Investigating the Roles of SOX9 and Cortactin in the Onset, Progression and Transformation of Gastric Carcinogenesis

Abstract

Gastric cancer is a severe disease that poses a significant threat to human health. Intestinal-type gastric cancer, the most common type, develops through sequential stages of cell lineage conversion and functional dysregulation beginning with pyloric metaplasia. A key feature of pyloric metaplasia is the transdifferentiation of gastric chief cells into spasmolytic polypeptide-expressing metaplastic (SPEM) cells. The final stage is dysplasia, which is a precancerous lesion defined as a direct precursor to cancer and is histologically defined as a transition stage between pre-cancer and cancer. While this series of stages is histologically well defined, the molecular mechanisms behind its progression are only just beginning to be understood. In this work, we utilize knock-out mouse and organoid models alongside microscopy and single-cell RNA-sequencing to investigate the functional roles of specific proteins observed in SPEM and dysplastic cells. Ultimately, we discover the crucial role of the actin stabilization and exosome secretion-regulatory protein cortactin in dysplastic cell transformation to adenocarcinoma, as well as define the transcription factor SOX9 as a master driver of metaplasia onset and progression.