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Identifier |
000452281 |
Title |
Dissection of intrinsic and extrinsic factors contributing to cancer growth in a fly brain tumor model |
Alternative Title |
Ανάλυση ενδογενών και εξωγενών παραγόντων που συμβάλλουν στην ανάπτυξη ενός όγκου του νευρικού συστήματος στη drosophila |
Author
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Βουτυράκη Χρυσάνθη Ι
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Thesis advisor
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Δελιδάκης, Χρήστος
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Reviewer
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Giangrande, Angela
Ταλιανίδης, Γιάννης
Γαρίνης, Γεώργιος
Χαμηλός, Γεώργιος
Πιτσούλη, Χρυσούλα
Κρετσόβαλη, Ανδρονίκη
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Abstract |
Brain tumors (e.g. Glioblastomas) are very aggressive tumors with poor prognosis which are
characterized by genetic and epigenetic diversity, making the development of therapies that
eliminate all tumor cells challenging and currently impossible. Cancer Stem Cells, major
components of brain tumors, are tumorigenic stem-cell like cells with self-renewing capacity
which maintain tumor growth. Additionally, interactions of the tumor with its microenvironment
shape tumor progression. Drosophila has proven a valuable tool when it comes to modeling basic
molecular mechanisms which are deregulated in human diseases.
In Drosophila, similar to the mammalian systems, brain development is achieved by asymmetric
cell divisions of neural stem cells (NSCs) which self-renew to produce a cell with stem cell identity
and also generate progeny that is routed to differentiation. Previous work in the lab has shown
that Notch signaling in the developing brain tightly regulates the differentiation status of neural
lineages with NSCs receiving Notch signal from their progeny. Notch induces the expression of
HES proteins which repress the expression of differentiation genes, thus ensuring stem cell
maintenance. Genetic insults, such as excess of Notch signaling, perturb the normal NSC
proliferation programs and trigger the formation of NSC hyperplasias at the expense of
differentiated neuronal progeny.
During my Ph.D., I showed that neural stem cell hyperplasias induced by Notch or HES
overexpression are prone to malignant overgrowth and metastasis to distant sites upon
allografting to an adult fly host. I investigated whether loss of HES genes has an impact on the
malignant potential of Notch induced hyperplasias and I showed that the E(spl) genes (which
belong to HES family) are important mediators in the progression to malignancy. I also performed
transcriptomic analysis of Notch and HES induced tumors at different stages of tumor
progression. This analysis revealed that both types of NSC-derived tumors, whether triggered by
Notch or by HES, are quite similar and retain stem cell characteristics, while differentiationpromoting transcription factors are downregulated. This is accompanied by an upregulation of
stress-response genes, growth control genes and metabolic reprogramming. An interesting
finding of the transcriptomic analysis was the de novo expression of immunity genes in the
allografts, which, together with immunohistochemistry, revealed the attraction of hemocytes
(Drosophila blood cells) to the allografted tumor.
I was intrigued by this finding and tried to assess the functional role of host hemocytes in tumor
progression. By genetic manipulation of host hemocytes, fixed and live imaging experiments we
showed that hemocytes impede tumor growth by associating with tumor cells and performing
phagocytosis. I also performed an RNAi screen in host hemocytes by knocking down factors
related to phagocytosis, ROS production and hemocyte migration. The screen revealed that loss
of phagocytic receptors in hemocytes accelerates allograft tumor growth while perturbing ROS
production results in slower tumor expansion, suggesting that phagocytosis restricts tumor
growth whereas hemocyte ROS production accelerates it. The Drosophila respiratory system
(trachea) was also found to associate with tumor cells in the fly host. I therefore, investigated
whether this association impacts tumor growth and showed that integrity of the trachea might
contribute to tumor suppression, although more experiments are needed to substantiate this
model.
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Language |
English |
Subject |
Hemocytes |
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Neural stem cell |
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Notch signaling |
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Αιμοκύτταρα |
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Δροσόφιλα |
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Καρκίνος |
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Μονοπάτι σηματοδότησης Notch |
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Νευρικά βλαστοκύτταρα |
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Νευρικό σύστημα |
Issue date |
2022-11-23 |
Collection
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School/Department--School of Sciences and Engineering--Department of Biology--Doctoral theses
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Type of Work--Doctoral theses
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Permanent Link |
https://elocus.lib.uoc.gr//dlib/3/b/c/metadata-dlib-1669104283-541840-32473.tkl
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Views |
473 |
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