Abstract 252: Functional and lineage atlas of salivary gland regeneration charted by rapid in vivo gene targeting

Abstract

Abstract The crucial function of the salivary gland of keeping the oral cavity lubricated to facilitate breathing, swallowing, and lingual communication is often compromised following cancer radiotherapies. Due to the ultra-high radiosensitivity and low regeneration potential of the salivary epithelium, radiation-induced damage is largely permanent, representing a major clinical challenge. To solve this problem, we have developed a scalable rapid gene targeting system in the murine salivary gland using in-utero injection of lentiviruses. This allows us to transduce ectodermal progenitors of salivary glands with high efficiency and full randomness. Barcoded lentiviral lineage tracing suggests that every major salivary gland originated from a defined number of progenitors, each progenitor-derived clone has relatively equal expansion potential during development and equally contributes to regeneration post radiation challenge. This observation indicates that the major salivary glands of a single mouse can be used as a platform to study lineage dynamics or test up to ~2600 different genetic conditions during regeneration. With this robust approach in hand, we identified major barriers to salivary gland regeneration from among hundreds of differentially regulated signaling pathways and genes post-irradiation. Based on these discoveries, we are currently in the process of 1) Understanding the molecular mechanisms underlying the top regeneration barriers; 2) Dissecting the cell fate dynamics of salivary gland regeneration with or without regeneration barriers; and 3) Testing if we can restore the salivary gland in situ via combinatorial removal of regeneration barriers. Our work will provide unbiased functional and lineage roadmaps of post-irradiation salivary gland regeneration and potentially serve as the cornerstones of future therapeutic interventions. Citation Format: Qiwen Gan, Zhe Ying. Functional and lineage atlas of salivary gland regeneration charted by rapid in vivo gene targeting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 252.