A mouse to human approach to trace stem cell dynamics in development and cancer of salivary glands (360G-Wellcome-333834_Z_25_Z)

Salivary glands (SG) exhibit a remarkable ability to regenerate following mechanical injury by enhancing the lineage potential of epithelial stem cells (EpSC) to adapt fates of adjacent compartments. Radiotherapy or autoimmune disorders can impair this process leading to xerostomia that severely compromises oral health and digestion. Although pharmacological stimulation of developmental pathways can enhance regeneration, their constitutive activation can lead to preneoplastic transformation. Therefore, to design better therapeutic strategies it is important to understand the signals that regulate EpSC plasticity in development, homeostasis and preneoplastic transformation. While mouse models are instrumental in uncovering key developmental and regenerative mechanisms, interspecies variation in size, developmental timing, and cellular composition requires a comparative analysis. This research will explore the human-specific adaptation that regulate EpSC dynamics in development and how conserved mechanisms drive preneoplastic transformation. By combining human organotypic cultures with in vivo 3D deep tissue imaging, lineage tracing and biophysical modelling I will identify the extrinsic and intrinsic signals that regulate human SG development. In parallel by combining mouse models of tumour initiation with human organotypic tumour cultures, I will resolve the conserved transformation mechanisms. Collectively, this research will facilitate strategies to regenerate diseased SGs by harnessing the mechanisms of normal tissue development.