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Role of the bone marrow niche in breat cancer metastasis and therapy response

English title Role of the bone marrow in breast cancer metastasis and therapy response
Applicant Hynes Nancy E.
Number 149751
Funding scheme Project funding (Div. I-III)
Research institution Friedrich Miescher Institute for Biomedical Research
Institution of higher education Institute Friedrich Miescher - FMI
Main discipline Experimental Cancer Research
Start/End 01.01.2014 - 31.12.2015
Approved amount 366'560.00
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All Disciplines (2)

Discipline
Experimental Cancer Research
Molecular Biology

Keywords (2)

in vivo metastatic models; breast cancer, metastasis, bone marrow, CXCR4, ID1

Lay Summary (German)

Lead
Mammakarzinome im Brustgewebe können erfolgreich chirurgisch behandelt werden. Sind die Tumore aber bereits metastasiert, sinken die Chancen für ein 5-Jahres Überleben auf ca. 20%. Aus diesem Grund sind Forschungsarbeiten, die sich mit dem Prozess der Metastasierung befassen, von grosser Wichtigkeit. Unser Forschungsprojekt untersucht die Interaktionen zwischen Mammakarzinom-Zellen und dem Knochenmilieu, mit dem Ziel wichtige Erkenntnisse für die Entwicklung neuer, Therapien zu gewinnen.
Lay summary
Maligne Tumoren des Brustgewebes können erfolgreich chirurgisch behandelt werden, was mit einer guten Langzeit-Überlebensprognose einhergeht. Sind einige Tumorzellen aber bereits vor der operativen Entfernung des Primärtumors in der Brust über Blutgefässe ausgeschwemmt worden, und haben sich diese in anderen Organen wie Knochen, Lungen oder Gehirn niedergelassen - was dem so genannten Prozess der Tumor-Metastasierung entspricht - sinkt die Überlebensrate markant ab. In diesem Stadium ist Brustkrebs meist nicht mehr heilbar, weil Therapieoptionen für eine metastasierte Erkrankung sehr begrenzt sind. Daher sind Forschungsarbeiten, die zum Verständnis des Metastasierungsprozesses von Tumorzellen beitragen, von grosser Wichtigkeit. Es wird angenommen, dass das Tumor-Wachstum und die Metastasen-Bildung von den Tumor umgebenden Stromazellen abhängt, sodass eine Blockade der Interaktionen zwischen Tumor- und Stromazellen eine vielversprechende therapeutische Strategie in der Behandlung von Brustkrebs darstellen könnte. Unser Forschungsprojekt untersucht den Prozess der Metastasenbildung im Knochenmark (KM) bei Mammakarzinomen. Die klinische Relevanz unserer experimentellen Ansätze ist hoch, weil KM-Metastasen häufig für späte Krankheitsrezidive verantwortlich sind, und zudem mehr als 70% der Patientinnen im fortgeschrittenen Stadium ossäre Metastasen vorweisen. Die Ziele unserer Forschung sind es, neue Mechanismen der Einwanderung (sogenannt „homing“), des Überlebens und der Proliferation von Mammakarzinomzellen im KM aufzudecken und zu charakterisieren. Wir erhoffen uns mit diesem Projekt wichtige Erkenntnisse für die Entwicklung neuer Therapien für Patienten mit ossär metastasiertem Brustkrebs zu gewinnen.
Direct link to Lay Summary Last update: 12.11.2013

Lay Summary (English)

