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From cancer cell plasticity to differentiation therapy

Ronen, Dana Ishay. From cancer cell plasticity to differentiation therapy. 2016, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_12157

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Abstract

Cancer is a systemic heterogeneous disease that can undergo several rounds
of latency and activation. Malignant tumours evolve by increasing diversity and
in progressive response to microenvironment signals and resistance
development after therapeutic interventions. Thus, adaptation is required for
cancer cell survival during tumour dissemination and metastatic outgrowth.
An epithelial-mesenchymal transition (EMT) plays a major role in
facilitating cell plasticity in cancer and allows cancer cells to escape
chemotherapy and targeted therapies by dedifferentiation and signalling
adaption processes. EMT commonly describes a process in which
differentiated epithelial cells lose their epithelial characteristics such as cellcell
adhesions and apical-basal polarity and gain migratory properties. While
an EMT is mainly responsible for primary tumour cell invasion, its reversal
mesenchymal-epithelial plasticity (MET) has been shown to contribute to the
metastatic outgrowth of disseminated cancer cells in distant organs. Hence,
the therapeutic reversion of an EMT in cancer could be counterproductive.
However, it has also been noted that cells undergoing an EMT and/or an MET
are in a state of high cell plasticity and thus, may offer a window of opportunity
for therapeutic targeting.
Here, I have aimed at utilizing breast cancer cell plasticity by inducing
terminal differentiation into postmitotic adipocytes. Giving the inherent growth
arrest of adipocytes they are unlikely to adapt and dedifferentiate, and
therefore lose cellular plasticity. I report the efficient conversion of breast
cancer cells, which have undergone an EMT, into functional post-mitotic
adipocytes. By combining the diabetic drug Rosiglitazone and bone
morphogenetic protein 2 (BMP2) I have been able to achieve almost 100%
adipogenesis efficiency in mesenchymal breast cancer cells in vitro.
Delineation of the molecular pathways underlying such trans-differentiation has
motivated a combination therapy with a MEK inhibitor and Rosiglitazone to
demonstrate the conversion of invasive cancer cells into adipocytes and the
repression of primary tumour invasion and metastasis formation in mouse
models of breast cancer. The results indicate the high potential of utilizing the
increased cell plasticity inherent to invasive cancer cells for differentiation
therapy. They consequently raise the possibility of employing pharmacological
treatments to interfere with tumour invasion and metastasis.
Advisors:Christofori, Gerhard M. and Bentires-Alj, Mohamed
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Division of Biochemistry and Genetics > Tumor Biology (Christofori)
UniBasel Contributors:Christofori, Gerhard M. and Bentires-Alj, Mohamed
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:12157
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:1 Online-Ressource (101 Seiten)
Language:English
Identification Number:
Last Modified:05 Apr 2018 17:35
Deposited On:20 Jun 2017 09:44

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