Cancer and the breakdown of multicellularity: What <i>Dictyostelium discoideum</i>, a social amoeba, can teach us

Mathavarajah, Sabateeshan; VanIderstine, Carter; Dellaire, Graham; Huber, Robert J.

doi:10.1002/bies.202000156

Cited by 12 publications

(7 citation statements)

References 121 publications

(150 reference statements)

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“…One such organism is the eukaryote D. discoideum ( McLaren et al, 2019 ), a soil microbe that has historically served as an excellent model system for studying conserved cellular and developmental processes ( Mathavarajah et al, 2017 ). More recently, D. discoideum has been used as a biomedical model to study a variety of human diseases, such as Alzheimer's disease ( Sharma et al, 2019 ), Huntington's disease ( Myre et al, 2011 ) and cancer ( Mathavarajah et al, 2021 ). The 34-megabyte D. discoideum genome has been estimated to encode ∼12,500 proteins ( Eichinger et al, 2005 ), including homologs of 11 of the 13 human proteins that are linked to the NCLs ( Huber, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Altered protein secretion in Batten disease

Huber

2021

Disease Models &Amp; Mechanisms

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The neuronal ceroid lipofuscinoses (NCLs), collectively known as Batten disease, are a group of neurological diseases that affect all ages and ethnicities worldwide. There are 13 different subtypes of NCL, each caused by a mutation in a distinct gene. The NCLs are characterized by the accumulation of undigestible lipids and proteins in various cell types. This leads to progressive neurodegeneration and clinical symptoms including vision loss, progressive motor and cognitive decline, seizures, and premature death. These diseases have commonly been characterized by lysosomal defects leading to the accumulation of undigestible material but further research on the NCLs suggests that altered protein secretion may also play an important role. This has been strengthened by recent work in biomedical model organisms, including Dictyostelium discoideum, mice, and sheep. Research in D. discoideum has reported the extracellular localization of some NCL-related proteins and the effects of NCL-related gene loss on protein secretion during unicellular growth and multicellular development. Aberrant protein secretion has also been observed in mammalian models of NCL, which has allowed examination of patient-derived cerebrospinal fluid and urine for potential diagnostic and prognostic biomarkers. Accumulated evidence links seven of the 13 known NCL-related genes to protein secretion, suggesting that altered secretion is a common hallmark of multiple NCL subtypes. This Review highlights the impact of altered protein secretion in the NCLs, identifies potential biomarkers of interest and suggests that future work in this area can provide new therapeutic insight.

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Section: Introductionmentioning

confidence: 99%

Altered protein secretion in Batten disease

Huber

2021

Disease Models &Amp; Mechanisms

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“…Importantly, D. discoideum is genetically tractable and a variety of expression constructs have been generated to facilitate studies on protein localization and function ( Levi et al, 2000 ; Kuspa, 2006 ; Veltman et al, 2009 ; Faix et al, 2013 ; Müller-Taubenberger and Ishikawa-Ankerhold, 2013 ; Friedrich et al, 2015 ; Yamashita et al, 2021 ). For these and other reasons, it has also been used as a high-throughput biomedical model for studying variety of human diseases ( Huber, 2021 ; Kirolos et al, 2021 ; Mathavarajah et al, 2021 ; Pain et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

The Cellular and Developmental Roles of Cullins, Neddylation, and the COP9 Signalosome in Dictyostelium discoideum

