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The contribution of extracellular matrix to epigenetic regulation of cell fate in stem cell niches

English title The contribution of extracellular matrix to epigenetic regulation of cell fate in stem cell niches
Applicant Hynes Nancy E.
Number 156740
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 01.10.2014 - 30.09.2017
Approved amount 508'214.00
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All Disciplines (6)

Discipline
Experimental Cancer Research
Pathophysiology
Embryology, Developmental Biology
Cellular Biology, Cytology
Molecular Biology
Biochemistry

Keywords (13)

mechanotransduction; stem cell niche; gene regulation; metastasis; extracellular matrix; breast cancer; tenascin; liver pathologies; wnt/beta-catenin signaling; fibrosis; TGF-beta; Megakaryoblastic Leukemia-1 (MKL1); gene regulation

Lay Summary (German)

Lead
Stammzellen bilden die Grundlage zur Gewebserneuerung und Erhaltung im gesunden Organismus. Diese Stammzellen befinden sich in einer speziellen Umgebung (Nische), die ihnen das Ueberleben gewährleistet. In unserem Projekt untersuchen wir die Faktoren, die zur Erhlatung der Stammzellen benötigt werden und vergleichen die normalen Stammzellnischen mit denen von Krebszellen.
Lay summary

 Inhalt und Ziele des Forschungsprojektes

Eine wichtige Komponente der Stammzellnischen ist die extrazelluläre Matrix, die aus speziellen Nischenproteinen besteht. Unser Ziel ist es einerseits bekannte Nichenproteine zu untersuchen, und andererseits neue solche Proteine zu entdecken und beschreiben. Wir untersuchen die Nichenproteine auf ihre Auswirkung auf das Proliferations- und Differenzierungsverhalten. Deshalb ist ein wichtiger Teil unserer Arbeit die Untersuchung der Interaktion der Matrixproteine mit Wachstums- und Differenzierungsfaktoren. Wir wollen dem Unterschied von nomalen Stammzellnischen und Krebs-Stammzellnischen auf den Grund gehen. Es ist bekannt, dass ein Zusammenhang zwischen Fibrose und Krebsentstehung besteht, ein weiterer wichtiger Aspekt unserer Untersuchungen. Das Protein Tenascin-C, z.B., ist in vielen Stammzellnischen, in fibrotischem Gewebe aber auch in Tumoren angereichert und je mehr Tenascin-C ein Tumor enthält, desto wahrscheinlicher ist es, dass Metastasen entstehen. Natürlich ist Tenascin-C nicht der einzige wichtige Faktor, und die Identifizierung zusätzlicher Proteine, die bei der Metastasierung eine Rolle spielen, verhelfen uns weitere Aspekte der Tumorausbreitung im Körper zu verstehen.

 

 Wissenschaftlicher und gesellschaftlicher Kontext

Unser Projekt befasst sich mit der Grundlagenforschung, hat aber das Ziel neue Krebstherapien zu ermöglichen. Dazu entwickeln wir Antikörper gegen die Nischenproteine, die in Zukunft zur Diagnose, aber auch zur Krebsbehandlung verwendet werden können.

 

 Key words

Stammzellnischen, Krebs, Metastasen, Extrazelluläre Matrix, Antikörper, Therapie

Direct link to Lay Summary Last update: 29.09.2014

Responsible applicant and co-applicants

Employees

Collaboration

Group / person Country
Types of collaboration
Prof. C. Rüegg/ University of Fribourg Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. Manuel Koch/University of Cologne Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Lotfi Hendaoui/Mongi Slim University Hospital La Marsa Tunisia (Africa)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Johannes Schittny/University of Berne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. L. Terracciano/ University Hospital of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. R.P. Tucker/ University of Califorina Davis United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
MMP Gordon Research Conference Talk given at a conference Characterization of the Metalloproteinase ADAMTS16 and its Role in Fibronectin Assembly 09.07.2017 Biddeford, ME , United States of America Schnellmann Rahel;
American Society for Matrix Biology Talk given at a conference Characterization of the metalloproteinase ADAMTS16 and its role in fibronectin assembly 13.11.2016 St. Petersburg, Florida, United States of America Schnellmann Rahel;


Associated projects

Number Title Start Funding scheme
135584 From extracellular matrix to cytoskeleton to nucleus: mechanotransduction in cancer progression 01.04.2011 Project funding (Div. I-III)

Abstract

Background: The regulation of stem cell renewal versus differentiation is regulated by the stem cell niche, composed of other supporting cells as well as the extracellular matrix and growth and differentiation factors contained in the microenvironment of the niche. Tenascin-C and tenascin-W are enriched in stem cell niches and many phenotypes of the tenascin-C-deficient mice relate to aberrant stem cell differentiation. Working Hypothesis: We are proposing a novel model of epigenetic control of cell fate through signal integration not only by chromatin modifications in the nucleus, but by the modification of the ECM in the cellular microenvironment through expression of niche-specific ECM proteins and the binding of growth and differentiation factors to this ECM. In contrast to common chromatin-mediated epigenetic control, such an ECM-mediated epigenetic mechanism has the potential to be propagated beyond the death of cells that have established a certain code by instructing new cells that will invade the pre-existing microenvironment or niche, read the code, and act accordingly. We will investigate the presence of tenascin-C and tenascin-W in stem cell niches and will determine whether these niche ECM proteins are changing Wnt/beta-catenin signaling in vivo. Furthermore, we plan to analyze in detail the function of the transcriptional regulator megakaryoblastic leukemia-1 (MKL1) in preparing the niche for sustained Wnt/beta-catenin signaling by induction of tenascin-C expression. Since we have found that a specific variant of MKL1 is induced by TGF-beta, this will provide us with the opportunity to investigate a possible link between TGF-beta and Wnt-signaling mediated by the tenascin-containing niche which may be particularly relevant in fibrosis and cancer-associated niches.Specific Aims: We will be focusing on two main aspects, normal stem cell niches and the metastatic niche in cancer progression defined by four interconnected subprojects: A. We will analyze stem cell differentiation in Tnc-/- and Tnw-/- whiskers and determine Wnt/beta-catenin signaling in these whisker niches. B: We will analyze stem cell differentiation in other niches with high Wnt signaling and investigate a potential correlation with tenascin-C and -W expression and investigate potential phenotypes in these niches in the Tnc and Tnw-deficient mice. C: We will investigate the mechanism of MKL1 induced tenascin-C expression in 4T1 mammary tumors and the lung metastatic niche and a possible connection to matrix stiffening and Wnt/beta-catenin signaling. In addition we will perform an unbiased screen for other SAP-dependent MKL1 target genes using mRNA isolated from 4T1 tumors. D: We will study the expression of MKL1 isoforms and tenascin-C and -W expression in liver pathologies including fibrosis and cancer. Also in this model we will investigate a possible connection to Wnt- and TGF-beta signaling.Expected Value of proposed project: In the present proposal we combine our findings on the regulation of tenascin-W expression and the induction of the short isoform of MKL1 by TGF-beta, with the findings that both tenascin-C and tenascin-W induce Wnt-signaling to shed light on the interaction of these two pathways of utmost importance in stem cell niches as well as in cancer progression. Our variant-specific MKL1 antibodies promise to become novel tools in the identification of fibrotic changes in normal tissues and in tumors. Furthermore, an unbiased screen for SAP-dependent MKL1 transcripts in 4T1 mammary tumors in vivo, will provide novel signaling pathways relevant for tumor progression and metastasis.
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