Mechanisms of salivary epithelium-specific expansion post-irradiation

Intact salivary glands facilitate several fundamental human needs, including breathing, swallowing, and lingual communication. However, salivary glands are extremely sensitive to irradiation (IR), and their critical functions are often irreversibly compromised following cancer radiation therapies. Previous attempts have identified mechanisms that could prevent IR damage and/or regenerate salivary epithelium in murine models. However, many of these pathways also promote cancer growth post-IR, significantly limiting their selectivity. Therefore, identifying mechanisms that can specifically protect or regenerate salivary glands without benefiting cancer growth post-IR remains a crucial scientific challenge that lacks efficient models. To solve this problem, we developed a scalable and rapid gene targeting system that can test over 2,600 genetic conditions in the salivary glands of a single mouse, significantly improving the efficiency of the current “one mouse one condition” paradigm of genetic modeling. Using this robust platform and a TetOn-shRNA pool, we tested 255 potential regulators of salivary epithelium growth for their ability to promote clonal expansion in salivary glands and syngeneic OSCC grafts post-IR. Contrasting these two sets of screens led to the identification of Smarca2 depletion as the top promoter of salivary gland-specific expansion post-IR without supporting cancer growth, standing out from the majority of hits shared by both tissues. In long-term observation, we found that Smarca2 depletion specifically promoted salivary epithelium growth by expanding the acinar population, which is particularly hard to replenish post-IR and represents a key area the field is trying to address. Pre-IR induction of shSmarca2 suggested that Smarca2 depletion did not prevent salivary epithelium from DNA damage, apoptosis, or senescence. While post-IR induction of shSmarca2 showed that Smarca2 depletion robustly increased the dividing population and their division potential in acinar cells during early-stage regeneration. Mechanistically, depleting Smarca2, a core component of the SWI/SNF chromatin remodeler complex, resulted in the shutdown of key terminal differentiation genes enriched for Smarca2 occupancy. Additionally, Smarca2 depletion drove robust indirect activation of regeneration genes, potentially through retargeting SWI/SNF or other remodelers. Intriguingly, this program was uncoupled from Smarca2 depletion in OSCC cells, potentially blocked by the cancer-specific epigenetic landscape. In the current project we will explore the cellular strategies of Smarca2 depletion driven salivary epithelium expansion and underlying chromatin remodeling mechanisms using both murine/human salivary gland and cancer models. Our discovery of Smarca2 depletion-driven acinar cell expansion represents a salivary gland-specific regeneration switch without promoting cancer growth. Accomplishing this project will establish a paradigm for understanding the distinct post-IR growth control mechanisms between salivary epithelium and cancer at the chromatin level, an area that is significantly underexplored. Project Number: 5R01DE034100-02 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Dental and Craniofacial Research (NIDCR) | Principal Investigator: ZHE YING | Institution: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI, NEW YORK, NY | Award Amount: $714,711 | Activity Code: R01 | Study Section: Oral, Dental and Craniofacial Sciences Study Section[ODCS] View on NIH RePORTER: https://reporter.nih.gov/project-details/11360716