Tumour-host interactions in Drosophila: mechanisms in the tumour micro- and macroenvironment

Traditionally, cancer has been viewed largely as a disease of the cell, with extensive research centred on how mutations in driver genes trigger cellular transformation. Beyond cell-intrinsic changes, cancer unfolds as a systemic disease driven by an intricate dialogue between malignant cells and the host's organs and tissues. Modelling this multilayered phenomenon is challenging, as it requires recapitulating coordinated interactions within and across multiple organs, inside an organism that is contended with maintaining normal physiology. In recent years, Drosophila melanogaster has emerged as a powerful model for revealing fundamental mechanisms by which the tumour and host mutually interact. In this review, we highlight recent findings that unravel the intricacies of tumour-host biology using Drosophila. At the microenvironment level, we synthesise mechanistic findings on how tumour growth is modulated through interactions with neighbouring tumour subclones, nonmutated wild-type cells and the immune system. At the macroenvironment level, work in Drosophila has provided mechanistic insights into how tumourigenesis causes systemic host health degeneration and accelerates death, collectively termed paraneoplastic effects. Tumours can remotely induce systemic metabolic rewiring and cachectic tissue wasting to promote progression, while simultaneously compromising the function of several tissues, such as the renal system, blood-brain barrier, the gut and blood haemostasis. Additionally, we discuss how the microbiota and sexual dimorphism have been shown to affect the tumour-host interplay. With this review, we synthesise recent advances in Drosophila tumour-host biology and illustrate how this model illuminates cancer's systemic nature.