A childhood experience spurred Keefe's desire to understand what makes normal cells turn 'bad'
On my very first day of primary school as I was walking to the car to be picked up, another kid twice my size pounced on me and ground his knuckles into my skull. My worried mother quickly got out of the car racing to my aid thinking I was getting beaten up. I laughed and told her, “This is my friend Raymond.” I was so elated to have made my very first friend that day. Unfortunately, in the third grade Raymond got sick and passed away from leukaemia. I felt deeply saddened by the loss of my friend and repeatedly asked myself, “What went wrong with his normal healthy cells that made them turn into bad ones?”
Normal cells in the body are highly resilient to numerous everyday stresses such as exposure to UV light and environmental toxins. However, sometimes these stresses become overwhelming, leading to excessive DNA damage to the cells that can turn them cancerous, multiplying uncontrollably and spreading throughout the body.
There are two key ways to prevent damaged cells from becoming cancerous: i) by causing cell death or ii) putting the cells to sleep (termed senescence). Senescent cells do not divide and many, like the moles on our skin, can be present in the body for decades. Since senescent cells are still metabolically active, some are dormant and can reawaken through secondary genetic/epigenetic changes and become cancerous. My research at the Peter Mac has revealed a number of genes that maintain the senescence brake in normal cells that when inactivated, results in the formation of initial seeds for cancer.
Often overlooked is that many therapies aimed at killing proliferating cancer cells can also induce senescence, known as therapy-induced senescence. At first glance, this seems like a good way to stop cancer cells from growing. A complication arises in that senescent cells secrete molecules that promote the growth of blood vessels or cause inflammation, which can fuel cancer development. This creates a double-edged sword: by treating cancers we can prevent tumour formation and progression, but senescent cancer cells have the potential to reawaken and create a pro-tumour environment.
We aim to further understand the double-edged sword of therapy-induced senescence using high-grade serous ovarian cancer (HGSOC), the most aggressive and lethal form of ovarian cancer, as a model. Recent evidence indicates senescence is a key response of HGSOC to chemotherapy and patients with tumours showing more senescence biomarkers have improved survival. Unfortunately, 85% of HGSOC patients relapse after two years. We believe some of the senescent cells are a source of post-treatment relapse.
Visualisation of oncogene-induced senescent cells (blue staining) in human cells
We are currently trying to identify ways to strengthen the positive aspect of the senescence response in stopping cancer cell growth whilst mitigating the potential negative effects. We are also exploring ways to selectively eliminate therapy-induced senescent cells to prevent them from re-emerging.
As a researcher now knowing that cancer is highly complex, the question I have had since I was as a child is one that may never be fully answered. However, with the tireless efforts of many other researchers and clinicians here at the Peter Mac and across the world, we are undoubtedly continuing to learn more about cancer and finding better treatments for patients.
Dr Keefe Chan is a Postdoctoral Fellow in the Cancer Signalling (Pearson) Laboratory. His expertise includes molecular and cell biology, and mechanisms of oncogene- and therapy-induced senescence.
Email: [email protected]
Twitter: https://twitter.com/KeefeChan1
Google scholar: https://scholar.google.com/citations?user=sCdgu54AAAAJ&hl=en
Researchgate: https://www.researchgate.net/profile/Keefe_Chan
