UC Berkeley

Cancer is the abnormal growth of cells. This growth can kill by disrupting the normal function of its organ of residence or through long-range pathophysiological interactions with distant tissues. Despite the morbidity and mortality associated with cancer, the mechanisms underlying these lethal interactions have remained elusive.

We have established a Drosophila tumor model to explore the poorly-understood mechanisms of tumor-host interactions. Using a classic technique, we transplanted larval tumors into adult flies and investigated the effects imposed on host tissues. We find that only 5 days post-transplantation, malignant fly tumors induce robust wasting of muscle, adipose and gonadal tissues. Interestingly, these wasting phenotypes recapitulate key characteristics of the enigmatic cancer cachexia suffered by about half of human cancer patients. We have identified the Insulin Growth Factor Binding Protein (IGFBP) homolog ImpL2 as key mediator of these cachexia-like phenotypes. This factor is secreted specifically by malignant tumors and is both necessary and sufficient for tissue wasting. Consistent with its role as an insulin antagonist, tumor-secreted ImpL2 interrupts systemic insulin signaling to induce insulin resistance, resulting in the cachexia-like wasting of peripheral host tissues.

Our work demonstrates that this Drosophila model lends itself to the dissection of complex tumor-host interactions, such as cachexia. We have also used this model to investigate other important features of tumor-host interactions, including metastasis, bloating, immune response and lethality.

The genetic manipulability of this system has facilitated the identification of a critical factor mediating the observed cachexia-like phenotypes and can now be used to explore other contributors to the tumor-induced systemic wasting or the molecular mechanisms underlying other important tumor-host interactions.