Fellow's research: Switch in cell identities can drive cancer-formation: Insights from fruit fly
12 Feb 2020
Anjali Bajpai, Early Career Fellow, Indian Institute of Technology, Kanpur
In our latest research, we show the role of HedgeHog (Hh), a protein that regulates growth of cells, in dictating whether an ‘oncogenic hit’ leads to development of cancer or not.
Cells in an organ have unique identities and are constantly kept under very stringent control of growth and proliferation. Mutations resulting in loss of function of a “tumor suppressor gene” or activation of an “oncogene” disrupt the strict proliferative control of cells and results in runaway cancers. Intriguingly not every oncogenic mutation gives rise to cancer. Why is this so? Does a cell’s identity play a role in determining the outcome of an oncogenic hit?
We have tried to address this question using the simple yet genetically very powerful model of the fruit fly, Drosophila melanogaster. In the fruit fly larvae, there are present sac-like structures called “imaginal discs”, which give rise to the future structures in the adult fly. For instance, the larval wing imaginal disc forms the wings of the adult fruit fly.
Remarkably, different cells of the larval wing disc express distinct cell fate genes that confer it unique identity; such as, cells of one half of the disc express the cell fate gene engrailed (en) which confers on them a “Posterior identity”. On the other hand, the “Anterior” half of the disc expresses the transcription factor Ci (Gli in mammals). The “Posterior” cells secrete the ligand Hedgehog (Hh) and therefore trigger Hh and Dpp signaling in the “Anterior” cells of the wing disc.
We observed that cells with loss of tumor suppressor gene, lgl, along with gain of en, undergo cancerous transformation, but strikingly in only the Anterior half of the wing disc, while they grow poorly and fail to transform in the Posterior half of the wing disc. This dichotomous behavior could be traced to the developmental role of En. Gain of En in lgl mutant cells triggers aberrant Hh signaling in the surrounding normal Ci-expressing cells of the Anterior half of the wing disc. The Hh and Dpp signaling from these normal neighbors in turn facilitate abnormal growth and transformation of the mutant lgl cell. On the other hand, lgl mutant cells with gain of ci undergo cancerous transformation in only the Posterior half of the wing disc wherein these display autonomous gain of Hh and Dpp signaling.
We also show that in the developing eye, where the Hh signaling triggers retinal differentiation, ci- or en-expressing lgl mutant cells fail to become cancerous and instead undergo differentiation to retinal fate.
Many human cancers are Hh-dependent and are peculiar owing to their tissue-specific occurrences. Taking a clue from the current study in Drosophila, a look at the developmental context of their origin may offer better mechanistic understanding and novel therapeutic strategies for their inhibition.
Hh signaling from de novo organizers drive lgl neoplasia in Drosophila epithelium. Anjali Bajpai and Pradip Sinha. Dev Biol. 2020 Jan 1; 457(1):1-8.
This research work was featured on the cover page of the January issue of the journal Developmental Biology.
Banner image: In this immuno-fluorescent image of a larval wing disc (marked by nuclear stain TOPRO, in blue) is shown GFP-marked tumors (in green). In red is pSmad, a molecular readout of the Dpp signaling. Note that while the wing disc has a double stripe of the pSmad (the one on the right) that represents the Anterior/Posterior (A/P) boundary of the wing disc, the tumor (green) creates a duplicate A/P boundary (on the left, overlapping with the GFP-marked tumor) which facilitates its growth acting as a source of Hh and Dpp signaling.