AbstractAlthough their existence was once controversial, cancer stem cells (CSCs) are now widely accepted as an important source of metastasis and drug resistance. Recent advances in genetic engineering allowing hierarchies of cell lineages to be traced in vivo have led to the discovery of specific markers of CSCs. Doublecortin-like kinase 1 (DCLK1) is one such marker that specifically identifies chemosensory cells known as tuft cells in normal conditions, that become CSCs in the presence of mutation and inflammation in mouse models of colon and pancreatic cancer.
Using in vitro, in vivo, and in silico techniques, the studies discussed in this PhD investigation demonstrate four key aspects of DCLK1 biology in injury and cancer. First, DCLK1 is essential to the maintenance of the intestinal epithelium and inducing its loss in radiation injury and colitis leads to barrier disruption, dysregulation of key pathways, and exacerbated disease severity. Second, DCLK1 kinase inhibition using small molecule drugs demonstrates efficacy in models of colon and pancreatic cancer. Third, direct and surrogate markers of DCLK1 may have potential as prognostic markers in gastrointestinal cancers. Finally, DCLK1 may have a comparable CSC/tumor supportive role in kidney cancer and likely other cancers outside of the GI tract.
Despite an expanding body of knowledge concerning DCLK1, many aspects remain mysterious. It is clear from the literature that DCLK1 is a regulator of epithelialmesenchymal transition and functional stemness, but a complete understanding of this complex molecule will require an understanding of the role of each of its primary isoforms, interacting partners, and upstream and downstream signaling. Clinically, the development of biomarkers and targeted therapies against DCLK1 is warranted and has the potential to improve outcomes in subsets of cancer patients.
|Date of Award||Jan 2018|
|Supervisor||Sassan Hafizi (Supervisor)|