Translational regulation in malignant transformation of intestinal epithelium

Colorectal cancer development is characterized by successive acquisition of key oncogenic mutations in cellular grow factor signaling pathways that drive malignant transformation from healthy intestinal epithelium to cancer. Understanding colorectal cancer development requires knowledge on the fundamental cellular processes that are altered, breached or exploited by these mutations. This dissertation, containing eight chapters of basic cell biological research, discusses how the presence of oncogenic driver mutations in intestinal epithelial cells affects various hallmarks of cancer, by interfering with fundamental cell biological functions that include global mRNA synthesis and adaptation to endoplasmic reticulum stress. To study this, we made use of several murine and human genetically manipulated organoid models of colorectal cancer that harbor mutations in APC, KRAS, SMAD4 and TP53. In addition, we used genetic mouse models and associated ex vivo organoid culture models to investigate modulation of the endoplasmic reticulum stress response in the context of a healthy and malignant intestinal epithelial cell. Taken together, this work may deeper our understanding of underlying mechanisms of malignant transformation. It also exposes factors in pathway related to regulation of global mRNA translation that may be used to modulate aberrant biological cell behavior, which could provide opportunities for development of targeted anti-cancer therapy.