Abstract
Pediatric neural tumors are often initiated during early development and can undergo very rapid transformation. However, the molecular basis of this early malignant susceptibility remains unknown. During Drosophila development, neural stem cells (NSCs) divide asymmetrically and generate intermediate progenitors that rapidly differentiate in neurons. Upon gene inactivation, these progeny can dedifferentiate and generate malignant tumors. Here, we find that intermediate progenitors are prone to malignancy only when born during an early window of development while expressing the transcription factor Chinmo, and the mRNA-binding proteins Imp/IGF2BP and Lin-28. These genes compose an oncogenic module that is coopted upon dedifferentiation of early-born intermediate progenitors to drive unlimited tumor growth. In late larvae, temporal transcription factor progression in NSCs silences the module, thereby limiting mitotic potential and terminating the window of malignant susceptibility. Thus, this study identifies the gene regulatory network that confers malignant potential to neural tumors with early developmental origins.
Highlights
Many pediatric tumors are thought to initiate during prenatal stages and are able to rapidly progress towards malignancy, sometimes within a few months (Marshall et al, 2014)
All NBs are absent in the adult ventral nerve cord (VNC). (B) In poxn-GAL4, UAS-prosRNAi, UASGFP, UAS-dcr2 larvae, six tumors of dedifferentiated NBs (dNBs) are generated. dNBs are represented on the scheme as green circles filled in red
No tumor is observed in wt adults. 1 day-old poxn>prosRNAi, GFP VNCs (n= 5 VNCs, m = 1.4x105, SEM = 6.3x104) and 6 dayold poxn>prosRNAi, GFP VNCs (n = 7 VNCs, m = 1.5x106, SEM = 1.8x105). p-value is 2.5x10-3. (E) poxn>prosRNAi, GFP tumors are almost exclusively composed of dNBs in late L3, and devoid of neurons (Elav)
Summary
Many pediatric tumors are thought to initiate during prenatal stages and are able to rapidly progress towards malignancy, sometimes within a few months (Marshall et al, 2014). They contain very few genetic alterations (Huether et al, 2014; Parsons et al, 2011; Pugh et al, 2013; Vogelstein et al, 2013; Wu et al, 2014) suggesting that transformation in infancy is not driven by the gradual accumulation of genetic lesions over many years, as for most adult cancers. The underlying mechanisms of transformation are still unknown (Caussinus and Gonzalez, 2005; Knoblich, 2010)
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