Notch Mediates Inter-tissue Communication to Promote Tumorigenesis

Boukhatmi, Hadi; Martins, Tiago Costa; Pillidge, Zoe; Kamenova, Tsveta; Bray, Sarah

doi:10.1016/j.cub.2020.02.088

Cited by 33 publications

(42 citation statements)

References 55 publications

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“…The tumoral epithelial cells upregulate and transport the Notch ligand Delta in cytonemes, that contact and communicate with the healthy mesenchymal cells to activate Notch signaling in a nonautonomous manner. Notch activity keep the mesenchymal cell precursors in an undifferentiated and proliferative state that is critical to sustain tumor progression (Boukhatmi et al, 2020). This cell to cell interaction is similar to our findings in glianeuron communication in GB, where glial cells use cytonemes/TMs to hijack neuronal Egr and activate JNK signaling in the tumor cells to sustain tumor progression.…”

Section: Progressive Neurodegenerationsupporting

confidence: 86%

Cell to cell communication is an early event in glioblastoma

Portela

Mitchell

Casas‐Tintó

2020

Preprint

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Glioblastoma (GB) is a type of brain tumour that involves the transformation of glial cells. This is the most aggressive and lethal tumour of the central nervous system and currently there are not efficient treatments. In GB, glial cells display a network of membrane projections (cytonemes) which mediate cell to cell communication. Under pathological conditions like GB, cytonemes transform into ultra-long tumour microtubes (TMs) that infiltrate into the brain, enwrap neurons and deplete wingless (Wg)/WNT from the neighbouring healthy tissue. GB cells establish a positive feedback loop including Wg signalling, JNK and matrix metalloproteases (MMP) required for GB progression and neuronal synapse loss and degeneration. Frizzled1 receptor mediates Wg signalling upregulation which is required for JNK activation in GB. Consequently, MMPs are upregulated and facilitate TMs infiltration in the brain, hence GB TMs network expands and mediate further Wg depletion to close the loop. Thus, cellular signals other than primary mutations emerge as a central feature of GB which correlates with a poor prognosis in patients and animal models. Here we describe the molecular mechanisms that regulate TMs production, infiltration and maintenance, in a Drosophila model of GB. The contribution of the bi-directional signals between healthy tissue (neurons) and GB cells, mediate the progression of the disease. JNK pathway signalling mediated by Grindelwald (Grnd) receptor is activated by the ligand Eiger (Egr)/TNFα secreted by the neurons surrounding the GB.Then, MMPs are secreted to facilitate TM progression and GB dissemination. Here we show that the coordination among different signals facilitate GB progression and contribute to the complexity and versatility of these incurable tumours.

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Section: Progressive Neurodegenerationsupporting

confidence: 86%

Cell to cell communication is an early event in glioblastoma

Portela

Mitchell

Casas‐Tintó

2020

Preprint

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“…The tumoural epithelial cells upregulate and transport the Notch ligand Delta in cytonemes, which contact and communicate with the healthy mesenchymal cells to activate Notch signalling in a non-autonomous manner. Notch activity keep the mesenchymal cell precursors in an undifferentiated and proliferative state that is critical to sustain tumour progression ( Boukhatmi et al, 2020 ). This cell to cell interaction goes in line with our findings in glia–neuron communication in GB, where glial cells use cytonemes/TMs to retrieve Egr from the surrounding healthy tissue and activate JNK signalling in the tumour cells to sustain tumour progression.…”

Section: Discussionmentioning

confidence: 99%

Cell to cell communication mediates glioblastoma progression in Drosophila

2020

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Glioblastoma (GB) is the most aggressive and lethal tumour of the central nervous system (CNS). GB cells grow rapidly and display a network of projections (ultra-long tumour microtubes (TMs)), that mediate cell to cell communication. GB-TMs infiltrate throughout the brain, enwrap neurons and facilitate the depletion of the signalling molecule wingless (Wg)/WNT from the neighbouring healthy neurons. GB cells establish a positive feedback loop including Wg signalling upregulation that activates cJun N-terminal kinase (JNK) pathway and matrix metalloproteases (MMPs) production, which in turn promote further TMs infiltration, GB progression and neurodegeneration. Thus, cellular and molecular signals other than primary mutations emerge as central players of GB. Using a Drosophila model of GB, we describe the temporal organization of the main cellular events that occur in GB, including cell to cell interactions, neurodegeneration and TMs expansion. We define the progressive activation of JNK pathway signalling in GB mediated by the receptor Grindelwald (Grnd) and activated by the ligand Eiger (Egr)/TNFα produced by surrounding healthy brain tissue. We propose that cellular interactions of GB with the healthy brain tissue precede TM expansion and conclude that non-autonomous signals facilitate GB progression. These results contribute to deciphering the complexity and versatility of these incurable tumours.

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“…Interestingly, while Neur promotes EMT, Notch has been shown to prevent mesenchymal transition in fly imaginal disc epithelia (Boukhatmi et al, 2020) and human lung cancer (Ito et al, 2017). This raises the possibility that high Notch activity in the TZ blocks the NE-to-NSC transition in all TZ cells prior to the Notch ON/OFF switch.…”

Section: Discussionmentioning

confidence: 99%

Neuralized regulates a travelling wave of Epithelium-to-Neural Stem Cell morphogenesis inDrosophila

Shard

Luna-Escalante

Schweisguth

2020

Preprint

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Many tissues are produced during development by specialized progenitor cells emanating from epithelia via an Epithelial-to-Mesenchymal Transition (EMT). Most studies have so far focused on cases involving single or isolated groups of cells. Here we describe an EMT-like process that requires tissue level coordination. This EMT-like process occurs along a continuous front in the Drosophila optic lobe neuroepithelium to produce neural stem cells (NSCs). We find that emerging NSCs remain epithelial and apically constrict before dividing asymmetrically to produce neurons. Apical constriction is associated with contractile myosin pulses and requires the E3 ubiquitin ligase Neuralized and RhoGEF3. Neuralized downregulates the apical protein Crumbs via its interaction with Stardust. Disrupting the regulation of Crumbs by Neuralized led to defects in apical constriction and junctional myosin accumulation, and to imprecision in the integration of emerging NSCs into the transition front. Neuralized therefore appears to mechanically couple NSC fate acquisition with cell-cell rearrangement to promote smooth progression of the differentiation front. excitable reaction-diffusion mechanism. Accordingly, an activator signal, the Epidermal Growth Factor (EGF) Spitz, spreads in the NE by diffusion and self-induction and triggers a negative feed-back via the production of a non-diffusible inhibitor, i.e. the proneural factor Lethal of scute (L'sc) that inhibits the production of active Spitz by promoting NE-to-NSC

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Notch Mediates Inter-tissue Communication to Promote Tumorigenesis

Cited by 33 publications

References 55 publications

Cell to cell communication is an early event in glioblastoma

Cell to cell communication is an early event in glioblastoma

Cell to cell communication mediates glioblastoma progression in Drosophila

Neuralized regulates a travelling wave of Epithelium-to-Neural Stem Cell morphogenesis inDrosophila

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