2022

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“Cullins (CULs) are a core components” of cullin-RING E3 ubiquitin ligases (CRLs), which regulate the degradation, function, and subcellular trafficking of proteins. CULs are post-translationally regulated through neddylation, a process that conjugates the ubiquitin-like modifier protein neural precursor cell expressed developmentally downregulated protein 8 (NEDD8) to target cullins, as well as non-cullin proteins. Counteracting neddylation is the deneddylase, COP9 signalosome (CSN), which removes NEDD8 from target proteins. Recent comparative genomics studies revealed that CRLs and the CSN are highly conserved in Amoebozoa. A well-studied representative of Amoebozoa, the social amoeba Dictyostelium discoideum, has been used for close to 100 years as a model organism for studying conserved cellular and developmental processes owing to its unique life cycle comprised of unicellular and multicellular phases. The organism is also recognized as an exceptional model system for studying cellular processes impacted by human diseases, including but not limited to, cancer and neurodegeneration. Recent work shows that the neddylation inhibitor, MLN4924 (Pevonedistat), inhibits growth and multicellular development in D. discoideum, which supports previous work that revealed the cullin interactome in D. discoideum and the roles of cullins and the CSN in regulating cellular and developmental processes during the D. discoideum life cycle. Here, we review the roles of cullins, neddylation, and the CSN in D. discoideum to guide future work on using this biomedical model system to further explore the evolutionarily conserved functions of cullins and neddylation.

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“…Diversely from vegetative cells, aggregating cells have acquired different properties, such as the ability to produce and secrete the chemoattractant cAMP and to tightly adhere to each other by virtue of the adhesion molecule gp80/csA ( Noegel et al, 1985 ). Accordingly, Dictyostelium cell aggregates have recently been regarded as a potential and challenging model to investigate solid tumor mass ( Trigos et al, 2018 ; Mathavarajah et al, 2021 ). Under hypoxic conditions, the aggregates became loose and portions of them detached within minutes.…”

Section: Discussionmentioning

confidence: 99%

The Dynamics of Aerotaxis in a Simple Eukaryotic Model

Biondo

Panuzzo

Ali

et al. 2021

Front. Cell Dev. Biol.

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In aerobic organisms, oxygen is essential for efficient energy production, and it acts as the last acceptor of the mitochondrial electron transport chain and as regulator of gene expression. However, excessive oxygen can lead to production of deleterious reactive oxygen species. Therefore, the directed migration of single cells or cell clumps from hypoxic areas toward a region of optimal oxygen concentration, named aerotaxis, can be considered an adaptive mechanism that plays a major role in biological and pathological processes. One relevant example is the development of O2 gradients when tumors grow beyond their vascular supply, leading frequently to metastasis. In higher eukaryotic organisms, aerotaxis has only recently begun to be explored, but genetically amenable model organisms suitable to dissect this process remain an unmet need. In this regard, we sought to assess whether Dictyostelium cells, which are an established model for chemotaxis and other motility processes, could sense oxygen gradients and move directionally in their response. By assessing different physical parameters, our findings indicate that both growing and starving Dictyostelium cells under hypoxic conditions migrate directionally toward regions of higher O2 concentration. This migration is characterized by a specific pattern of cell arrangement. A thickened circular front of high cell density (corona) forms in the cell cluster and persistently moves following the oxygen gradient. Cells in the colony center, where hypoxia is more severe, are less motile and display a rounded shape. Aggregation-competent cells forming streams by chemotaxis, when confined under hypoxic conditions, undergo stream or aggregate fragmentation, giving rise to multiple small loose aggregates that coordinately move toward regions of higher O2 concentration. By testing a panel of mutants defective in chemotactic signaling, and a catalase-deficient strain, we found that the latter and the pkbR1null exhibited altered migration patterns. Our results suggest that in Dictyostelium, like in mammalian cells, an intracellular accumulation of hydrogen peroxide favors the migration toward optimal oxygen concentration. Furthermore, differently from chemotaxis, this oxygen-driven migration is a G protein-independent process.

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Cancer and the breakdown of multicellularity: What Dictyostelium discoideum, a social amoeba, can teach us

Cited by 12 publications

References 121 publications

Altered protein secretion in Batten disease

Altered protein secretion in Batten disease

The Cellular and Developmental Roles of Cullins, Neddylation, and the COP9 Signalosome in Dictyostelium discoideum

The Dynamics of Aerotaxis in a Simple Eukaryotic Model

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