REGULATION OF CELL DEATH AND COMPENSATORY CELL PROLIFERATION IN TISSUE HOMEOSTASIS
In multicellular organisms, tissue homeostasis requires coordinated cell death, cell proliferation and cell differentiation. Disruption of this balance can lead to many human diseases including degenerative disorders and cancer. Our research is to investigate the molecular control of cell death and how dying cells communicate with their neighbours to maintain tissue homeostasis.
How do cells die?
In response to stresses such as radiation and toxins, cells can get damaged and are removed primarily by apoptosis, a major form of programmed cell death. Regulation of apoptosis is conserved from worms to flies to mammals. Although the core apoptosis pathway has been well studied, it is not yet clear how cells modulate their susceptibilities toward apoptosis. By using the Drosophila eye as a model, we have revealed striking dynamics in the apoptotic susceptibilities of different cell types in a developing organ (Fan and Bergmann, Dev Cell 30: 48). One of our research interests is to dissect the molecular mechanisms controlling cellular responses to apoptotic stresses.
In addition to apoptosis, necrosis is another type of cell death that frequently occurs in response to stresses. Unlike apoptosis, necrosis has long been considered to be passive and uncontrolled. However, recent studies have revealed that necrosis can be genetically regulated therefore potentially manageable. We have developed a Drosophila model to study regulation of necrosis in vivo and its relevance to tumour suppression (Li et al., Cell Death Dis 10: 613). This allows us to further identify and characterise novel regulators of necrosis, with the aim to explore how necrosis can be managed in human diseases including cancer, ischemic injury, neurodegenerative disorders, and inflammatory diseases
How do dying cells communicate?
Work by us and others has revealed that, surprisingly, stress-induced apoptotic cells can actively induce proliferation of their neighbouring cells to compensate for the cell loss. This evolutionarily conserved phenomenon has been termed apoptosis-induced compensatory cell proliferation (apoptosis-induced proliferation or AiP). It is critical for tissue recovery and organismal survival. Under pathological conditions, uncontrolled apoptosis-induced proliferation contributes to tumour development and recurrence.
We have discovered that apoptosis can induce cell proliferation through distinct mechanisms in a context-dependent manner, e.g. in proliferating versus differentiating tissues (Fan and Bergmann, Dev Cell 14: 339). However, our understanding of the molecular mechanisms underlying apoptosis-induced proliferation is far from complete. By taking advantages of Drosophila as a genetically tractable model organism, we have developed several assays to systematically identify and characterize novel regulators of apoptosis-induced proliferation (Fan et al., PLoS Genet 10: e1004131). Deciphering these mechanisms will make substantial contributions to our understanding of the cellular strategies and genetic pathways used to maintain tissue homeostasis in response to apoptosis. Our long-term research goal is to elucidate the relevance of apoptosis-induced proliferation in tissue regeneration and tumorigenesis.
Dr Fan’s research is supported by the EU FP7 Marie Curie Actions (CIG) and the Biotechnology and Biological Sciences Research Council in the UK.
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