Transformed Epithelia Trigger Non-Tissue-Autonomous Tumor Suppressor Response by Adipocytes via Activation of Toll and Eiger/TNF Signaling

Parisi, Federica; Stefanatos, Rhoda; Strathdee, Karen; Yu, Yiqiang; Vidal, Marcos

doi:10.1016/j.celrep.2014.01.039

Cited by 96 publications

(146 citation statements)

References 37 publications

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“…The antimicrobial immune response, triggered by bacterial infections and perhaps wounds, may act as a danger signal and boost a general arousal of the cellular defenses. Similarly, Parisi et al [41] recently described an interaction between hemocytes, the Toll-activated fat body, and epithelial tumors, eventually leading to tumor cell death. These phenomena suggest that the fat body, and perhaps other tissues too, participate in a systemic response that controls the general activity level of the organism's defense systems.…”

Section: Discussionmentioning

confidence: 86%

Control of Drosophila Blood Cell Activation via Toll Signaling in the Fat Body

Schmid

Ines

Vesala³

et al. 2014

PLoS ONE

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The Toll signaling pathway, first discovered in Drosophila, has a well-established role in immune responses in insects as well as in mammals. In Drosophila, the Toll-dependent induction of antimicrobial peptide production has been intensely studied as a model for innate immune responses in general. Besides this humoral immune response, Toll signaling is also known to activate blood cells in a reaction that is similar to the cellular immune response to parasite infections, but the mechanisms of this response are poorly understood. Here we have studied this response in detail, and found that Toll signaling in several different tissues can activate a cellular immune defense, and that this response does not require Toll signaling in the blood cells themselves. Like in the humoral immune response, we show that Toll signaling in the fat body (analogous to the liver in vertebrates) is of major importance in the Toll-dependent activation of blood cells. However, this Toll-dependent mechanism of blood cell activation contributes very little to the immune response against the parasitoid wasp, Leptopilina boulardi, probably because the wasp is able to suppress Toll induction. Other redundant pathways may be more important in the defense against this pathogen.

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Section: Discussionmentioning

confidence: 86%

Control of Drosophila Blood Cell Activation via Toll Signaling in the Fat Body

Schmid

Ines

Vesala³

et al. 2014

PLoS ONE

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“…Considering that ectopic activation of STAT alone in basally extruded nTSG-knockdown cells did not induce tumorigenesis in the coldspot, apical delamination provides the pro-tumor cells with a crucial survival advantage. Apoptosis of pro-tumor cells, such as nTSG mutant cells, is known to be induced by Eiger, the Drosophila homolog of mammalian tumor necrosis factor (TNF)-α, which is produced by circulating hemocytes recruited to tumor tissues [41]. Because hemocytes directly associate with cells along the basal side of the epithelial layer [42], apical delamination could have prevented the pro-tumor cells from receiving the death signal.…”

Section: Resultsmentioning

confidence: 99%

Epithelial Tumors Originate in Tumor Hotspots, a Tissue-Intrinsic Microenvironment

2016

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Malignant tumors are caused by uncontrolled proliferation of transformed mutant cells that have lost the ability to maintain tissue integrity. Although a number of causative genetic backgrounds for tumor development have been discovered, the initial steps mutant cells take to escape tissue integrity and trigger tumorigenesis remain elusive. Here, we show through analysis of conserved neoplastic tumor-suppressor genes (nTSGs) in Drosophila wing imaginal disc epithelia that tumor initiation depends on tissue-intrinsic local cytoarchitectures, causing tumors to consistently originate in a specific region of the tissue. In this “tumor hotspot” where cells constitute a network of robust structures on their basal side, nTSG-deficient cells delaminate from the apical side of the epithelium and begin tumorigenic overgrowth by exploiting endogenous Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling activity. Conversely, in other regions, the “tumor coldspot” nTSG-deficient cells are extruded toward the basal side and undergo apoptosis. When the direction of delamination is reversed through suppression of RhoGEF2, an activator of the Rho family small GTPases, and JAK/STAT is activated ectopically in these coldspot nTSG-deficient cells, tumorigenesis is induced. These data indicate that two independent processes, apical delamination and JAK/STAT activation, are concurrently required for the initiation of nTSG-deficient-induced tumorigenesis. Given the conservation of the epithelial cytoarchitecture, tumorigenesis may be generally initiated from tumor hotspots by a similar mechanism.

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“…Hemocytes are recruited to neoplastic tumors, which are often sites of basement membrane disruption, and thus bear some similarities to non-healing wounds or tissue damage challenges [207–209]. Hemocytes adhere to epithelial tumors, and their numbers increase in response to tumor formation [208, 209] involving tumor-derived signals that stimulate JAK/STAT or Pvr signaling in hemocytes [208, 210]. Where hemocytes mount an immune attack against tumors, responses such as phagocytosis, induction of apoptosis, and melanization/encapsulation by crystal cells and lamellocytes, which is considered a functional equivalent to granulomas in vertebrates, are seen [207, 208, 210].…”

Section: Introductionmentioning

confidence: 99%

“…In the case of Ras -transformed, scribble mutant tumors, activation of TNF signaling has a tumor-promoting effect [209]. In contrast, in a different epithelial tumor model based on discs large (dlg) mutants, TNF signaling acts to suppress tumors [210]. …”

Section: Introductionmentioning

confidence: 99%

“…In the Drosophila dlg tumor model, hemocytes not only secrete TNF but also Spätzle, the Toll pathway ligand. This results in a two-pronged tumor defense response: TNF signaling from hemocytes promotes tumor death directly, and Spätzle triggers a systemic immune response in the fat body, which acts in parallel to induce tumor cell apoptosis [210]. …”

Section: Introductionmentioning

confidence: 99%

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Macrophages and cellular immunity in Drosophila melanogaster

Gold¹,

Brückner

2015

Seminars in Immunology

125

122

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The invertebrate Drosophila melanogaster has been a powerful model for understanding blood cell development and immunity. Drosophila is a holometabolous insect, which transitions through a series of life stages from embryo, larva and pupa to adulthood. In spite of this, remarkable parallels exist between Drosophila and vertebrate macrophages, both in terms of development and function. More than 90% of Drosophila blood cells (hemocytes) are macrophages (plasmatocytes), making this highly tractable genetic system attractive for studying a variety of questions in macrophage biology. In vertebrates, recent findings revealed that macrophages have two independent origins: self-renewing macrophages, which reside and proliferate in local microenvironments in a variety of tissues, and macrophages of the monocyte lineage, which derive from hematopoietic stem or progenitor cells. Like vertebrates, Drosophila possesses two macrophage lineages with a conserved dual ontogeny. These parallels allow us to take advantage of the Drosophila model when investigating macrophage lineage specification, maintenance and amplification, and the induction of macrophages and their progenitors by local microenvironments and systemic cues. Beyond macrophage development, Drosophila further serves as a paradigm for understanding the mechanisms underlying macrophage function and cellular immunity in infection, tissue homeostasis and cancer, throughout development and adult life.

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Transformed Epithelia Trigger Non-Tissue-Autonomous Tumor Suppressor Response by Adipocytes via Activation of Toll and Eiger/TNF Signaling

Cited by 96 publications

References 37 publications

Control of Drosophila Blood Cell Activation via Toll Signaling in the Fat Body

Control of Drosophila Blood Cell Activation via Toll Signaling in the Fat Body

Epithelial Tumors Originate in Tumor Hotspots, a Tissue-Intrinsic Microenvironment

Macrophages and cellular immunity in Drosophila melanogaster

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