Genetic dissection of factors contributing to disease severity in a fly brain tumour model
Worldwide Cancer Research
Foundation for Research and Technology Hellas
Since the discovery of oncogenes and tumour suppressors, it is known that a small number of genetic insults can transform healthy cells into precancerous. Decades later, we are still trying to fathom the multitude of additional defects that underlie full-blown malignancy. Model organism cancer models with carefully controlled genetic make-up are invaluable in achieving progress in this direction. In the past decade, a number of Drosophila cancer models were developed, that have helped understand aspects of carcinogenesis, such as multiclonality and metastasis. We are studying a cancer model from juvenile fly neural progenitors, which can be immortalized by serial allografting. We have performed transcriptome and histological analysis of this tumour, as well as two genetically defined variants, where we knocked down two key chromatin regulators, the NuRD nucleosome remodeling complex and the PRC2 histone methyltransferase. One of these variants grows more aggressively whereas the other is more benign. From analysis of differentially expressed genes, we have zeroed-in on a number of putative enhancers and suppressors of malignancy; these are the focus of the present proposal. Curiously, a cohort of 15 transcription factors, normally associated with early steps of neuronal differentiation, is upregulated in the more malignant NuRD-compromised variant. At the opposite end, activation of the Toll and JNK pathways is a hallmark of the less malignant PRC2-compromised variant. We propose to perform an in-depth in vivo study of tumours manipulated for these putative modulators in order to determine whether their upregulation causally underlies increased/suppressed malignancy or is simply a collateral effect. In parallel, we shall address the ability of these tumours to induce organ wasting to their hosts: this is more pronounced in the less aggressive tumour. We shall therefore scrutinize its secretome and use genetic manipulations to ask whether one or more tumour-produced cytokines are responsible for host cachexia.
2.1 Biological and endogenous factors