View Program - 63rd Annual Drosophila Research Conference

Apoptosis, the most common form of programmed cell death in animal development and homeostasis, is mediated by the activation of a unique family of proteases called caspases. However, an ever-growing list of studies suggest that caspases have an essential role in ensuring non-lethal cellular functions during normal development, tissue repair and regeneration, including in cell differentiation, proliferation, migration, signaling and cellular remodeling. Moreover, upon dysregulation, these caspase-dependent non-lethal cellular processes (CDPs) can also instigate disease. We previously discovered and characterized a novel non-apoptotic role of caspases in maintaining epithelial tissue integrity in Drosophila. We showed that upon ionizing irradiation or even spontaneously during development, epithelial cells compromised for caspase activity gain high migratory and invasive capacities. Furthermore, low levels of effector caspase activity, far below the threshold required to induce apoptosis, potently inhibit this process, which we termed irradiation-induced cell migration (ICM). Previous work showed that ICM is mediated by the DNA damage response (DDR) pathway, but the molecular mechanisms and signaling pathways underlying ICM downstream of the DDR remained largely elusive. Here we show that ICM shares many features with the process of epithelial-mesenchymal transition (EMT). Inactivation of key EMT-driving genes, which are also potential caspase substrates, including twist and zfh1 (ZEB1), attenuates ICM. We further show evidence that the Notch signaling pathway is involved in ICM, and that effector caspases are important regulators of Notch-mediated ICM. Furthermore, members of the ADAM family of metalloproteinases, which among other functions are also responsible for the activation of the Notch signaling pathway, are also involved in ICM and may function as potential extracellular matrix modifiers during this process. Collectively, our findings indicate that ICM is an EMT-like process activated by genotoxic stress and is potently attenuated by non-lethal levels of caspase activity. Given that ionizing irradiation has been a common treatment for many cancers, and that one of the hallmarks of cancer cells is their ability to evade cell death, these findings may have implications for cancer malignancy and the induction/aggravation of metastasis in some patients undergoing radiotherapy.

Irradiation-Induced Cell Migration: An Epithelial-Mesenchymal Transition Process Regulated By Low-Level Caspase Activity