Lead
Primary breast tumors can be successfully removed by surgery and women with breast cancer have an excellent chance of long-term survival. However, if tumors have metastasized to sites like the bone or the lungs the overall chance of survival, 5 years after surgery, are only ~ 23%. Thus, studies on the metastatic process are extremely important.
Lay summary
Primary breast tumors can be efficiently removed by surgery and patients have a very high chance of surviving for many years. However, if the tumor cells have migrated out of the tumor before surgery and have entered distant organs like the bone, the lungs or the brain, a process referred to as metastatic dissemination,  patients have a much higher chance of dying from the consequences of tumor growth in these organs. Currently there are no successful therapeutic options for metastatic disease. Accordingly, studies that further our understanding of mechanisms controlling movement of primary tumor cells to distant organs as well as growth of tumors in these sites are extremely relevant. Considering the metastatic site, crosstalk between cancer cells and their surrounding stromal cells is known to impact on tumor growth. Targeting this interaction is considered to be an excellent therapeutic strategy for cancer treatment. The experiments proposed in this grant are aimed at studying the process of breast tumor metastasis and growth in the bone marrow (BM). The clinical significance of this work is high considering that BM is the most frequent site of late relapse and that more than 70% of patients with advanced breast cancer have skeletal lesions. The goal of our work is to uncover and dissect new mechanisms that regulate homing, survival and proliferation of breast tumor cells in the BM environment. This approach will be essential in order to discover effective therapeutic strategies to target bone metastases.
Direct link to Lay Summary Last update: 12.11.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Transcriptional regulation of tenascin-W by TGF-beta signaling
Chiovaro Francesca et al (2015), Transcriptional regulation of tenascin-W by TGF-beta signaling, in International Journal of Cancer, 137(2015), 1842-1854.
Oncogenes and angiogenesis: a way to personalize anti‑angiogenic
Bottos Alessia and Bardelli Alberto (2014), Oncogenes and angiogenesis: a way to personalize anti‑angiogenic, in Cellular and Molecular Life Sciences, 10(3), 1-10.

Collaboration

Group / person Country
Types of collaboration
Prof Veronika Sexl Austria (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Esteller group/Bellvitge Biomedical Research Institute Spain (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Ruth Chiquet/FMI Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Dr. Manel Esteller, IDIBELL Spain (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Dr. M. Esteller Spain (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
2015 Annual Meeting LBI-CR Talk given at a conference Insights into Mechanisms of Breast Cancer Metastasis 08.11.2015 Seggau Castle, Styria, Austria Hynes Nancy E.;
5th Basel Postdoctoral Network Retreat Talk given at a conference “Decreased NK cell-mediated anti-tumor immunity consequent to JAK pathway inhibition enhances metastasis in preclinical models of breast cancer.” 17.09.2015 Kandersteg, Switzerland Gattelli Albana; Bottos Alessia;
6th International Conference on Tumor-Host Interaction and Angiogenesis. Poster The immunomodulatory effect of JAK inhibitors enhances metastasis 12.05.2015 Ascona, Switzerland Bottos Alessia;
ETH Zurich Individual talk Insights into Mechanisms of Breast Cancer Metastasis 06.05.2015 Zurich, Switzerland Hynes Nancy E.;
German Society for Experimental and Clinical Pharmacology & Toxicology Talk given at a conference Insights into Mechanisms of Breast Cancer Metastasis 10.03.2015 Kiel, Germany Hynes Nancy E.;
LBG Meeting for Life Sciences Talk given at a conference Breast Cancer Therapy: Today and the Future 09.12.2014 Vienna, Austria Hynes Nancy E.;
San Antonio Breast Cancer Symposium Poster Effects of JAK pathway inhibition in models of breast cancer metastasis 07.12.2014 San Antonio, TX, United States of America Bottos Alessia;
CGC.nl Meeting Cellular Signalling and cancer therapeutics Talk given at a conference Insights into Mechanisms of Breast Cancer Metastasis 13.11.2014 Amsterdam, Netherlands Hynes Nancy E.;
NBCF-IABCR Meeting Talk given at a conference Insights into Mechanisms of Breast Cancer Metastasis 17.09.2014 Sydney, Australia Hynes Nancy E.;
FMI Annual Meeting 2014. Talk given at a conference “Effects of JAK pathway inhibition in pre-clinical models of bone marrow metastasis.” 11.09.2014 Pontresina, Switzerland Gattelli Albana; Bottos Alessia; Wodnar-Filipowicz Aleksandra; Frei Anna;
Gordon Research Conference on Mammary Gland Biology Talk given at a conference Scientific Travels from MMTV to Human Breast Cancer 12.06.2014 Il Ciocca, Italy Hynes Nancy E.; Frei Anna;
2015 AACR Annual Meeting Poster The immunomodulatory effect of JAK inhibitors enhances metastasis by impairing anti-tumor immunity in pre-clinical models of breast cancer 18.04.2014 Philadelphia, United States of America Hynes Nancy E.;
2014 AACR Annual Meeting Talk given at a conference Insights into Mechanisms of Breast Cancer Metastasis 05.04.2014 San Diego, United States of America Hynes Nancy E.;
Genentech Individual talk Two tales in breast cancer: A nw transgenic model to investigate Ret in mammary cancer; Studies on Memo, a novel metastatic regulator 03.04.2014 San Francisco, United States of America Hynes Nancy E.;
ISREC Symposium on Metastatic Colonization. Talk given at a conference “Effects of JAK pathway inhibition in pre-clinical models of bone marrow metastasis.” 15.01.2014 Crans Montana, Switzerland Bottos Alessia;


