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From extracellular matrix to cytoskeleton to nucleus: mechanotransduction in cancer progression

English title From extracellular matrix to cytoskeleton to nucleus: mechanotransduction in cancer progression
Applicant Chiquet-Ehrismann Ruth
Number 135584
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 01.04.2011 - 31.03.2014
Approved amount 375'000.00
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All Disciplines (5)

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

Keywords (8)

cancer; invasion; mechanotransduction; cancer associated fibroblasts ; extracellular matrix ; metastasis; tenascin; MKL1

Lay Summary (English)

Lead
Lay summary

By now it is well recognized that mechanical signals influence cellular functions and that mechanical signals are transduced into biochemical signals, a mechanism termed mechanotransduction. Cells will adapt to increased strain by remodeling of the cytoskeleton. This favors the nuclear accumulation of the transcriptional regulator MKL1 which will function in fine tuning of the transcriptional response to stretch. From our previous studies we also know that tenascin-C is highly over-expressed in cancer stroma and favors cell migration and invasion. We found that MKL1 is the major factor required for stretch-induced tenascin-C expression and discovered that the mechanism of this induction is distinct from the known SRF-dependent induction of gene expression by MKL1. Data from the literature have indicated that the stiffness or rigidity of the cancer stroma is a crucial determinator of the invasive behavior of cancer cells and e.g. tissue stiffness is a bad prognostic factor in human breast cancer. We now postulate that mechanical stimulation of cells induces similar cellular responses as the contact of cells with rigid matrices does. Just like cells react to exogenous mechanical strain by cytoskeletal stiffening, the rigidity or stiffness of the extracellular matrix will cause a matching cytoskeletal adaptation in cells contacting and probing this matrix. If the microenvironment is stiff, the cytoskeleton will contract, actin polymerizes leading to signaling by the actin sensor MKL1 resulting in the expression of tenascin-C as well as other proteins co-regulated with tenascin-C yet to be discovered.

We will use in vitro cultures of mouse fibroblasts, normal epithelial and cancer epithelial cells in 2D and 3D cultures as well as cultures on flexible silicone membranes for the analysis of stretch-induced effects. We will perform a screen for MKL1 target genes that are co-regulated with tenascin-C by transcript profiling approaches of stable cell strains expressing different MKL1 variants.

By these approaches we anticipate to discover novel sets of genes and signaling pathways important in stroma-mediated cancer progression by taking advantage of the development of a screening method using overexpression of an MKL1 variant specifically inducing a subset of genes co-regulated with tenascin-C

