Oncogenic and Tumor-Suppressive Functions of NOTCH Signaling in Glioma

Parmigiani, Elena; Taylor, Verdon; Giachino, Claudio

doi:10.3390/cells9102304

Cited by 54 publications

(62 citation statements)

References 166 publications

(255 reference statements)

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“…NOTCH1 inhibitors have been tried in various preclinical studies, partially demonstrating effects on stem-like cells, although conflicting data exists and evidence for efficacy in clinical trials is still lacking 42 , 43 . Making use of the shRNA mediated knockdown of NOTCH1 we provide one possible explanation for those conflicting results: Although downregulation of NOTCH1 led to a depletion of the perivascular cell population, reduced tumor growth and reduced therapy resistance of cells in the PVN in line with previous reports 7 , 26 , 44 , 45 , it also induced TM- and network formation, thereby rendering the growth-deficient tumors virtually unsusceptible for the cytotoxic effects of radiotherapy. NOTCH1 proficiency is hence a key mechanism for the resilience of cells in the PVN, firstly by allowing population of that niche and secondly by being prerequisite for the protective properties of this specific microenvironment.…”

Section: Discussionsupporting

confidence: 71%

Tumor cell plasticity, heterogeneity, and resistance in crucial microenvironmental niches in glioma

et al. 2021

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Both the perivascular niche (PVN) and the integration into multicellular networks by tumor microtubes (TMs) have been associated with progression and resistance to therapies in glioblastoma, but their specific contribution remained unknown. By long-term tracking of tumor cell fate and dynamics in the live mouse brain, differential therapeutic responses in both niches are determined. Both the PVN, a preferential location of long-term quiescent glioma cells, and network integration facilitate resistance against cytotoxic effects of radiotherapy and chemotherapy—independently of each other, but with additive effects. Perivascular glioblastoma cells are particularly able to actively repair damage to tumor regions. Population of the PVN and resistance in it depend on proficient NOTCH1 expression. In turn, NOTCH1 downregulation induces resistant multicellular networks by TM extension. Our findings identify NOTCH1 as a central switch between the PVN and network niche in glioma, and demonstrate robust cross-compensation when only one niche is targeted.

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Section: Discussionsupporting

confidence: 71%

Tumor cell plasticity, heterogeneity, and resistance in crucial microenvironmental niches in glioma

et al. 2021

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“…Indeed, by manipulating this pathway through different approaches (constitutively-activated form, pharmacology and DLL4 ligand), we found that Notch1 activation globally reduced the expression of oligodendrocytic genes, while concomitantly increasing KCNN3 and APOE, which are typically associated with the astrocytic lineage. This was accompanied by reduction of proliferation in LGG275 cells as previously seen in high grade gliomas [27,59]. Using non-tumoural human O4-purified cells, we also found that activation of Notch1 reduced oligodendrocytic gene expression while upregulating CRYAB, KCNN3 and SOX9.…”

Section: Discussionsupporting

confidence: 83%

“…S14B). Collectively, these data fuel the emerging notion that Notch1 pathway acts as a tumor suppressor in DLGG [59].…”

Section: Discussionsupporting

confidence: 63%

Identification of CRYAB⁺KCNN3⁺SOX9⁺astro-like and EGFR⁺PDGFRA⁺OLIG1⁺oligo-like tumoral cells in diffuse low-grade gliomas and implication of Notch1 signalling in their genesis

Augustus

Pineau

Aimond

et al. 2021

Preprint

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IDH1-mutated gliomas are slow growing brain tumours, which progress into high-grade gliomas. They present intra-tumoural cell heterogeneity, but no good markers are available to distinguish the different cell subtypes. The molecular mechanisms underlying the formation of this cell diversity is also ill defined. Here we report that the SOX9 and OLIG1 transcription factors, which specifically label astrocytes and oli-godendrocytes in the normal brain, reveal the presence of two largely non-overlapping tumoural populations in IDH1-mutated oligodendrogliomas and astrocytomas. Astro-like SOX9+ cells additionally stain for APOE, CRYAB, ID4, KCNN3, while oligo-like OLIG1+ cells stain for ASCL1, EGFR, IDH1, PDGFRA, PTPRZ1, SOX4, and SOX8. GPR17, an oligodendrocytic marker, was expressed by both cells. These two sub-populations appear to have distinct BMP, NOTCH1, and MAPK active pathways as stainings for BMP4, HEY1, HEY2, p-SMAD1/5 and p-ERK were higher in SOX9+ cells. We used primary cultures and a new cell line to explore the influence of NOTCH1 activation and BMP treatment on low-grade glioma cell phenotype. This revealed that NOTCH1 globally reduced oligodendrocytic markers and IDH1 expression while upregulating APOE, CRYAB, HEY1/2 and an electrophysiologically Ca2+-activated apamin-sensitive K+ channel (KCNN3/SK3). This was accompanied by reduction in proliferation. Similar effects of NOTCH1 activation were observed in non-tumoural human oligodendrocytic cells, which additionally induced strong SOX9 expression. BMP treatment reduced OLIG1/2 expression and strongly upregulated CRYAB and NOGGIN, a negative regulator of BMP. The presence of astro-like SOX9+ and oligo-like OLIG1+ cells in diffuse low-grade gliomas raise new questions about their role in the pathology.

