Elucidating the mechanisms by which the extracellular matrix contribute to gastroesophageal cancer pathobiology

ABSTRACT Gastric cancer (GC), the third leading cause of cancer death worldwide, is characterized both by histologic and molecular criteria. The two most common forms include Diffuse GC (DGC) and Intestinal GC (IGC). Each class of GC is associated with early inactivation of a distinct tumor suppressor, DGC with CDH1 (encoding E-cadherin) and IGC with p53. Beyond genetic changes,

gastric cancer development is promoted by environmental factors, specifically Helicobacter infection and exposure to dietary nitrates. We posit that addressing two fundamental questions in the gastric cancer field, defining the cells of and defining the distinct mediators of progression, should be addressed together given their interconnectedness. We will evaluate the interplay of

genetic and environmental precipitants to gastric cancer using novel engineered mouse models where we can selectively target key tumor suppressors in the gastric epithelium in concert with relevant exposures. We will then deeply interrogate tissues with the combination of multi-omic single cell technologies enabling dual analysis of gene expression and chromatin accessibility in

individual cells and the subsequent use of spatial transcriptomic tools allowing us to map features of individual cell types spatially to refine the cellular origins of these altered cell types. In concert to defining cellular origins of the two primary classes of gastric cancer, our integrated multi-omic

and spatial analyses will be evaluated to define changes in cellular programs and candidate mediators of these altered phenotypes. Furthermore, we can define the interaction of environmental exposures in gastric tumorigenesis. Subsequently, we will perform functional validation of candidate mediators of progression, evaluating both features intrinsic to gastric

epithelial cells and those emerging from the microenvironment. These studies will both address longstanding debates over origins of these cancers and define new targets to prevent cancer development.