Gao ZHANG, PhD | The University of Hong Kong;Martin Chi Hang CHEUNG, PhD; Yuanhua HUANG, PhD
Competition Sponsor: Research Grants Council of the Hong Kong Special Administrative Region, China
Award Year: 2024
Healthy longevity is largely impacted by ageing and cellular senescence. It is well known that there are three forms of cellular senescence, including replicative senescence, oncogene-induced senescence (OIS) and therapy-induced senescence (TIS). For normal cells, there is a definitive lifespan, which is termed Hayflick limit that determines replicative senescence. Oncogene-induced senescence (OIS) is a phenomenon that occurs both in vitro and in vivo as a tumor suppressive mechanism. Some small molecules, such as BRAF or MEK inhibitors, are more potent triggers of premature senescence in cancer cells than others, which is a phenomenon of TIS; however, cancer cells develop a sophisticated yet not well-understood mechanism to overcome and subsequently repress TIS in order to evade cancer therapy. Intriguingly, we uncovered two distinct forms of TIS, which were dependent on the specific type of therapies. By implementing a systems biology approach, we identified a core senescence component that was sufficient and necessary for the induction of TIS in cancer cells, which resembled OIS in normal cells. We were able to quantify heterogeneous responses of cells to various stimuli of cellular senescence by employing an integrated fluorescence-activated cell sorting (FACS) approach. In this project, we will aim to unravel molecular underpinnings of TIS in cancer cells which will be distinguished from replicative senescence and OIS in normal cells. Furthermore, we will aim to identify a rationale-based combination therapy that would have the potential of exploiting TIS and converting it towards apoptosis in order to maximize cell death of cancer cells.