Loss of PRP4K is linked to anoikis resistance and partial epithelial-to-mesenchymal transition
Date
2021-01-12T17:21:34Z
Authors
Clarke, Livia
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Abstract
Metastatic disease is the primary cause of cancer-related death, and as a result the metastatic potential of a tumor is an important indicator of patient survival. For tumor cells to metastasize, they must overcome a special kind of programmed cell death known as anoikis, which occurs when cells detach from the extracellular matrix (ECM). Our lab has recently demonstrated that depletion of PRP4K leads to anoikis resistance due to sustained pro-survival signaling. In this thesis, I further characterized pathways promoting anoikis resistance in PRP4K depleted cells. I determined that PRP4K loss could trigger increased expression of the kinase TrkB as well as activation of the PI3K signaling pathway. I also determined that loss of PRP4K could induce partial epithelial-to-mesenchymal transition (EMT). Specifically, I determined that depletion of PRP4K in several cell lines did not alter the expression of epithelial markers such as E- cadherin yet correlated with increased levels of mesenchymal markers such as vimentin, fibronectin and the EMT transcription factor Zeb1. This partial EMT phenotype was associated with altered cell migration in non-transformed mammary epithelial cell lines, and depletion of PRP4K promoted increased migration in the triple negative breast cancer cell line MDA-MB-231. On the other hand, induction of EMT in non-transformed mammary cell lines had different effects on PRP4K expression depending on the method of EMT induction. While some EMT induction methods had no effect on PRP4K protein expression, others resulted in reduced PRP4K expression. One difference between these induction methods was whether YAP signaling was activated, with activation of YAP gene targets being associated with reduced PRP4K expression. This data together supports a role for PRP4K as a tumor suppressor, where PRP4K loss promotes anoikis resistance and correlates with both EMT and increased YAP activity, which in turn increases the metastatic potential of cancer cells.
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Keywords
Cancer biology, PRP4K, Epithelial-to-mesenchymal transition