| Περίληψη |
Drosophila melanogaster is an ideal system to study stem cell biology and innate immune
responses. Through its genetic tractability and the evolutionary conservation of molecular effectors,
the fly constitutes a workhorse for functional and lineage tracing studies. In this work, we built
upon recent advances in innate immunity concerning tumorigenesis by incorporating a model of
allograft series from neural-derived (primary) tumors. Powerful genetic tools allowed us to,
temporally, obscure the lineage progression of the neural stem cell population (neuroblasts),
specifically, in the larval brain. During larval neurogenesis, the majority of the adult neurons and
glia are generated from asymmetric divisions of these neural stem-like cells. Neuroblasts (NBs) are
endowed with spatiotemporal cues that unfold a highly stereotyped and dynamic transcriptional
trajectory during the asymmetric segregation of their daughter cells, called ganglion mother cells
(GMCs). This remarkable division mode ensures two distinct fates. First, NBs retain their stemlike characteristics, performing repeated rounds of asymmetric division. Second, the resultant
GMCs are gradually specified and divide once more to generate post-mitotic neurons/glia. Notchsignaling and a plethora of conserved effectors are essential for the developmental orchestration of
proper NB-lineage progression. Through RNA-interference (RNAi) we abrogated the self-renewal
capacity of NBs by knocking-down the RNA-binding protein Imp (insulin-like growth factor II
mRNA-binding protein) and the proto-oncogene Myc. In combination, we overactivated Nsignaling within the NB lineages during larval neurogenesis. This resulted to a hyperplastic larval
central nervous system that facilitated the foothold for our experimental method. By injecting these
primary tumors in adult hosts, we set out to explore the tumor progression in vivo. Previous work
in our laboratory from Eva Zacharioudaki and Chrysanthi Voutiraki has shown close interaction
between tumor secondary masses and the cellular arm of the fly’s immunity, called haemocytes.
Part and parcel of the adult immunosurveillance system, haemocytes (plasmatocytes) exhibit
phagocytic activity and active migratory behavior, mimicking the macrophage population of
vertebrates. Focused on the neural stem cell-derived tumors and haemocyte interplay, we generated
a survival screen of adult hosts deficient in haemocyte-specific genes (RNAi) and identified two
scavenger-receptors as essential for preserving host lifespan during tumor progression. This work
establishes an early view of the dynamics of tumor and haemocyte interaction and provides the
framework of an in vivo model to decipher the fundamental mechanisms of tumorigenesis within
an invertebrate system.
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Haemocyte and tumor interplay in a neural stem-cell-derived model of tumorigenesis in Drosophila melanogaster
