Karen Mann, PhD
Moffitt Cancer Center
Research Project: RBFOX2-Mediated Alternative Splicing in Pancreatic Cancer Metastasis
Award: 2018 Skip Viragh Pancreatic Cancer Action Network Career Development Award
Award Period: July 1, 2018 – June 30, 2020
Dr. Karen Mann is an assistant member in the department of molecular oncology at Moffitt Cancer Center in Tampa, Fla. She earned her PhD in genetics from Case Western Reserve University and trained as a postdoctoral fellow under Drs. Neal Copeland and Nancy Jenkins, during which time she developed her expertise in modeling human cancers in mice. Dr. Mann developed a model of pancreatic cancer and uncovered new driver genes (genes that are responsible for causing cancer-like behavior) that impact patient outcome.
The focus of the Mann lab is to identify driver genes that are activated in ways other than mutation. Specifically, their focus is on genes that play a role in pancreatic cancer cells’ ability to metastasize, or spread to other organs in the body.
Ongoing projects are investigating how alternative methods of gene activation drive metastasis in mouse models. They also examine how this biology can be harnessed to better understand metastatic lesions (tumors that have spread to other areas of the body) in human patients. The Mann lab aims to improve disease outcome and to potentially uncover new therapeutic targets, or unique aspects of cancer cells that can be targeted and treated by drugs.
The most common genetic change that causes cancerous characteristics in cells involves mutation – for example, the gene KRAS is mutated in around 95 percent of pancreatic cancer cases. Mutations are errors in the genetic code, and these errors then get translated into proteins that can alter cellular behavior in ways that lead to cancer. However, there are other ways that cells change the genetic information that encodes proteins. One way is called alternative splicing, whereby pieces of genetic material are either removed or rearranged in a new pattern. Splicing can change the function or regulation of proteins within the cell. RNA metabolism, and specifically splicing regulation, is an understudied aspect of pancreatic cancer development that has a major potential to affect disease progression.
Dr. Mann and her research team found that expression of a protein called RBFOX2, which regulates RNA splicing of other genes, was elevated in some pancreatic cancer cases. RBFOX2 activity leads to gene and related protein changes that influence cellular migration, or movement, which is required for cells to be able to spread outside the pancreas. In fact, dysfunctional RBFOX2 splicing regulation is associated with a poorer patient prognosis.
Dr. Mann therefore proposes to investigate how RBFOX2-mediated splicing contributes to primary pancreatic cancer tumor cells’ potential to metastasize. Her research team also aims to understand how RBFOX2 splicing events may influence pancreatic liver metastases. This research may give insight into disease markers that can be tested for signs of primary disease and potential metastasis. In addition, the research team can use this information to design therapies that target the proteins encoded by these spliced transcripts that participate in cell migration, possibly treating patients at the time of surgical removal of their primary tumor. This would be a major step forward in the treatment of metastatic disease.