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
SAP domain-dependent Mkl1 signaling stimulates proliferation and cell migration by induction of a distinct gene set indicative of poor prognosis in breast cancer patients.
Gurbuz Irem, Ferralli Jacqueline, Roloff Tim, Chiquet-Ehrismann Ruth, Asparuhova Maria B (2014), SAP domain-dependent Mkl1 signaling stimulates proliferation and cell migration by induction of a distinct gene set indicative of poor prognosis in breast cancer patients., in Molecular cancer, 13, 22-22.
TGF-β-induced differentiation into myofibroblasts involves specific regulation of two MKL1 isoforms.
Scharenberg Matthias A, Pippenger Benjamin E, Sack Ragna, Zingg Dominik, Ferralli Jacqueline, Schenk Susanne, Martin Ivan, Chiquet-Ehrismann Ruth (2014), TGF-β-induced differentiation into myofibroblasts involves specific regulation of two MKL1 isoforms., in Journal of cell science, 127(Pt 5), 1079-91.
Tenascin-C and tenascin-W in whisker follicle stem cell niches: possible roles in regulating stem cell proliferation and migration.
Tucker Richard P, Ferralli Jacqueline, Schittny Johannes C, Chiquet-Ehrismann Ruth (2013), Tenascin-C and tenascin-W in whisker follicle stem cell niches: possible roles in regulating stem cell proliferation and migration., in Journal of cell science, 126(Pt 22), 5111-5.
Tenascin-W is a better cancer biomarker than tenascin-C for most human solid tumors.
Brellier Florence, Martina Enrico, Degen Martin, Heuzé-Vourc'h Nathalie, Petit Agnès, Kryza Thomas, Courty Yves, Terracciano Luigi, Ruiz Christian, Chiquet-Ehrismann Ruth (2012), Tenascin-W is a better cancer biomarker than tenascin-C for most human solid tumors., in BMC clinical pathology, 12, 14-14.
The adhesion modulating properties of tenascin-W.
Brellier Florence, Martina Enrico, Chiquet Matthias, Ferralli Jacqueline, van der Heyden Michael, Orend Gertraud, Schittny Johannes C, Chiquet-Ehrismann Ruth, Tucker Richard P (2012), The adhesion modulating properties of tenascin-W., in International journal of biological sciences, 8(2), 187-94.
The transcriptional regulator megakaryoblastic leukemia-1 mediates serum response factor-independent activation of tenascin-C transcription by mechanical stress.
Asparuhova Maria B, Ferralli Jacqueline, Chiquet Matthias, Chiquet-Ehrismann Ruth (2011), The transcriptional regulator megakaryoblastic leukemia-1 mediates serum response factor-independent activation of tenascin-C transcription by mechanical stress., in FASEB journal : official publication of the Federation of American Societies for Experimental Biolog, 25(10), 3477-88.
Tenascins in stem cell niches.
Chiquet-Ehrismann Ruth, Orend Gertraud, Chiquet Matthias, Tucker Richard P, Midwood Kim S, Tenascins in stem cell niches., in Matrix biology : journal of the International Society for Matrix Biology.

Collaboration

Group / person Country
Types of collaboration
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
- Research Infrastructure
- Exchange of personnel
Prof.S.W. Morris/ St. Jude Children's Hospital United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Prof. C. Rüegg/ University of Fribourg Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Profs M. Tamm and M. Roth/ University Hospital of Basel 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
Annual Meeting of the British Society of Matrix Biology Individual talk Matrix stiffening and SAP-dependent Mkl1 signaling regulate prometastatic gene expression in breast cancers 06.04.2014 Bristol, Great Britain and Northern Ireland Chiquet-Ehrismann Ruth;
FASEB Summer Conference: Matricellular proteins in Development, Health and Disease Talk given at a conference Discovery of novel Mkl1 target genes co-regulated with tenascin-C 28.07.2013 Saxtons River, VT, United States of America Chiquet-Ehrismann Ruth;
Onco-Day Basel Talk given at a conference Matrix stiffening and SAP-dependent Mkl1 signaling regulate pro-metastatic gene expression in breast cancer 13.06.2013 Basel, Switzerland Asparuhova Mariya;
Annual Meeting of the German Society for Matrix Biology Talk given at a conference The Importance of Cancer Stroma in Tumor Progression 07.03.2013 Tübingen, Germany Chiquet-Ehrismann Ruth;
Gordon Research Conference: Signal Transduction by Engineered Extracellular Matrices Poster A Novel Isoform of Human MKL1/MRTF-A is a Potent Transcriptional Activator of a Group of Extracellular Proteins in HEK 293 Cells 08.07.2012 Biddeford, ME, United States of America Chiquet-Ehrismann Ruth; Scharenberg Schmidt Matthias;
American Society for Cell Biology (ASCB) Annual Meeting Poster Megakaryoblastic leukemia-1 influences proliferation and cell migration by transcriptional regulation of tenascin-C and other cancer-relevant genes 03.12.2011 Denver, United States of America Asparuhova Mariya; Chiquet-Ehrismann Ruth;
American Society for Cell Biology (ASCB) Annual Meeting Poster Study of the promoter of the cancer-associated extracellular matrix protein tenascin-W 03.12.2011 Denver, United States of America Chiquet-Ehrismann Ruth;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Tage der Genforschnung: Forschung von heute - Innovation von morgen am Beispiel Krebsforschung 11.06.2013 Friedrich Miescher Institute for Biomedical Research, Switzerland Chiquet-Ehrismann Ruth;
Tage der Genforschnung: Forschung von heute - Innovation von morgen am Beispiel Krebsforschung 09.05.2012 Friedrich Miescher Institute for Biomedical Research, Switzerland Chiquet-Ehrismann Ruth;
Tage der Genforschung: Forschung von heute - Innovation von morgen am Beispiel Krebsforschung 18.05.2011 Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland Chiquet-Ehrismann Ruth;


