Targeted Expression of Mutated ALK Induces Neuroblastoma in Transgenic Mice

Heukamp, Lukas C.; Thor, Theresa; Schramm, Alexander; Preter, Katleen De; Kumps, Candy; Wilde, Bram De; Odersky, Andrea; Peifer, Martin; Lindner, Sven; Spruessel, Annika; Pattyn, Filip; Mestdagh, Pieter; Menten, Björn; Kuhfittig-Kulle, Steffi; Künkele, Annette; König, Katharina; Meder, Lydia; Chatterjee, Sampurna; Ullrich, Roland T.; Schulte, Stefanie; Vandesompele, Jo; Speleman, Franki; Büttner, Reinhard; Eggert, Angelika; Schulte, Johannes H.

doi:10.1126/scitranslmed.3003967

Cited by 156 publications

(154 citation statements)

References 23 publications

(44 reference statements)

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“…However, due to abdominally located tumors in the TH-MYCN mice, it is challenging to determine an objective endpoint to monitor the longitudinal effects of the treatment. Facilitated by imaging tools, several well-established murine models of neuroblastoma should be used, in order to further explore the mechanistic insights and longitudinal impact of combination immunotherapy (51)(52)(53)(54). Taken together, we conclude that tumor-driven CSF-1R signaling regulates the induction of suppressive myeloid cells, which hampers antitumor effects of checkpoint inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Targeting Suppressive Myeloid Cells Potentiates Checkpoint Inhibitors to Control Spontaneous Neuroblastoma

Mao

Eißler

Blanc

et al. 2016

Clinical Cancer Research

124

105

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Purpose: Neuroblastoma is the most common extracranial solid cancer type in childhood, and high-risk patients have poor prognosis despite aggressive multimodal treatment. Neuroblastoma-driven inflammation contributes to the induction of suppressive myeloid cells that hamper efficient antitumor immune responses. Therefore, we sought to enhance antitumor immunity by removing immunosuppression mediated by myeloid cells.Experimental

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Section: Discussionmentioning

confidence: 99%

Targeting Suppressive Myeloid Cells Potentiates Checkpoint Inhibitors to Control Spontaneous Neuroblastoma

Mao

Eißler

Blanc

et al. 2016

Clinical Cancer Research

124

105

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“…To validate how well the cell line-based ALK downstream transcriptional profile recapitulates ALK oncogenic activity, we evaluated ALK signature scores in 2 independent gene expression datasets consisting of respectively 252 and 283 neuroblastoma tumors (19,24,25), as well as data of 2 in vivo neuroblastoma model systems (20). In human primary tumors with ALK amplification or ALK mutations, ALK signature scores were significantly higher than ALK wild-type tumors ( Fig.…”

Section: Aldh6a1mentioning

confidence: 99%

“…Next, a stringent cross-species genomics analyses for differentially expressed genes in MYCN-versus ALK F1174L -driven murine neuroblastoma tumors (16,20), yielded 7 genes expressed significantly higher in ALK F1174L ;DBH-iCre-positive neuroblastoma tumors. In addition to 3 known MAPK-regulated genes (SPRY4, DUSP6, ETV5), also 4 neuronal markers were identified: RET, ENC1, VGF, and VIP.…”

Section: Mutant Alk Upregulates Markers Of Adrenergic and Cholinergicmentioning

confidence: 99%

Upregulation of MAPK Negative Feedback Regulators and RET in Mutant ALK Neuroblastoma: Implications for Targeted Treatment

Lambertz

Kumps

Claeys

et al. 2015

Clinical Cancer Research

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Purpose: Activating ALK mutations are present in almost 10% of primary neuroblastomas and mark patients for treatment with small-molecule ALK inhibitors in clinical trials. However, recent studies have shown that multiple mechanisms drive resistance to these molecular therapies. We anticipated that detailed mapping of the oncogenic ALK-driven signaling in neuroblastoma can aid to identify potential fragile nodes as additional targets for combination therapies.Experimental Design: To achieve this goal, transcriptome profiling was performed in neuroblastoma cell lines with the ALK F1174L or ALK R1275Q hotspot mutations, ALK amplification, or wild-type ALK following pharmacologic inhibition of ALK using four different compounds. Next, we performed cross-species genomic analyses to identify commonly transcriptionally perturbed genes in MYCN/ALK F1174L double transgenic versus MYCN transgenic mouse tumors as compared with the mutant ALKdriven transcriptome in human neuroblastomas.Results: A 77-gene ALK signature was established and successfully validated in primary neuroblastoma samples, in a neuroblastoma cell line with ALK F1174L and ALK R1275Q regulable overexpression constructs and in other ALKomas. In addition to the previously established PI3K/AKT/mTOR, MAPK/ERK, and MYC/ MYCN signaling branches, we identified that mutant ALK drives a strong upregulation of MAPK negative feedback regulators and upregulates RET and RET-driven sympathetic neuronal markers of the cholinergic lineage.Conclusions: We provide important novel insights into the transcriptional consequences and the complexity of mutant ALK signaling in this aggressive pediatric tumor. The negative feedback loop of MAPK pathway inhibitors may affect novel ALK inhibition therapies, whereas mutant ALK induced RET signaling can offer novel opportunities for testing ALK-RET oriented molecular combination therapies.

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“…Activation of ALK increases the expression of MYCN by enhancing the activity of the MYCN promoter and stabilizing MYCN protein likely via activation of AKT and ERK pathways [9][10][11]. In vivo, compared to ALKF1174L and MYCN alone, co expression of these two oncogenes leads to the development of neuroblastoma tumors with earlier onset, higher penetrance and enhanced lethality [10,12,13]. In our recent study, neuroblastoma cells harboring both ALKF1174L mutation and MYCN amplification showed less responsive to an ALK inhibitor, crizotinib, comparing to other variants [14].…”

Section: Introductionmentioning

confidence: 99%

Advances in ALK Targeted Therapy for Neuroblastoma

Zhang¹,

Baruchel²

2017

J Oncol Transl Res

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Targeted Expression of Mutated ALK Induces Neuroblastoma in Transgenic Mice

Abstract: ALK inhibitors induce complete tumor regression in a mouse model of ALK-driven neuroblastoma.

Cited by 156 publications

References 23 publications

Targeting Suppressive Myeloid Cells Potentiates Checkpoint Inhibitors to Control Spontaneous Neuroblastoma

Targeting Suppressive Myeloid Cells Potentiates Checkpoint Inhibitors to Control Spontaneous Neuroblastoma

Upregulation of MAPK Negative Feedback Regulators and RET in Mutant ALK Neuroblastoma: Implications for Targeted Treatment

Advances in ALK Targeted Therapy for Neuroblastoma

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