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Cancer cells alter protein synthesis rates to drive tumorigenesis

Institution: University of California, San Francisco
Investigator(s): Kevin Wilkins,
Award Cycle: 2019 (Cycle 30) Grant #: T30DT1004 Award: $135,738
Subject Area: Cancer
Award Type: Dissertation Awards

Initial Award Abstract
Cancers caused by smoking, like all cancers, arise when cells in the body stop abiding the normal rules of proliferation and start dividing uncontrollably, hurting the rest of the body in the process. In order to achieve such growth, cancer cells need a higher than usual amount of proteins, the building blocks of all cells and life. Normally, protein production starts with the DNA, which contains the sequences of all proteins, which is copied into mRNA which is then translated into proteins by specialized structures called ribosomes. Because this process of translation is key in producing proteins, cancer cells try to hijack the ribosome and the rest of the translational machinery in order to alter which and how much proteins are produced. One component that is hijacked by cancer is a protein called DDX3, which in its normal function untangles mRNA to allow it to be translated. Because DDX3 only untangles specific mRNA structures, it affects only a specific subset of mRNAs and hence it can promote the production of only a subset of proteins. Different cancers, including cancers related to tobacco, take advantage of DDX3 in different ways to promote the production of different proteins, based on what is more useful to each cancer type. In order to be able to treat these tumors, we need a better understanding of DDX3 and what it does in order to counteract its activity. The research outlined in this proposal will investigate what makes up this subset of mRNAs and proteins and how increasing their production contributes to the spread of cancer. First, I will make different mRNA sequences and structures to determine which ones are being untangled by DDX3. Secondly, I will use a technique called ribosome profiling to determine which proteins are produced when DDX3 increases in cells exposed to tobacco. Finally, I will grow different cancer cells in the lab that have different amounts of DDX3 in order to investigate which cancers take advantage of DDX3. We will determine if they used the proteins that are produced thanks to DDX3 to move, grow, metastasize, and/or replicate. In conclusion, once this study will be over, we will know more about one mechanism that cancer uses to grow and spread, and we will be able to develop new drugs to stop cancer from employing DDX3 in such a way.