Determining Sox10-mediated plasticity in irradiated salivary gland cells

PROJECT SUMMARY/ABSTRACT Therapeutic irradiation, a commonly used treatment for head and neck cancer patients, irreversibly damages the salivary glands (SGs). Current therapies aim to alleviate the resulting xerostomia (dry mouth syndrome) but fail to address the underlying mechanism of dysfunction, thus new strategies for tissue regeneration are needed. Given that endogenous repair of irradiated SGs is majorly hampered due to the loss of saliva-producing acinar cells and their progenitors, inducing the ability of the remaining ductal cells to behave as acinar progenitors (i.e. plasticity) is an attractive repair strategy. Inducing plasticity is a complex process whereby transcription factors often interact with chromatin modulators, such as Hdac1, to induce downstream gene regulators of progenitor cell potency. Interestingly, it has been shown that some irradiated ductal cells can spontaneously revert towards a progenitor-like state to enable acinar differentiation under severe stress conditions, although too few undergo this transition to fully restore the gland. In order to enhance plasticity, we recently demonstrated that overexpression of transcription factor Sox10 in non-irradiated ductal cells induces plasticity, allowing acinar differentiation ex vivo. However, whether this set-up is applicable to irradiated ductal cells is unclear. Based on preliminary data, we hypothesize that plasticity can be induced in irradiated ductal cells through overexpression of Sox10, which activates a downstream regulatory network through binding with Hdac1. To prove this hypothesis, our objectives are to evaluate the binding capacity of Sox10 to Hdac1, as well as the altered downstream gene network and acinar formation capacity in irradiated cells after inducing a Sox10-mediated plasticity. Overall, these data will then be used to formulate a new translational therapy in our in vivo radiation- induced xerostomia animal model to aid in the repair of SGs post-radiation.