Radiotherapy is a life-saving treatment for those with cancer and the majority of those with head and neck cancer will receive radiotherapy. Although radiotherapy mostly succeeds in treating the cancer, a severe side-effect is damage to healthy tissue. Cells which produce saliva can be destroyed, leading to chronic dry mouth (termed xerostomia), resulting in many mouth problems, such as a difficulty in eating and speaking, which diminishes a patient’s quality of life. Existing treatments only give short-term relief from such side-effects. Our current research focusses on permanently restoring salivary gland function, via a number of different methods.
Firstly, we are exploring the use of stem cells (unspecialised cells that can develop into mature cells), where we aim to isolate stem cells from a patient before they undergo radiotherapy and then transplant them back in after treatment, hoping to regenerate the damaged gland. So far we have discovered the identity of a population of stem cells that can replace the saliva-producing cells in the gland, in both normal day-to-day life and after irradiation injury, by using genetically-modified mice, where stem cells are labelled with a fluorescent protein. We have successfully separated these cells using this very same fluorescent protein and grown them in an incubator. However, for us to be able to do the same in humans, who do not have stem cells that are labelled with a fluorescent protein, we need to know what else is unique about these cells. We are currently comparing stem cells isolated from mice with cells that have been isolated from human donors, in order to find similarities (a marker) that will allow us to successfully isolate stem cells from human salivary gland biopsies.
Secondly, to date there has been limited research on how the cell environment impacts stem cell behaviour. Nerves surround all organs and form part of this specialised cell environment. Nerves interact with stem cells, and without nerve input following radiotherapy, these cells diminish. Our research also investigates how the signals the nerves produce can be mimicked to promote salivary gland regeneration. We know that the drug pilocarpine, which is sometimes prescribed to xerostomia patients to stimulate saliva production, can also signal to stem cells to multiply and replace damaged saliva-producing cells. However, pilocarpine is often associated with side-effects, including excessive sweating and nausea. This is because pilocarpine signals through a receptor that is found in many organs in the human body. In order to overcome this, we are working with experts in chemistry within the University of Edinburgh, to develop a local drug delivery system that will not lead to the same side-effects as pilocarpine. We have developed a protocol to test a wide range of drugs for their effectiveness to improve stem cell multiplication, and we have developed a computational method in order to quantify this. In future experiments, we will alter the chemical structure of the drug so it cannot have the side-effects throughout the rest of the body and will only be active in the salivary glands. We will then treat mice with this newly developed drug and assess how efficient it is in regenerating injured glands.
Finally, we are aiming to understand how other cells in the salivary gland also influence the function and restoration of the gland after irradiation injury. In recent years there have been numerous reports of immune cells acting in a beneficial way following injury, rather than in a typically inflammatory and problematic way as previously considered. So far, there has been very little study of how immune cells in the salivary gland behave after radiotherapy. We have generated a detailed map of all the different immune cells in the salivary gland at various times after irradiation, in mice that have had their necks irradiated, which mimics the radiation treatment that head and neck cancer patients have. We are now studying what happens if we do not have any one of these many different cell populations, using mice that genetically lack one cell type only; and aiming to discover where these cells originally come from. This will help us to understand whether drugs that affect the immune system may be a viable option following radiotherapy in the future.
However, since 16th March 2020, and following the government guidance and regulations from the University of Edinburgh, the Emmerson lab have been almost entirely working from home, and with that, we have encountered some obvious challenges and complications, given the lab-based nature of our work. We were given special permission to continue some mouse experiments so we did not waste valuable animals, but we have been unable to start any new experiments or continue any lab-based analysis. My group have been working on home-based tasks and we are pleased to have published a review article since the shutdown, describing the range of causes of salivary gland dysfunction and the limited treatment options and future approaches (Rocchi and Emmerson, 2020, https://www.sciencedirect.com/science/article/pii/S1471491420300897). In addition to this, the group have been working on data analysis, writing papers, reviews, their theses and grant applications, and participating in online public engagement. We are all looking forward to being able to return to laboratory work when we have been advised that we can safely, but it is clear that our research will be very different for the foreseeable future, which will ultimately influence our progress and outputs. I am very proud to say that the group have shown remarkable strength and resilience throughout this period and we remain determined to continue developing our understanding and expertise in order to tackle this debilitating side-effect of radiotherapy.
