Research SummaryA translational exploration of the Drosophila cancer model for biomedical research
When a cell turns cancerous it is often seen to lose its developmentally acquired cell state exemplified by loss of its commitment to a given cell fate or cell differentiation program. Carcinogenesis (oncogeny), hence, is essentially a developmental program (ontogeny) that has gone awry. Restoration of a developmental program, therefore, holds promise of reversal of cancer progression: ontogeny being the anti-thesis of oncogeny.
Importance of this study stems from its relevance to an enduring riddle of cancer biology: namely, cell type-specific carcinogenesis, which in its turn is intractably linked to the question of cells of origin in cancer – an area of intense investigation in recent years. It is clear that a given oncogenic lesion transforms only certain cell types and not others, those that transform exhibit an aberrant re-programming of their cell fate. However, cellular processes that trigger a reversal in ontogeny continue to be largely elusive. As a consequence, the immense possibilities of finding novel therapeutic/diagnostic strategies based on a ‘developmental’ understanding of carcinogenesis also have gone largely underexplored, so far.
Drosophila, provides an excellent platform to explore these oncogeny-ontogeny links. Our recent results (Khan, Bajpai et al., 2013) show that cell fate reversals in developing wing epithelia, marked by loss of the wing fate selector Vestigial, sets in upon loss of the highly conserved tumor suppressor Lgl and, by contrast, its overexpression arrests Lgl loss mediated neoplasia. Further, we have early leads that suggest the role of developmentally regulated non-coding RNA hsr-ω in impacting tumor progression upon loss of Lgl.
I therefore aim to unravel the mechanisms of cell fate changes, namely loss of Vestigeal in the developing wing upon tumor initiation and arrest of tumor progression upon gain of Vg. I believe, that similar to Vestigeal the genome carries within itself many more such developmental suppressors of tumorigenesis; using a genetic screen I would therefore like to uncover other such “genetic inhibitors”. This study therefore, besides providing mechanistic understanding of cell fate reversal in cancer, would initiate a field of study involving novel tumor regulators from within an organism’s own genome.
Figure Legend: The immuno-fluorescence image shows tumors (Green) due to loss of tumor suppressor Lgl on wing imaginal disc of Drosophila larva. Note that the domain which has acquired Vestigial (Red) to become the future adult wing is tumor free. The focus of my investigation is to understand why committed/differentiated cells fail to transform unless they reprogram; particularly, why cells expressing Vestigial fail to succumb to an oncogenic lesion. Answers to these questions also present potential therapeutic possibilities.