Neuroblastoma—A Neural Crest Derived Embryonal Malignancy

Johnsen, John Inge; Dyberg, Cecilia; Wickström, Malin

doi:10.3389/fnmol.2019.00009

Cited by 213 publications

(179 citation statements)

References 128 publications

(189 reference statements)

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“…As proof-of-concept, we generated a modular "all-in-one" vector system based on clinically applied third generation lentiviral self-inactivating (SIN) vectors designed to constitutively express a CAR in combination with NFAT-inducible cytokine expression, for example, IL12 or IL18. Therefore, we further codon-optimized a well-established second generation CAR that targets the cell-surface disialoganglioside G D2 [25], which has restricted expression in normal tissues, but is expressed on several solid tumors, including glioblastoma [26], neuroblastoma [27], and sarcomas [28]. Clinical trials already support the safety and efficacy of G D2 -redirected CAR T cells without undesirable adverse effects [29][30][31].…”

Section: Introductionmentioning

confidence: 99%

Design and Characterization of an “All-in-One” Lentiviral Vector System Combining Constitutive Anti-GD2 CAR Expression and Inducible Cytokines

Zimmermann

Kuehle

Dragon

et al. 2020

Cancers

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Genetically modified T cells expressing chimeric antigen receptors (CARs) so far have mostly failed in the treatment of solid tumors owing to a number of limitations, including an immunosuppressive tumor microenvironment and insufficient CAR T cell activation and persistence. Next-generation approaches using CAR T cells that secrete transgenic immunomodulatory cytokines upon CAR signaling, known as TRUCKs (“T cells redirected for universal cytokine-mediated killing”), are currently being explored. As TRUCKs were engineered by the transduction of T cells with two separate vectors, we developed a lentiviral modular “all-in-one” vector system that combines constitutive CAR expression and inducible nuclear factor of activated T cells (NFAT)-driven transgene expression for more efficient production of TRUCKs. Activation of the GD2-specific CAR via GD2+ target cells induced NFAT promoter-driven cytokine release in primary human T cells, and indicated a tight linkage of CAR-specific activation and transgene expression that was further improved by a modified NFATsyn promoter. As proof-of-concept, we showed that T cells containing the “all-in-one” vector system secrete the immunomodulatory cytokines interleukin (IL)12 or IL18 upon co-cultivation with primary human GD2+ tumor cells, resulting in enhanced effector cell properties and increased monocyte recruitment. This highlights the potential of our system to simplify application of TRUCK-modified T cells in solid tumor therapy.

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Section: Introductionmentioning

confidence: 99%

Design and Characterization of an “All-in-One” Lentiviral Vector System Combining Constitutive Anti-GD2 CAR Expression and Inducible Cytokines

Zimmermann

Kuehle

Dragon

et al. 2020

Cancers

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“…The depletion of LIN7A in neurons has previously been shown to result in abnormal neuronal migration (36), a feature of neuroblastoma (37). Clinical cases have also shown that loss of the LIN7A loci results in cellular hyperplasia (36).…”

Section: Discussionmentioning

confidence: 96%

The loss of DLG2 isoform 7/8, but not isoform 2, is critical in advanced staged neuroblastoma

