Programmed cell death (PCD) or apoptosis is a physiological process that is critical for normal development and tissue homeostasis. Defects in the regulation of PCD contribute to the pathogenesis of multiple diseases including those associated with reduced rates of cell death (cancer, autoimmunity) or with excessive cell death (neurodegeneration, stroke, myocardial infarction). 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. The overall objective of this scientific program is to gain a comprehensive understanding of the biological principles that underlie the regulation of apoptosis and AiP in the context of a multi-cellular organism, to identify and characterize the genes involved in these processes, and to develop methods to manipulate them. We are using the genetic model organism Drosophila melanogaster for these studies. During Drosophila development many cells die by apoptosis. This cell death shares this developmental plasticity with vertebrates. Genetic screening for gene discovery and molecular genetic analysis in Drosophila promise considerable potential for advancing our understanding of the basic control mechanisms involved in the regulation of apoptosis and AiP in vertebrates including humans. This program is also very relevant for understanding of human cancer. Our studies elucidate mechanisms by which potential tumor cells increase their resistance to apoptosis, a hallmark of cancer, which may generate immortalized (undead) cells. Moreover, recent evidence has suggested that apoptotic tumor cells promote caspase-dependent AiP. For example, although radio- and chemotherapy attempt to cure cancer by killing tumor cells, relapse of treated tumors is frequently observed which may be due to an AiP-promoting activity of dying tumor cells. In summary, this program promises to improve our understanding of apoptosis and regenerative proliferation under normal conditions and tumor phenotypes under pathological conditions.

Public Health Relevance

The scientific program of the principal investigator includes an investigation of the genes and mechanisms that control apoptosis and that initiate regenerative responses after massive stress- or injury induced apoptosis in multi-cellular organisms. Understanding the mechanisms of these processes may lead to new therapeutic interventions for cancer and regeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
1R35GM118330-01
Application #
9078956
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Maas, Stefan
Project Start
2016-08-01
Project End
2021-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Biology
Type
Graduate Schools
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
Diwanji, Neha; Bergmann, Andreas (2018) An unexpected friend - ROS in apoptosis-induced compensatory proliferation: Implications for regeneration and cancer. Semin Cell Dev Biol 80:74-82
Amcheslavsky, Alla; Wang, Shiuan; Fogarty, Caitlin E et al. (2018) Plasma Membrane Localization of Apoptotic Caspases for Non-apoptotic Functions. Dev Cell 45:450-464.e3
Pérez, Ernesto; Bergmann, Andreas (2017) Intercellular cannibalism fuels tumor growth. Cell Death Differ 24:759-760
Yenigun, Vildan Betul; Sirito, Mario; Amcheslavky, Alla et al. (2017) (CCUG)n RNA toxicity in a Drosophila model of myotonic dystrophy type 2 (DM2) activates apoptosis. Dis Model Mech 10:993-1003
Fogarty, Caitlin E; Bergmann, Andreas (2017) Killers creating new life: caspases drive apoptosis-induced proliferation in tissue repair and disease. Cell Death Differ 24:1390-1400
Diwanji, Neha; Bergmann, Andreas (2017) The beneficial role of extracellular reactive oxygen species in apoptosis-induced compensatory proliferation. Fly (Austin) 11:46-52
Pérez, Ernesto; Lindblad, Jillian L; Bergmann, Andreas (2017) Tumor-promoting function of apoptotic caspases by an amplification loop involving ROS, macrophages and JNK in Drosophila. Elife 6:
Kamber Kaya, Hatem Elif; Ditzel, Mark; Meier, Pascal et al. (2017) An inhibitory mono-ubiquitylation of the Drosophila initiator caspase Dronc functions in both apoptotic and non-apoptotic pathways. PLoS Genet 13:e1006438
Li, Mingli; Lindblad, Jillian L; Perez, Ernesto et al. (2016) Autophagy-independent function of Atg1 for apoptosis-induced compensatory proliferation. BMC Biol 14:70
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

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