Final Report Summary - MECHAIP (Deciphering the molecular mechanisms of apoptosis-induced cell proliferation)
Apoptosis, a major form of programmed cell death, is critical for removal of stress-induced damaged cells and maintenance of organismal health. However, it has long been a mystery how tissue recovers after damaged cells are removed. Work by us and others has revealed that apoptotic cells can actively promote compensatory proliferation of their neighbouring cells, a process termed Apoptosis-induced Proliferation (AiP). Therefore, AiP is important for tissue recovery and regeneration. While in pathological conditions when apoptotic cells are kept “undead” due to defective apoptosis, persistent AiP leads to tissue overgrowth. AiP is thus a phenomenon relevant to cancer as cancer cells frequently evade apoptosis. Intriguingly, recent studies showed that AiP can promote cell invasiveness and faster tumour recurrence after radiotherapy. These findings are paradigm-shifting because traditional chemo- and radio-therapies often attempt to kill tumour cells by activating apoptosis. Such cancer treatments can be ineffective or even counterproductive because of AiP. Hence, understanding the molecular mechanisms of AiP may help develop novel cancer therapies.
Studies in the past decade have demonstrated that AiP is an evolutionary conserved phenomenon. Caspases, a family of cysteine proteases which execute apoptosis, also play key roles in activation of AiP. By using Drosophila as a model organism, it has been shown that distinct mechanisms of AiP are employed in tissues at different developmental states. In the proliferating tissues in which cells are dividing, the initiator caspase (Capase-9 like) activates the c-Jun N-terminal Kinase (JNK) signalling pathway leading to AiP. While in the differentiating tissue in which cells have exited the cell cycle, the effector caspase (Caspase-3 like) triggers cell cycle re-entry. However, our knowledge about how these pathways are regulated is far from complete. Therefore, keys to advance the field of AiP rely on identification and characterisation of the missing links for understanding of AiP.
In this MechAiP project, we employed various innovative Drosophila assays with the aim to systematically identify and characterise novel regulators of AiP by focusing on the proliferating epithelial tissue. We have successfully completed a kinome-wide genetic screen with identification of a set of kinases as key players regulating AiP. Further characterisation of these AiP regulators showed that 1) actin cytoskeletal reorganisation mediates activation of JNK by caspases; 2) the Autophagy-related gene 1 (Atg1) is transcriptionally induced by JNK and mediates activation of mitogenic signals such as Wg/Wnt signalling for AiP; and 3) in addition to Wg/Wnt, the EGFR signalling pathway is also activated downstream of JNK for AiP. In addition to these analyses, during the course of the project, we have carried out genome-wide analyses to identify cleavage substrates of caspases and transcriptional targets of apoptotic stresses. These have set up a stage for our future work to further elucidate the molecular regulation of AiP.
Throughout the project we have undertaken a number of activities for dissemination and public engagement as well as knowledge transfer. These include publishing our up-to-date results in scientific journals, attending national and international conferences to present our research work, hosting and organising research seminars and workshops, setting up research collaborations within the institution and beyond, teaching and supervising students at the undergraduate, Masters and PhD levels, showcasing our research to general public in events such as the British Science Festival, the Community Days, the University Open Days and Applicant Visit Days. These have been integrated with our research progress during the project.
Studies in the past decade have demonstrated that AiP is an evolutionary conserved phenomenon. Caspases, a family of cysteine proteases which execute apoptosis, also play key roles in activation of AiP. By using Drosophila as a model organism, it has been shown that distinct mechanisms of AiP are employed in tissues at different developmental states. In the proliferating tissues in which cells are dividing, the initiator caspase (Capase-9 like) activates the c-Jun N-terminal Kinase (JNK) signalling pathway leading to AiP. While in the differentiating tissue in which cells have exited the cell cycle, the effector caspase (Caspase-3 like) triggers cell cycle re-entry. However, our knowledge about how these pathways are regulated is far from complete. Therefore, keys to advance the field of AiP rely on identification and characterisation of the missing links for understanding of AiP.
In this MechAiP project, we employed various innovative Drosophila assays with the aim to systematically identify and characterise novel regulators of AiP by focusing on the proliferating epithelial tissue. We have successfully completed a kinome-wide genetic screen with identification of a set of kinases as key players regulating AiP. Further characterisation of these AiP regulators showed that 1) actin cytoskeletal reorganisation mediates activation of JNK by caspases; 2) the Autophagy-related gene 1 (Atg1) is transcriptionally induced by JNK and mediates activation of mitogenic signals such as Wg/Wnt signalling for AiP; and 3) in addition to Wg/Wnt, the EGFR signalling pathway is also activated downstream of JNK for AiP. In addition to these analyses, during the course of the project, we have carried out genome-wide analyses to identify cleavage substrates of caspases and transcriptional targets of apoptotic stresses. These have set up a stage for our future work to further elucidate the molecular regulation of AiP.
Throughout the project we have undertaken a number of activities for dissemination and public engagement as well as knowledge transfer. These include publishing our up-to-date results in scientific journals, attending national and international conferences to present our research work, hosting and organising research seminars and workshops, setting up research collaborations within the institution and beyond, teaching and supervising students at the undergraduate, Masters and PhD levels, showcasing our research to general public in events such as the British Science Festival, the Community Days, the University Open Days and Applicant Visit Days. These have been integrated with our research progress during the project.