Hierarchy of oncogenic gene mutations in gastric carcinogenesis

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ABSTRACT This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-23-045. Gastric cancer is the 4th leading cause of cancer-related death worldwide and it most commonly develops within a carcinogenic cascade from pre-cancerous metaplasia to dysplasia and adenocarcinoma. Metaplasias first arise as a response to injury through the chief cell transdifferentiation into spasmolytic polypeptide- expressing metaplasia (SPEM) cells. While this initial process is possibly reversible, oncogenic gene activation or chronic inflammation can activate SPEM cell plasticity, which promotes SPEM cell progression to intestinal metaplasia (IM) and dysplasia. This neoplastic process may also lead to transcriptional and epigenetic changes, and incite cell lineage conversion, where multiple intermediate cell types are produced that can evolve into cancerous cells, including dysplastic stem cells which may arise during the neoplastic transition. Furthermore, the oncogenic gene mutation burden may be associated with the cell lineage conversion and diversification of the dysplastic stem cells to cancerous cells. However, it is not clear whether the SPEM cell plasticity is responsible for the cell heterogeneity and evolution of pre-cancerous metaplasia to incomplete IM, which carries a higher risk of patient progression to dysplasia and what mechanisms are involved in the carcinogenic process. We therefore hypothesize that SPEM cells are key gastric cancer precursor cells, which display functional properties and cell lineage conversion capacity to drive metaplasia progression to dysplasia. Our overarching goal is to define mechanisms that control the cell lineage conversion of reparative SPEM cells towards incomplete IM and more cancerous cell lineages, which display a higher mutational burden. To address these questions directly, we have established novel in vivo transgenic mouse models and in vitro metaplastic or dysplastic organoid models derived from transgenic mouse stomachs following induction of active Kras or from human patient samples with metaplasia or dysplasia. Using these novel models, we will assess critical SPEM cell lineage derivation and define cell populations that account for the key transcriptional and epigenetic changes arising during metaplasia progression. We will pursue three specific aims: First we will assess functional properties of SPEM cells during mucosal recovery or neoplastic progression following mucosal injury. Second, we will examine regulatory mechanisms of cell lineage diversification and conversion during metaplasia progression. Third, we will investigate molecular mechanisms driving cell linage diversification and clonal evolution of dysplastic stem cells to adenocarcinoma. Our studies will define critical transition points which lead to neoplastic transitions for SPEM cells as the origin of gastric carcinogenesis. An understanding of regulatory mechanisms in cell plasticity and the ability to reverse such transitions could lead to therapeutic interventions to prevent gastric cancer.