Dr Ella Fung: exploring resiliency to radiotherapy cancer treatment
When a patient receives the news that they have cancer they need to make some immediate and perhaps life-changing decisions, including what kind of treatment to pursue. Deciding on how to proceed may feel like walking a tightrope—the patient must weigh the pros of chemotherapy, radiotherapy, or immunotherapy treatment against the cons, including the quality of life they may experience, both physically and psychologically, during treatment. As chemotherapy and radiotherapy are also toxic to healthy cells, there is often a fine balance between finding a dose that is high enough to treat cancer, but low enough to be tolerated by the patient.
In particular, as cancer cells build up resistance to chemo or radiation exposure, patients’ recovery rate might not be as promising as that after the first round of treatment. “Sensitising cancer cells to chemo or radiotherapy would increase the effectiveness of treatment while reducing adverse side effects on the patient,” Fung states.
Arriving at the Oxford Institute of Radiation Oncology in 2014, Fung pursued research that would make cancer cells less resistant (more sensitised) to ionising radiation therapy, a treatment that uses photon beams to target and destroy malignant tumour cells. Fung’s mission was to investigate a particular protein, designated FBXL13, to determine its function and which other cellular proteins it interacts with. Fung was the first scientist to drill down to the cellular level to explore this protein and identify what function it served in maintaining a healthy cell.
Cellular Biology 101
DNA resides in the nucleus of each human cell. Genes are segments of DNA that produce cellular proteins, each of which serves a function in keeping the cell healthy. When a segment of DNA is damaged, it can no longer instruct the proteins needed to maintain the cell, which results in the cell’s eventual death.
But protein synthesis is only half of the story. “In order for a cell to stay healthy, it must discard old proteins periodically,” Fung explained. “Proteins not only comprise the majority of cell contents, they serve as signalling molecules—that is, they are messengers that relay information throughout the cell. As proteins become damaged or relay information that is out of date, the cell destroys them to make way for new ones,” she continued. “This destruction is very carefully regulated, and is primarily accomplished by a network of proteins known as the ubiquitin-proteasome system.”
The Pathway to Cell Normalcy
Ubiquitin and proteasome molecules are two types of complex proteins that interact with one another to remove damaged proteins from cells, a process known as protein degradation. Ubiquitins mark damaged and unwanted proteins by binding to them, a function that has earned ubiquitins the title of the ‘molecular kiss of death.’ It guides the impaired proteins to the cell’s proteasomes, which in turn shred and recycle them, a process Fung refers as targeted cell destruction. Fung’s doctoral lab specialises in studying how this marking process functions differently in cancer cells that are resistant to radiotherapy. “Researchers have even succeeded in manipulating the ubiquitin-proteasome pathway to destroy cancer-causing proteins,” she revealed.
“Cancer cells can degrade warning signals to bias cell proliferation,” she stated. “We are interested in seeing how cancer cells ignore these signals by rewiring the ubiquitin-proteasome system.” In other words, a smoothly operating pathway triggers alarms when the cell is stressed (for example when DNA is damaged by exposure to radiotherapy) and signals internally for the cell to stop reproducing. Cancer cells not only ignore these alarms they often rewire them, resulting in uncontrolled growth, or proliferation.
Her research focused on whether FBXL13 protein contributes to the re-wiring of ubiquitin-proteasome pathway, which in turns reduces the cell’s ability to resist radiotherapy.
In the end, Fung observed no evidence that FBXL13 played a part in increasing the cell’s resistance to ionising radiation treatment. But that doesn’t mean her research was for naught. She discovered that this protein did play a part in cell motility, that is, the ability of cells to move spontaneously.
The protein regulates the cell’s centrosomes, which are microtubule organising centres. Microtubules form a cell skeleton that is important for its structure and motility. Fbxl13 hinders the centrosome’s dynamic ability to nucleate microtubules, in turn impacting cell motility. Cancer cells that are highly motile tend to be more invasive to healthy tissue and often form secondary tumours. In the worst scenario, they migrate into the bloodstream where they are distributed throughout the body. “Most healthy adult cells, barring blood cells, are relatively stationary,” Fung explained. “Only cancer cells have regained the ability to move around.”
Fung adds that another research path would be to analyze FBXL13 levels in cancer patients, to determine if FBXL13 levels correlate with the development of malignant tumours and secondary tumour sites (metastasis). The team’s hypothesis is that elevated Fbxl13 in cancer cells could lead to increased cell motility. “If this is true, it will be a precursor to cancer cell invasion of surrounding tissues and we might be possible to predict the formation of a secondary tumour site at earlier stages.”
It is Fung’s hope that future researchers at the Institute at Oxford will be able to identify further differences between radiotherapy-sensitive cancer cells vs. cancer cells that have become resistant to radiotherapy treatment—and down the line, leverage these differences to make radiotherapy more effective and more tolerable for patients.
As for Fung, she will continue to study the biological mechanisms behind disease. “My hope is to improve the understanding of specific diseases so as to more effectively design pharmaceuticals to treat them,” she explains. “In a nutshell, the continuing goal is to move forward from “what is wrong” to “how can we fix it?” And Fung would like to be one of the scientists in leading this effort.
Dr Ella Sui Ling Fung recently completed her PhD thesis at the Oxford Institute for Radiation Oncology. Fung’s main research interest is oncology, and the problem of chemotherapy and radiotherapy resistance. Her previous work focused on identifying novel molecular targets that can be used to re-sensitise cancers to treatment. In 2014, Fung was awarded a Croucher Scholarship to support her doctorate studies at the Oxford Institute for Radiation Oncology, under the supervision of Dr Vincenzo D’Angiolella.
To view Dr Fung’s Croucher profile, please click here.