Apoptosis-induced proliferation (AiP) describes the recently made discovery that apoptotic cells have the ability to induce proliferation of neighboring surviving cells, thus compensating for their loss. For instance, despite massive apoptotic tissue loss of up to 60% triggered by ionizing radiation, Drosophila wing imaginal discs induce regenerative cell proliferation which generates adult wings of normal proportion and size. Unexpectedly, evidence obtained in several organisms including Drosophila, Xenopus, Hydra, Mouse and human cancer suggests that regenerative AiP of amputated or otherwise damaged tissues including tumors depends on apoptotic caspases (highly specific cell death proteases) in a non-apoptotic function. Although progress has been made in the last few years, it is still poorly understood how caspases promote this non- apoptotic role in regenerative proliferation. The overall objective of this project is to identify the genes and elucidate the mechanisms of AiP using Drosophila as a model of gene discovery. Our approach is to induce apoptosis upstream, but simultaneously block apoptosis downstream of its AiP-promoting activity. Under these conditions, cells are kept alive ('undead'), but can still promote AiP because the block of apoptosis is downstream of its AiP-promoting activity. Because 'undead'cells do not die, but continue to promote AiP, they produce significant overgrowth phenotypes which provide convenient assays for genetic screening. These screening assays followed by phenotypic characterization of the identified genes will be explored in this project to address the objective. This project is also very relevant for understanding of human cancer. There are many similarities between tumor cells and 'undead'cells. Tumor cells are often apoptosis-incompetent due to inactivation of apoptotic genes or upregulation of anti-apoptotic genes. If this block of apoptosis occurs downstream of a potentially AiP-inducing activity of 'undead'tumor cells, this activity may significantly contribute to tumor growth which has indeed recently been shown. Furthermore, radio- and chemotherapy attempt to cure cancer by killing tumor cells. However, relapse of treated tumors is frequently observed and may be due to AiP-promoting activity of 'undead'tumor cells. In summary, this project promises to improve our understanding of both regenerative proliferation under normal conditions and tumor phenotypes under pathological conditions.

Public Health Relevance

This project investigates the mechanisms by which cells that undergo apoptosis in response to stress or injury can stimulate proliferation and tissue regeneration by secreting conserved cytokines that promote proliferation of non-apoptotic cells. Understanding the mechanisms of this process may lead to new therapeutic interventions for cancer and regeneration.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Cellular Signaling and Regulatory Systems Study Section (CSRS)
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Maas, Stefan
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University of Massachusetts Medical School Worcester
Schools of Medicine
United States
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Wu, Y; Lindblad, J L; Garnett, J et al. (2016) Genetic characterization of two gain-of-function alleles of the effector caspase DrICE in Drosophila. Cell Death Differ 23:723-32
Fogarty, Caitlin E; Diwanji, Neha; Lindblad, Jillian L et al. (2016) Extracellular Reactive Oxygen Species Drive Apoptosis-Induced Proliferation via Drosophila Macrophages. Curr Biol 26:575-84
Fogarty, Caitlin E; Bergmann, Andreas (2015) The Sound of Silence: Signaling by Apoptotic Cells. Curr Top Dev Biol 114:241-65
Fan, Yun; Wang, Shiuan; Hernandez, Jacob et al. (2014) Genetic models of apoptosis-induced proliferation decipher activation of JNK and identify a requirement of EGFR signaling for tissue regenerative responses in Drosophila. PLoS Genet 10:e1004131
Fogarty, Caitlin E; Bergmann, Andreas (2014) Detecting caspase activity in Drosophila larval imaginal discs. Methods Mol Biol 1133:109-17
Ryoo, Hyung Don; Bergmann, Andreas (2012) The role of apoptosis-induced proliferation for regeneration and cancer. Cold Spring Harb Perspect Biol 4:a008797