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The role of Myogenic Regulatory Factors in Rhabdomyosarcoma: Insights from zebrafish and beyond
Başlık:
The role of Myogenic Regulatory Factors in Rhabdomyosarcoma: Insights from zebrafish and beyond
Yazar:
Tenente, Inês Moreira, author.
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (212 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 76-07C.
Özet:
Rhabdomyosarcoma (RMS) is the most common pediatric sarcoma with skeletal muscle differentiation features, such as the expression of Myogenic Regulatory Factors (MRFs) (MYF5, MYOD1, MYOG, MRF4/MYF6) and skeletal muscle structural proteins (Desmin and Myosin). The aggressive treatment regimen eliminates self-renewing cells, but often leads to toxicity. Remaining self-renewing cells can evade treatment and lead to relapse. Understanding the molecular mechanisms of self-renewing cells in these cancers is thus paramount for the development of less toxic, targeted treatments that effectively eliminate these cells to prevent relapse.
A transgenic zebrafish model that is morphologically and molecularly similar to the human ERMS subtype was developed previously. Molecular analysis of mononuclear ERMS cells identified a sub-population of self-renewing tumor cells that is most similar to a MYF5-expressing, activated satellite cell. Given that MYF5 and MYOD1 are required for normal muscle development, are involved in muscle regeneration, and have roles in satellite cell self-renewal, we hypothesized that these genes and their transcriptional targets are responsible for eliciting stem cell self-renewal programs in a subset of ERMS cells. Through a series of transgenic multi-colour zebrafish, where sub-populations of RMS cells are labelled based on the expression of muscle differentiation markers, we were able to image discrete populations of proliferating MYF5-positive self-renewing cells and migratory MYOG-positive cells within RMS in live animals. Furthermore, we show that MYF5 is a marker of functionally-defined ERMS Tumor Propagating Cells.
Additionally to being a marker of these cells, we show that MYF5 is sufficient to confer self-renewal to differentiated zebrafish ERMS cells. These tumors initiate earlier, have higher penetrance and a tendency to be larger than control tumors. Consistent with redundant roles for MYF5 and MYOD1 in muscle development, regeneration and stem cell self-renewal, we identified two classes of human ERMS that express either high levels of MYF5 or MYOD1, with either MRF being required for sustained tumor growth in vitro and/or in vivo. ChIP-seq experiments went on to reveal that MYF5 and MYOD1 bind common DNA regulatory elements likely to arrest human ERMS in early stages of muscle development while simultaneously promoting cell cycle progression.
We suggest a model where MYF5 and MYOD1 converge on common molecular pathways to regulate human RMS growth and self-renewal, similar to their overlapping roles in muscle development and regeneration. Taken together, we show that cancer self-renewal pathways are likely shared with their non-malignant counterparts and that these processes are aberrantly activated during malignant transformation, an emerging concept in cancer biology.
Notlar:
School code: 5896
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(678848.1) | 678848-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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