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In vivo studies and screens for new factors that promote or suppress tumor metastasis

Final Report Summary - FINDMETASTASIS (In vivo studies and screens for new factors that promote or suppress tumor metastasis)

Dissecting Notch- and BTB-transcription factor-dependent invasive tumors in Drosophila
Alisson M. Gontijo and Maria Dominguez
Instituto de Neurociencias de Alicante, CSIC-UMH, Sant Joan d'Alacant, Alicante, 03550,
Spain.

Malignant growth comes about when cells divert from the regulatory circuits that govern normal proliferation and homeostasis. Hallmarks of cancer such as overgrowth, evasion of programmed cell death, tissue invasion and metastasis can be found in tumourous eye tissues of Drosophila, providing a powerful experimental model for the genetic dissection of tissue homeostasis, growth and cancer in vivo.

Here, using genome-wide transcriptional profiling, we have begun to unravel the several molecular steps by which ectopic activation of the Notch-ligand Delta produces larger eyes, as well as how it can be corrupted by different oncogene combinations to trigger metastatic tumour in Drosophila. One of these oncogenes is encoded by pipsqueak, which is a transcription factor with a conserved amino-terminal BTB domain and a carboxi-terminal DNA binding domain.

Identifying transcriptional outputs and decrypting the molecular mechanisms whereby BTB-containing oncogenes such as Pipsqueak functions on DNA, as crucial for our understanding of how these genes contribute to metastasis. We have characterised the transcriptional response to Pipsqueak, which includes the upregulation of two divergent members of known molecular pathways that have nevertheless escaped bioinformatics homology searches. Functional associations between these previously uncharacterised Drosophila genes with their human homologues suggested a role for at least one of them as a tissue-specific tumor suppressor.

Additionally, we have identified key molecular mechanisms controlling Pipsqueak protein activity posttranslationally that may explain its oncogenic activity. In collaboration with other members of the group, we have identified proteins that physically interact with Pipsqueak and investigated the direct consequences on transcriptional activity in tissue homeostasis and tumorigenesis.

Furthermore, the novel analytical schemes that we applied to our genome-wide expression data allowed us to make the unexpected discovery of several polymorphic loci with strong effects on gene expression. I have characterised in detail two particular polymorphisms, and our findings have implications for understanding sudden de novo gene birth.