Development of a Drosophila model for the study of cancer-stroma molecular interplay

OBJECTIVE While current therapies are conceived to target cancer cells, it is widely acknowledged that several non-cancer populations are involved in tumourigenesis. Dysfunction of epithelial-mesenchymal interactions are indeed known to promote progression of pre-neoplastic lesions to malignancy. What are the major molecular changes occurring in the mesenchymal cells co-opted by the growing cancer? Are these cells more treatable than cancer cells? We believe the success of cancer therapy requires an intimate understanding of the bi-directional feedback between the evolving tumour cells and the associated stromal tissue. The identification of specific molecules at work within the mesenchymal compartment during cancer growth may thus be instrumental for the development of novel therapeutics. Here we present the scheme of a project which starts with the development of a Drosophila cancer model aimed at analysing the expression profile of the mesenchymal cells in an organ whose epithelial cells are undergoing clonal malignant transformation. The resulting findings will be extended to the context of human cancer with the aim to identify a group of mesenchyma-derived molecular factors able to modulate cancer progression. MATERIALS AND METHODS We developed a Drosophila model of Ras-driven carcinogenesis that will be used to capture the expression profile of the mesenchymal cells populating the epithelial organ undergoing cancer growth. Mesenchymal cells will then be isolated from human Ras-driven epithelial cancer samples and a qRT-PCR analysis will be carried out to evaluate the expression of the human orthologues of the transcripts/miRs found deregulated in the fly model. The selected molecules whose expression will result conserved will be screened in vivo in Drosophila to assess their contribution to tumour progression. RESULTS This project aims at identifying a pool of mesenchymal players with cooperative or inhibitory effects on tumour progression, widening our understanding of the role that tumour-associated stroma plays in carcinogenesis. Morover, we expect that our approach will highlight significant molecular conservation between Drosophila and human Ras-driven cancer stroma and will thus represent an invaluabe model for further studies in the field. CONCLUSION It is well recognised that tumour microenvironment plays an essential role in cancer development, and it is thus considered as an additional cancer hallmark. Understanding the molecular basis of the social cell biology of cancer is thus indispensable to develop novel therapeutic approaches targeting the whole cancer-associated cell community.