mortality by approximately 30% over the past 30 years, breast cancer remains the leading cause of cancer-related mortality for women in industrialized countries. About one third of patients still die of the disease, due to the formation of metastases. In order to decrease breast cancer mortality, it is crucial to prevent or treat metastases. Relapses occur with a bimodal distribution kinetics, regardless of the breast cancer subtype, with peaks at 1-2 years and 4-5 years after surgery. These observations argue against a continuous growth kinetics of the disseminated tumour cells (DTC) but rather suggest a period of dormancy before rapid growth is resumed. Many cellular and molecular events of the metastatic cascade itself are well characterized, including the role of inflammatory cells. Three types of dormancy (i.e. celluar, angiogenic and immunological), have been reported, but the underlying cellular and molecular mechanisms have only been partially elucidated. My lab has a long-standing interest in the study of tumour-host interaction in cancer progression and therapy. In this project, we propose to investigate mechanisms of breast cancer dormancy and metastatic colonization by building on own previous results. We recently demonstrated that chemotherapy can induce immunological dormancy in breast cancer. Within this model we identified CD11b+ myelomonocytic cells as important regulators of dormancy, pointing to a critical role of the host cellular environment in its regulation. However, the exact function and modulation of CD11b+ cells in controlling dormancy remains elusive. Here we propose to interrogate their function in dormancy, how they are affected by inflammation and therapeutic interventions, and to characterize their role in breaking dormancy and promoting metastatic colonization. To achieve these goals, we will use in vitro cellular and molecular approaches in combination with in vivo models of dormancy, metastasis and therapy established in the laboratory. Experimental observations will be validated by a clinical study and clinical and epidemiological data analysis, in collaboration with clinicians, biostatisticians and translational scientists. We anticipate that results obtained from this project will have a broad scientific and clinical relevance. Firstly, they will deliver important insights into cellular and molecular mechanisms of breast cancer metastatic organ colonization and dormancy, and their regulation. Secondly, the gained knowledge will cast light on the role of the micro- and macro- environment to metastasis progression and modulation. Thirdly, we expect that identified cellular and molecular mechanisms governing dormancy may open novel therapeutic opportunity to maintain disseminated cells in a state of prolonged quiescence, as alternative to current cytotoxic therapies, to improve patient’s quality of life and survival.
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