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Doctoral theses

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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 Βουτυράκη Χρυσάνθη Ι
Thesis advisor Δελιδάκης, Χρήστος
Reviewer Giangrande, Angela
Ταλιανίδης, Γιάννης
Γαρίνης, Γεώργιος
Χαμηλός, Γεώργιος
Πιτσούλη, Χρυσούλα
Κρετσόβαλη, Ανδρονίκη
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.
Language English
Subject Hemocytes
Neural stem cell
Notch signaling
Αιμοκύτταρα
Δροσόφιλα
Καρκίνος
Μονοπάτι σηματοδότησης Notch
Νευρικά βλαστοκύτταρα
Νευρικό σύστημα
Issue date 2022-11-23
Collection   School/Department--School of Sciences and Engineering--Department of Biology--Doctoral theses
  Type of Work--Doctoral theses
Permanent Link https://elocus.lib.uoc.gr//dlib/3/b/c/metadata-dlib-1669104283-541840-32473.tkl Bookmark and Share
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