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Loss of tumorigenicity by transdifferentiation:from squamous cell carcinoma to melanocyte-like cells

Fehrenbach, Sabrina

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Abstract

Lineage-specific transcription factors determine the cell fate during development. Remarkably, several studies have demonstrated that ectopic overexpression of specific transcription factors can promote the direct conversion of one somatic cell type into another. Even the lineage of origin of cancer cells could be switched by this mechanism and the resulting cells showed impaired tumor forming potential. This approach might therefore be suitable as an alternative therapeutical strategy for the treatment of cancer. The aim of this project was to directly convert tumor cells from the keratinocytic lineage into functional and potentially non-tumorigenic cells from the melanocytic lineage. We hypothesize that the tumorigenic potential of a cancer cell is dependent on the differentiation lineage. Thus, transdifferentiation of squamous cell carcinoma cells (SCCs) into the melanocytic lineage should yield non-tumorigenic cells. In order to achieve this objective, different sets of candidate transcription factors were cloned into doxycycline-inducible lentiviral vectors and were ectopically overexpressed in a SCC line. This thesis is a proof of principle that transdifferentiation of cancer cells is possible and that this process can lead to loss of tumorigenic potential. After ectopic overexpression of the four transcription factors MITF, SOX10, SOX9 and LEF1, morphological changes towards a melanocyte-like appearance could be observed. Moreover, keratinocyte markers were downregulated and melanocyte marker expression was induced. Additionally, melanosome-like structures were present in the transdifferentiated cells. On genomic level only minor changes were observed using array CGH. Also the global gene expression and the methylation landscape remained very similar between the parental SCC and the transdifferentiated cells. Yet, several characteristics including proliferation, cell metabolism, migration and invasion were reduced. Additionally the cells were less responsive to a cancer cell-specific drug combination using autophagy inhibition and an AKT inhibitor as well as to the treatment with the chemotherapeutic drug cisplatin. Finally, the transdifferentiated cells lost their tumorigenic potential, which could be shown in vivo by subcutaneous injection into immunosuppressed mice. To find a mechanism that could explain these observations, whole genome microarray and methylation array analyses were performed. After a gene set enrichment analysis (GSEA) IL-24 was identified as the top hit. Probably due to the transdifferentiation into the melanocytic lineage IL-24 became upregulated and might have affected the tumorigenic potential of the cells. In conclusion, we could identify a specific transcription factor combination which promotes the conversion of tumorigenic SCCs into nontumorigenic melanocyte-like cells.

Item Type: Dissertation
Supervisor: Umansky, Prof. Dr. Viktor
Place of Publication: Heidelberg, Germany
Date of thesis defense: 10 March 2016
Date Deposited: 26 Apr 2016 06:13
Date: 2016
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 570 Life sciences
610 Medical sciences Medicine
Controlled Keywords: Transdifferentiation, Cancer, Regenerative Medicine
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