Keane

Martinsson

Kogner

et al. 2020

Preprint

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BACKGROUNDNeuroblastoma is a childhood neural crest tumor showing large clinical and genetic heterogeneity, one form displaying 11q-deletion is very aggressive. It has been shown that 11q-deletion results in decreased expression of DLG2, a gene residing in the deleted region. DLG2 has a number of different isoforms with the main difference is the presence or absence of a L27 domain. The L27 domain containing DLG proteins can form complexes with CASK/MPP and LIN7 protein family members, which will control cell polarity and signaling. METHODSWe evaluated the DLG gene family and the LIN7 gene family for their expression in differently INSS staged neuroblastoma from publically available neuroblastoma data and primary tumors, we included two distinct DLG1 and DLG2 N-terminal transcript isoforms encoding L27 domains for their expression. Functionality of DLG2 isoforms and of LIN7A were evaluated in the 11q-deleted neuroblastoma cell line SKNAS.RESULTSIn neuroblastoma only two DLG2 isoforms were expressed: isoform 2 and isoform 7/8. Using the array data we could determine that higher expression of DLG members that contain L27 domains correlated to better survival and prognosis. Whilst DLG1 showed a decrease in both isoforms with increased INSS stage, only the full length L27 containing DLG2 transcripts DLG2-isoform 7/8 showed a decrease in expression in high stage neuroblastoma. We could show that the protein encoded by DLG2-isoform 7 could bind to LIN7A, and increased DLG2-isoform 7 gene expression increased the expression of LIN7A, this reduced neuroblastoma cell proliferation and viability.CONCLUSIONWe have provided evidence that gene expression of the L27 domain containing DLG2-isoform 7/8 but not L27 domain lacking DLG2-isoform 2 is disrupted in neuroblastoma, in particular in the aggressive subsets of tumors. The presence of the complete L27 domain allows for the binding to LIN7A, which will control cell polarity and signaling, thus affecting cancer cell viability.

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Section: Discussionmentioning

confidence: 99%

The Loss of DLG2 Isoform 7/8, But Not Isoform 2, is Critical in Advanced Staged Neuroblastoma

Keane

Martinsson

Kogner

et al. 2020

Preprint

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BACKGROUND: Neuroblastoma is a childhood neural crest tumor showing large clinical and genetic heterogeneity, one form displaying 11q-deletion is very aggressive. It has been shown that 11q-deletion results in decreased expression of DLG2, a gene residing in the deleted region. DLG2 has a number of different isoforms with the main difference is the presence or absence of a L27 domain. The L27 domain containing DLG proteins can form complexes with CASK/MPP and LIN7 protein family members, which will control cell polarity and signaling. METHODS: We evaluated the DLG gene family and the LIN7 gene family for their expression in differently INSS staged neuroblastoma from publically available neuroblastoma data and primary tumors, we included two distinct DLG1 and DLG2 N-terminal transcript isoforms encoding L27 domains for their expression. Functionality of DLG2 isoforms and of LIN7A were evaluated in the 11q-deleted neuroblastoma cell line SKNAS.RESULTS: In neuroblastoma only two DLG2 isoforms were expressed: isoform 2 and isoform 7/8. Using the array data we could determine that higher expression of DLG members that contain L27 domains correlated to better survival and prognosis. Whilst DLG1 showed a decrease in both isoforms with increased INSS stage, only the full length L27 containing DLG2 transcripts DLG2-isoform 7/8 showed a decrease in expression in high stage neuroblastoma. We could show that the protein encoded by DLG2-isoform 7 could bind to LIN7A, and increased DLG2-isoform 7 gene expression increased the expression of LIN7A, this reduced neuroblastoma cell proliferation and viability.CONCLUSION: We have provided evidence that gene expression of the L27 domain containing DLG2-isoform 7/8 but not L27 domain lacking DLG2-isoform 2 is disrupted in neuroblastoma, in particular in the aggressive subsets of tumors. The presence of the complete L27 domain allows for the binding to LIN7A, which will control cell polarity and signaling, thus affecting cancer cell viability.

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Neuroblastoma—A Neural Crest Derived Embryonal Malignancy

Cited by 213 publications

References 128 publications

Design and Characterization of an “All-in-One” Lentiviral Vector System Combining Constitutive Anti-GD2 CAR Expression and Inducible Cytokines

Design and Characterization of an “All-in-One” Lentiviral Vector System Combining Constitutive Anti-GD2 CAR Expression and Inducible Cytokines

The loss of DLG2 isoform 7/8, but not isoform 2, is critical in advanced staged neuroblastoma

The Loss of DLG2 Isoform 7/8, But Not Isoform 2, is Critical in Advanced Staged Neuroblastoma

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