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“…In many other tumor types, oncogenic vs. tumor suppressor functions of Notch may strongly depend on the tissue of origin, the differentiation status, composition of the TME, invasion of immune cells or immune cell evasion, and the genetic background: It is clearly the context that matters most with Notch. For example, genetic GOF events of Notch receptors (amplification or point mutations) that promote Notch activity appear to support the initiation and progression of gliomas (neuronal differentiation, in [ 29 ]) and other non-epithelial cancers, such as osteosarcoma (mesenchymal differentiation; in [ 30 ]) or SCLCs (neuro-endocrine differentiation, in [ 31 ]); although the evidence is controversial: for example, recent articles report both oncogenic and tumor-suppressor functions for NOTCH in glioma [ 29 ]. However, also in some carcinomas, or tumors of epithelial origin, such as gastrointestinal (stomach, oesophagus) and colorectal cancers, GOF or oncogenic Notch mutations appear predominant.…”

Section: The Relevance Of Notch Mutations Amplification Pathwaysmentioning

confidence: 99%

“…The complex interactions between Notch and up- or downstream regulatory mechanisms often make it difficult to understand the true functional impact of NOTCH mutations and altered Notch signaling in the context of cancer cells and tissues. For example, in glioma, NOTCH can act as both tumor suppressor and oncogene (reviewed in detail in [ 29 ]). Oncogenic, activating Notch mutations recently identified in glioma may specifically promote and maintain the stem-cell characteristics of glioma cells, the most aggressive type of brain tumors in humans.…”

Section: The Relevance Of Notch Mutations Amplification Pathwaysmentioning

confidence: 99%

Context Matters: NOTCH Signatures and Pathway in Cancer Progression and Metastasis

Misiorek

Przybyszewska-Podstawka

Kałafut

et al. 2021

Cells

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The Notch signaling pathway is a critical player in embryogenesis but also plays various roles in tumorigenesis, with both tumor suppressor and oncogenic activities. Mutations, deletions, amplifications, or over-expression of Notch receptors, ligands, and a growing list of downstream Notch-activated genes have by now been described for most human cancer types. Yet, it often remains unclear what may be the functional impact of these changes for tumor biology, initiation, and progression, for cancer therapy, and for personalized medicine. Emerging data indicate that Notch signaling can also contribute to increased aggressive properties such as invasion, tumor heterogeneity, angiogenesis, or tumor cell dormancy within solid cancer tissues; especially in epithelial cancers, which are in the center of this review. Notch further supports the “stemness” of cancer cells and helps define the stem cell niche for their long-term survival, by integrating the interaction between cancer cells and the cells of the tumor microenvironment (TME). The complexity of Notch crosstalk with other signaling pathways and its roles in cell fate and trans-differentiation processes such as epithelial-to-mesenchymal transition (EMT) point to this pathway as a decisive player that may tip the balance between tumor suppression and promotion, differentiation and invasion. Here we not only review the literature, but also explore genomic databases with a specific focus on Notch signatures, and how they relate to different stages in tumor development. Altered Notch signaling hereby plays a key role for tumor cell survival and coping with a broad spectrum of vital issues, contributing to failed therapies, poor patient outcome, and loss of lives.

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Oncogenic and Tumor-Suppressive Functions of NOTCH Signaling in Glioma

Cited by 54 publications

References 166 publications

Tumor cell plasticity, heterogeneity, and resistance in crucial microenvironmental niches in glioma

Tumor cell plasticity, heterogeneity, and resistance in crucial microenvironmental niches in glioma

Identification of CRYAB⁺KCNN3⁺SOX9⁺astro-like and EGFR⁺PDGFRA⁺OLIG1⁺oligo-like tumoral cells in diffuse low-grade gliomas and implication of Notch1 signalling in their genesis

Context Matters: NOTCH Signatures and Pathway in Cancer Progression and Metastasis

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Oncogenic and Tumor-Suppressive Functions of NOTCH Signaling in Glioma

Cited by 54 publications

References 166 publications

Tumor cell plasticity, heterogeneity, and resistance in crucial microenvironmental niches in glioma

Tumor cell plasticity, heterogeneity, and resistance in crucial microenvironmental niches in glioma

Identification of CRYAB+KCNN3+SOX9+astro-like and EGFR+PDGFRA+OLIG1+oligo-like tumoral cells in diffuse low-grade gliomas and implication of Notch1 signalling in their genesis

Context Matters: NOTCH Signatures and Pathway in Cancer Progression and Metastasis

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Identification of CRYAB⁺KCNN3⁺SOX9⁺astro-like and EGFR⁺PDGFRA⁺OLIG1⁺oligo-like tumoral cells in diffuse low-grade gliomas and implication of Notch1 signalling in their genesis