Identification of novel drivers of cancer malignancy

SRY-box transcription factor 9 (SOX9) guides cell-fate decisions and maintenance of stem cells during development and adult homeostasis in a wide range of tissues, including the digestive system. SOX9 is frequently overexpressed in cancer where it exerts a pro-oncogenic activity by regulating cancer stem cells (CSCs). In this doctoral thesis, we demonstrate that SOX9 promotes tumor progression through the BMI1-p21 axis. In addition, we used its expression to identify novel drivers of cancer malignancy. Thus, among the top genes most positively correlated with SOX9, we identified a four-gene signature comprising KIF11, DIAPH3, TPX2 and ECT2 associated with poor patient survival and therapy resistance in multiple types of cancer. Among these genes, we focused on KIF11 and DIAPH3, deciphering their oncogenic role in CSCs, and cancer progression and malignancy. We also extended our study to the context of gastric homeostasis and Helicobacter pylori infection, finding that SOX9, KIF11 and DIAPH3 are mainly expressed in the pool of gastric progenitor cells and that Sox9+ cells are expanded in response to H. pylori infection. Finally, we identified and tested pharmacological inhibitors of KIF11 and DIAPH3 demonstrating their potential as targets for cancer therapy.