Awards

Title Year
Prize for best talk 5th Basel Postdoctoral Network Retreat. Title: “Decreased NK cell-mediated anti-tumor immunity consequent to JAK pathway inhibition enhances metastasis in preclinical models of breast cancer.” 2015
Selected for a platform presentation - Crans Montana (Switzerland), ISREC Symposium on Metastatic Colonization. Title: “Effects of JAK pathway inhibition in pre-clinical models of bone marrow metastasis.” 2014

Associated projects

Number Title Start Funding scheme
138417 Role of the bone marrow in breast cancer metastasis and therapy response 01.01.2012 Project funding (Div. I-III)

Abstract

‘Role of the bone marrow in breast cancer metastasis and therapy response”Metastatic dissemination of tumors is the major cause of death from breast cancer. Today, primary tumors are efficiently removed by surgical intervention, but there are no successful therapeutic options for metastatic disease. Accordingly, studies that further our understanding of mechanisms controlling metastatic dissemination and survival as well as growth of tumors in distant organs including the bone, lungs, liver and brain are extremely relevant. Considering the metastatic site, crosstalk between cancer cells and their surrounding stroma is known to impact on tumor growth. Targeting this interaction is considered to be an excellent therapeutic strategy for cancer treatment. Examining the effects of therapeutics on primary tumor outgrowth is essential for drug development, however, we cannot assume that metastatic tumors in distant sites will respond in the same manner as the primary. Thus, we need to study the metastasis in their resident environment, in order to develop new strategies to block dissemination and expansion of tumor metastases. To elucidate how tumor cells react to the host microenvironment, and how the microenvironment is influenced by tumor growth is an important, but challenging task. The experiments proposed in this grant are aimed at studying the process of breast tumor dissemination and maintenance in the bone marrow (BM). The clinical significance of this work is high considering that BM is the most frequent site of late relapse and that more than 70% of patients with advanced breast cancer have skeletal lesions. The goal of our work is to uncover and dissect new mechanisms that regulate homing, survival and proliferation of breast tumor cells in the BM environment. This approach will be essential in order to discover effective therapeutic strategies to target bone metastases. The proposal has three major aims:1) Identification of novel molecular targets important for the establishment and maintenance of breast cancer BM metastases. Using genome wide approaches we will identify new molecular targets to block tumor growth in the bone environment. Our work will focus on the primary tumor and BM metastases, and is aimed at understanding how the bone environment influence molecular characteristics of the tumor cells. 2) Characterization of selected targets in breast cancer BM metastases: molecular mechanisms regulating their expression and mechanistic analyses of their roles in bone metastases. In this aim, we will analyze molecular targets identified by the transcriptional profiling of BM resident, compared to primary mammary tumor cells. Based on results from our first grant, the differentially expressed targets that will be further studied are the chemokine receptor CXCR4 and the ID1/ID3 transcriptional regulators. 3) Targeting the JAK/STAT pathway in breast cancer bone metastases. The JAK/STAT pathway is aberrantly activated in breast and other cancers. We also found activation of this pathway in the metastatic bone marrow, where it might control bone remodeling and expansion of the tumor. We will test the effect of the JAK1/JAK2 inhibitor ruxolitinib, using different in vivo models of breast cancer bone metastases.
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