Investigating the Role of Sox2 in Stomach Tissue Homeostasis and Cancer.

Abstract

The transcription factor Sox2 is essential for the establishment and maintenance of multiple stem cell populations and its coding region is amplified in certain carcinomas. However, Sox2’s role in stomach homeostasis and cancer is poorly understood. In this thesis, I used mouse genetics to investigate the expression pattern and function of Sox2 in the adult stomach during normal tissue homeostasis and tumorigenesis. Using a genetic lineage tracing system, I found that Sox2 expression marks a gastric stem cell population capable of self renewal and differentiation throughout the lifetime of a mouse, raising the key question of whether Sox2 itself is required for adult stomach function. Using a combination of novel mouse models, I examined the consequences of Sox2 loss of function on stomach regeneration as well as the susceptibility of Sox2+ cells to transformation. Surprisingly, I found that Sox2 itself is dispensable during stomach homeostasis, although Sox2-expressing cells readily give rise to Wnt-driven adenomas. To gain insight into the molecular function of Sox2, I performed ChIP-Seq analysis which revealed that the majority of Sox2 targets in mouse gastric stem and progenitor cells are related to tissue-specific functions such as endoderm development, Wnt signaling and gastric cancer while only a small set of genes overlaps with targets occupied by Sox2 in other stem cell populations. SOX2 has been described as an amplified oncogene in several types of human cancers derived from the foregut endoderm including lung and esophageal squamous cell carcinomas. Unexpectedly, I found that Sox2 loss enhances stomach tumor formation and organoid growth in an Apc/Wnt depdendent adenoma mouse model. Using a reporter assay, I further showed that altered Sox2 levels modulate Tcf/Lef-dependent transcription, providing a molecular explanation for the observed proliferation phenotypes. In summary, my genetic and molecular studies offer insight into how Sox2 regulates stomach tissue homeostasis and cancer and evidence that Sox2’s mode of action is context and tissue specific.