Drosophila Lethal Giant Larvae Neoplastic Mutant as a Genetic Tool for Cancer Modeling

Abstract

Drosophila lethal giant larvae (lgl) is a tumour suppressor gene whose function in establishing apical-basal cell polarity as well as in exerting proliferation control in epithelial tissues is conserved between flies and mammals. Individu-als bearing lgl null mutations show a gradual loss of tissue architecture and an extended larval life in which cell prolifera-tion never ceases and no differentiation occurs, resulting in prepupal lethality. When tissues from those individuals are transplanted into adult normal recipients, a subset of cells, possibly the cancer stem units, are again able to proliferate and give rise to metastases which migrate to distant sites killing the host. This phenotype closely resembles that of mammalian epithelial cancers, in which loss of cell polarity is one of the hallmarks of a malignant, metastatic behaviour associated with poor prognosis. Lgl protein shares with its human counterpart Human giant larvae-1 (Hugl-1) significant stretches of sequence similarity that we demonstrated to translate into a complete functional conservation, pointing out a role in cell proliferation control and tumorigenesis also for the human homologue. The functional conservation and the power of fly genetics, that allows the researcher to manipulate the fly genome at a level of precision that exceeds that of any other mul-ticellular genetic system, make this Drosophila mutant a very suitable model in which to investigate the mechanisms un-derlying epithelial tumour formation, progression and metastatisation. In this review, we will summarise the results ob-tained in these later years using this model for the study of cancer biology. Moreover, we will discuss how recent ad-vances in developmental genetics techniques have succeeded in enhancing the similarities between fly and human tumori-genesis, giving Drosophila a pivotal role in the study of such a complex genetic disease.