Drivers of gastric pre-neoplasia

PROJECT SUMMARY / ABSTRACT Gastric cancer is one of the most common causes of cancer-related death worldwide. It develops in a sequential progression of a carcinogenic cascade from pre-cancerous metaplasia to cancerous dysplasia and adenocarcinoma. However, oncogenic drivers or master regulators which lead to carcinogenic transition between pre-cancerous and cancerous stages are uncertain. Previous investigations have noted that Kras activity is observed in up to 40% of patients with gastric cancer and have suggested that Ras activation in gastric cancer may promote the progression of metaplasia toward dysplasia and cancer. Our previous results described that Kras activation in chief cells can rapidly develop metaplasia and invasive metaplasia with dysplastic glands. These studies therefore imply that Kras activation might be a driving factor of gastric carcinogenesis and chief cells might be an origin of gastric cancer. However, there is a clear knowledge gap as to whether Kras activation is a critical oncogenic driver which controls the carcinogenic process of dysplasia to adenocarcinoma. Also, while roles of Sox transcription factor activation following the oncogenic Kras activation have been well-studied in other GI tract cancers, no studies have addressed whether such activities are important for metaplasia development or are associated with Ras activation in gastric carcinogenesis. We have therefore hypothesized that Kras activation is a driver of gastric carcinogenesis and metaplastic development and progression can be controlled by upregulation of Sox9 as a downstream effector of Kras signaling pathway. We propose two specific aims to elucidate a deeper understanding of cellular mechanisms and events of gastric carcinogenesis using a novel inducible driver mouse model, which is a stomach- and chief cell-specific driver mouse allele. First, we will define the oncogenic roles of Kras activation and the lineage contribution of active Kras-induced cells during gastric carcinogenesis. Second, we will assess functional roles of Sox9 transcription factor as a putative master regulator of metaplasia development and progression. Our proposed study will not only define the cells of origin for gastric cancer, but also determine the oncogenic potential and regulatory mechanisms of Kras activation during gastric cancer development. Consequently, our results from this proposed study would provide insights in pre-clinical information to design therapeutic interventions or to identify novel druggable targets by regulating transcriptional regulation of key factors in patients with gastric cancer.