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Transcriptional and Epigenetic Regulation of EMT

Applicant Meyer-Schaller Nathalie
Number 145508
Funding scheme Marie Heim-Voegtlin grants
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Experimental Cancer Research
Start/End 01.02.2013 - 31.01.2015
Approved amount 229'987.00
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All Disciplines (2)

Discipline
Experimental Cancer Research
Cellular Biology, Cytology

Keywords (5)

EMT; epigenetics; breast cancer; metastasis; transcription factors

Lay Summary (German)

Lead
Der Übergang vom epithelialen zum mesenchymalen Zustand einer Krebszelle, auch als EMT bekannt, ist ein entscheidender Schritt in der Entstehung von Metastasen. Tumorzellen, die eine EMT durchlaufen haben, brechen aus der Tumormasse aus, werden invasiv und gelangen in die Blutbahn. Durch die Blutzirkulation werden sie zu anderen Organen getragen, wo sie zu Metastasen auswachsen können. Um den Prozess der Metastasierung zu unterbinden, müssen wir den genauen Ablauf des EMT Prozesses verstehen.
Lay summary

Dieses Forschungsprojekt hat zum Ziel, die transkriptionellen und epigenetischen Faktoren zu untersuchen, die eine Rolle während EMT spielen. Mittels eines phenotypischen und eines funktionellen Screeningansatzes werden wir die Transkriptionsfaktoren und Kofaktoren identifizieren, die für die Plastizität von epithelialen Zellen, inbesondere für den Übergang von epithelialen, gutartigen Krebszellen in mesenchymale bösartige Krebszellen wichtig sind. Desweiteren werden wir die Interaktion dieser Faktoren untereinander analysieren, um ein Netzwerk von Transkriptionsfaktoren und Kofaktoren zu etablieren. Die Rolle der Schlüsselgene dieses Netzwerkes und von epigenetischen Faktoren in der Regulation der Genexpression während EMT wird dann im Detail untersucht.

Die Metastasierung von Krebszellen stellt ein weitgehend ungelöstes medizinisches Problem dar. Mit diesem Forschungsprojekt werden wir neues Wissen über den EMT Prozess generieren, welches gebraucht werden könnte, um neue therapeutische Strategien im Kampf gegen die Metastasierung von Krebszellen zu entwickeln.

Direct link to Lay Summary Last update: 08.01.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
A high-content EMT screen identifies multiple receptor tyrosine kinase inhibitors with activity on TGFβ receptor.
Lotz-Jenne Carina, Lüthi Urs, Ackerknecht Sabine, Lehembre François, Fink Tobias, Stritt Manuel, Wirth Matthias, Pavan Simona, Bill Ruben, Regenass Urs, Christofori Gerhard, Meyer-Schaller Nathalie (2016), A high-content EMT screen identifies multiple receptor tyrosine kinase inhibitors with activity on TGFβ receptor., in Oncotarget, 7(18), 25983-6002.
LIM-homeobox gene 2 promotes tumor growth and metastasis by inducing autocrine and paracrine PDGF-B signaling.
Kuzmanov Aleksandar, Hopfer Ulrike, Marti Patricia, Meyer-Schaller Nathalie, Yilmaz Mahmut, Christofori Gerhard (2014), LIM-homeobox gene 2 promotes tumor growth and metastasis by inducing autocrine and paracrine PDGF-B signaling., in Molecular oncology, 8(2), 401-4016.
VEGF-mediated angiogenesis links EMT-induced cancer stemness to tumor initiation
Fantozzi A, Gruber DC, Pisarsky L, Heck C, Kunita A, Yilmaz M, Meyer-Schaller N, Cornille K, Hopfer U, Bentires-Alj M, Christofori G (2014), VEGF-mediated angiogenesis links EMT-induced cancer stemness to tumor initiation, in Cancer Research, 74(5), 1566-1575.
Klf4 is a transcriptional regulator of genes critical for EMT, including Jnk1 (Mapk8).
Tiwari Neha, Meyer-Schaller Nathalie, Arnold Phil, Antoniadis Helena, Pachkov Mikhail, van Nimwegen Erik, Christofori Gerhard (2013), Klf4 is a transcriptional regulator of genes critical for EMT, including Jnk1 (Mapk8)., in PloS one, 8(2), e57329-e57329.
Sox4 is a master regulator of epithelial-mesenchymal transition by controlling Ezh2 expression and epigenetic reprogramming.
Tiwari Neha, Tiwari Vijay K, Waldmeier Lorenz, Balwierz Piotr J, Arnold Phil, Pachkov Mikhail, Meyer-Schaller Nathalie, Schübeler Dirk, van Nimwegen Erik, Christofori Gerhard (2013), Sox4 is a master regulator of epithelial-mesenchymal transition by controlling Ezh2 expression and epigenetic reprogramming., in Cancer cell, 23(6), 768-83.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Seventh Annual ENBDC workshop: Methods in mammary gland biology and breast cancer Poster Deciphering the transcription (co)factor network of EMT 08.05.2014 Weggis, Switzerland Meyer-Schaller Nathalie;
TEMTIA 2013: 6th International EMT Meeting Poster Deciphering the transcription (co)factor network of EMT 13.11.2013 Alicante, Spain Meyer-Schaller Nathalie;
Gordon Conference Cancer Genetics and Epigenetics Poster Sox4 transcription factor is required for epithelial to mesenchymal transition and regulates polycomb-mediated epigenetic reprogramming during EMT 21.04.2013 Lucca (Barga), Italy Meyer-Schaller Nathalie;


Abstract

The formation of metastasis from a primary tumor is achieved through a metamorphosis of adherent tumor cells to highly migratory and invasive cells. We are particularly interested in the fundamental questions on how these cells with an original epithelial imprinting de-differentiate into metastatic tumor cells with a mesenchymal gene expression profile. During this process, also known as EMT (epithelial to mesenchymal transition), tumorigenic cells undergo a major transcriptional reprogramming that leads to the conversion of benign, adhesive cells to malignant, invasive cells. The massive changes in gene expression during EMT argue for a critical role of master regulators that act on the level of chromatin modifications and direct transcriptional control. To study the epigenetic control of cellular de-differentiation, we induce EMT in vitro by the addition of TGFb to murine epithelial cells and follow the transcriptional and phenotypic changes over time. By combining RNAi screening approach together with microarray analysis and chromatin-immunoprecipitation, we aim at deciphering the complex networks driving EMT. More specifically, we will use a phenotypic microscopy-based screen of transcription (co)factors as well as a functional migration screen to identify and hierarchically group the factors regulating EMT. We are especially interested in epigenetic modifiers and their contribution to EMT and tumor metastasis. Using this approach, we hope to gain a more global understanding of the processes underlying malignant tumor progression and metastasis.
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