Associated projects

Number Title Start Funding scheme
120235 From extracellular matrix to cytoskeleton to nucleus: role of direct physical links in gene regulation by mechanical signals 01.04.2008 Project funding (Div. I-III)
156740 The contribution of extracellular matrix to epigenetic regulation of cell fate in stem cell niches 01.10.2014 Project funding (Div. I-III)

Abstract

Background: By now it is well recognized that mechanical signals influence cellular functions and that mechanical signals can be transduced into biochemical signals, a mechanism termed mechanotransduction. Stretch-application to cells induces specific signaling pathways leading to specific gene expression patterns. There are many ways how stretch can be perceived by cells including stretch sensing by stretch activated ion channels leading e.g. to Ca2+ signaling or by stretch-induced conformational changes in proteins to expose new interaction sites for e.g. kinases or other signal transducing proteins. Ultimately, the cell will adapt to increased strain by remodeling of the cytoskeleton. Upon stretch, actin polymerization is induced leading to a decrease in G-actin levels. This favors the nuclear accumulation of the transcriptional regulator MKL1 which will function in fine tuning of the transcriptional response to stretch. We found in the precursor project that MKL1 is the major factor required for the stretch-induced tenascin-C expression and discovered that the mechanism of this induction is distinct from the known SRF-dependent induction of gene expression by MKL1. From our previous studies we also know that tenascin-C is highly over-expressed in cancer stroma and favors cell migration and invasion. Finally, recent data from the literature have indicated that the stiffness or rigidity of the cancer stroma is a crucial determinator of the invasive behavior of cancer cells and e.g. tissue stiffness is a bad prognostic factor in human breast cancer. Working Hypothesis: We postulate that mechanical stimulation of cells induces similar cellular responses as the contact of cells with rigid matrices does. Just like the cells react to exogenous mechanical strain by cytoskeletal stiffening, the rigidity or stiffness of the extracellular matrix will cause a matching cytoskeletal adaptation in cells contacting and probing this matrix. If the microenvironment is stiff, the cytoskeleton will contract, actin polymerizes and G-actin levels fall. This will induce signaling by the actin sensor MKL1 and result in the expression of tenascin-C as well as other proteins co-regulated with tenascin-C to be discovered.Specific Aims: We plan to analyze the mechanical details of the induction of tenascin-C by MKL1 and will extend this study to tenascin-W, since this new tenascin family member is also expressed in cancer stroma. Since we found that tenascin-C is induced by MKL1 indepently of SRF, but requiring the SAP domain of MKL1, we will investigate whether the SAP domain binds to specific promoter elements of tenascin-C and whether there are more genes regulated by the same mechanism. We will extend our studies from fibroblasts to normal as well as cancer epithelial cells and determine whether stretching these cells induces the same transcriptional program as when they are cultured within rigid matrices in vitro as well as in in vivo models.Experimental Design: We will use in vitro cultures of mouse fibroblasts, normal epithelial and cancer epithelial cells in 2D and 3D cultures as well as cultures on flexible silicone membranes for the analysis of stretch-induced effects. We will perform a screen for MKL1 target genes that are co-regulated with tenascin-C by transcript profiling approaches of stable cell strains expressing different MKL1 variants. We will confirm our in vitro results both in mouse tumor models as well as in human cancer tissue and other human diseases accompanied by tissue stiffness, and high tenascin-C expression such as lung fibrosis, asthma and COPD.Expected Value of Proposed Project: We anticipate discovering novel sets of genes and signaling pathways important in stroma-mediated cancer progression by taking advantage of the development of a screening method using overexpression of an MKL1 variant specifically inducing a subset of genes co-regulated with tenascin-C.
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