11q Deletion or ALK Activity Curbs DLG2 Expression to Maintain an Undifferentiated State in Neuroblastoma

Siaw, Joachim Tetteh; Javanmardi, Niloufar; Eynden, Jimmy Van den; Lind, Dan E.; Fransson, Susanne; Martinez-Monleon, Angela; Djos, Anna; Sjöberg, Rose-Marie; Östensson, Malin; Carén, Helena; Trøen, Gunhild; Beiske, Klaus; Berbegall, Ana P.; Noguera, Rosa; Lai, Wei-Yun; Kogner, Per; Palmer, Ruth; Hållberg, Bengt; Martinsson, Tommy

doi:10.1016/j.celrep.2020.108171

Cited by 30 publications

(35 citation statements)

References 71 publications

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“…Together, ATM and ATR are two of the most central kinases involved in the DDR, with ATM responding to double-strand breaks and ATR to single-strand breaks such as those found at sites of replication stress 23 . In NB, loss of chromosome 11q is a well-known marker of poor prognosis and is used in patient stratification 13 , 14 , 17 . In addition to loss of tumour suppressors such as DLG2 or SHANK2 , this region contains many genes involved in the DDR, such as ATM , CHEK1 , H2AFX and MRE11 , as noted previously by others 37 , raising the possibility that, e.g.…”

Section: Discussionmentioning

confidence: 99%

ATR inhibition enables complete tumour regression in ALK-driven NB mouse models

et al. 2021

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High-risk neuroblastoma (NB) often involves MYCN amplification as well as mutations in ALK. Currently, high-risk NB presents significant clinical challenges, and additional therapeutic options are needed. Oncogenes like MYCN and ALK result in increased replication stress in cancer cells, offering therapeutically exploitable options. We have pursued phosphoproteomic analyses highlighting ATR activity in ALK-driven NB cells, identifying the BAY1895344 ATR inhibitor as a potent inhibitor of NB cell growth and proliferation. Using RNA-Seq, proteomics and phosphoproteomics we characterize NB cell and tumour responses to ATR inhibition, identifying key components of the DNA damage response as ATR targets in NB cells. ATR inhibition also produces robust responses in mouse models. Remarkably, a 2-week combined ATR/ALK inhibition protocol leads to complete tumor regression in two independent genetically modified mouse NB models. These results suggest that NB patients, particularly in high-risk groups with oncogene-induced replication stress, may benefit from ATR inhibition as therapeutic intervention.

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Section: Discussionmentioning

confidence: 99%

ATR inhibition enables complete tumour regression in ALK-driven NB mouse models

et al. 2021

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“…Through mRNA expression patterns in a variety of animal models [48,49,52,55], we know that ALK is expressed in neural crest cells during early development. Forced overexpression or deletion of ALK in neural crest cells leads to changes in neural crest migration [129], differentiation [131], and proliferation [89]. Nevertheless, we are still not able to postulate the exact role of ALK in the neural crest.…”

Section: Alk In Neural Crest and Neuroblastomamentioning

confidence: 93%

“…This was given emphasis when Siaw and colleagues proposed that ALK activation in neuroblastoma can inhibit DLG2 transcription via ERK1/2 and specificity protein 1 (SP1) signalling, thus impairing DLG2induced differentiation. DLG2 expression is shown to inhibit tumour growth in vivo and drive neuroblastoma cell differentiation [131]. Previous studies have described DLG2 expression in the "bridge cell" signature between Schwann cell precursors (SCP) and Schwann cells, and late bridge cell signatures in neuroblastoma tumours have been linked to better prognosis [127].…”

Section: Alk In Neural Crest and Neuroblastomamentioning

confidence: 99%

Defining Pathological Activities of ALK in Neuroblastoma, a Neural Crest-Derived Cancer

Wulf

Moreno

Paka

et al. 2021

IJMS

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Neuroblastoma is a common extracranial solid tumour of childhood, responsible for 15% of cancer-related deaths in children. Prognoses vary from spontaneous remission to aggressive disease with extensive metastases, where treatment is challenging. Tumours are thought to arise from sympathoadrenal progenitor cells, which derive from an embryonic cell population called neural crest cells that give rise to diverse cell types, such as facial bone and cartilage, pigmented cells, and neurons. Tumours are found associated with mature derivatives of neural crest, such as the adrenal medulla or paraspinal ganglia. Sympathoadrenal progenitor cells express anaplastic lymphoma kinase (ALK), which encodes a tyrosine kinase receptor that is the most frequently mutated gene in neuroblastoma. Activating mutations in the kinase domain are common in both sporadic and familial cases. The oncogenic role of ALK has been extensively studied, but little is known about its physiological role. Recent studies have implicated ALK in neural crest migration and sympathetic neurogenesis. However, very few downstream targets of ALK have been identified. Here, we describe pathological activation of ALK in the neural crest, which promotes proliferation and migration, while preventing differentiation, thus inducing the onset of neuroblastoma. Understanding the effects of ALK activity on neural crest cells will help find new targets for neuroblastoma treatment.

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“…Overview of commonly employed genetic aberrations in neuroblastoma. Data is accumulated from >400 Swedish neuroblastoma patients [21]. MNA, MYCN-amplified; 11q-, 11q deletion; 17q+, 17q gain.…”

Section: Introductionmentioning

confidence: 99%

Chromosome Imbalances in Neuroblastoma—Recent Molecular Insight into Chromosome 1p-deletion, 2p-gain, and 11q-deletion Identifies New Friends and Foes for the Future

Guan

Hållberg

Palmer

2021

Cancers

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Neuroblastoma is the most common extracranial solid pediatric tumor, with around 15% childhood cancer-related mortality. High-risk neuroblastomas exhibit a range of genetic, morphological, and clinical heterogeneities, which add complexity to diagnosis and treatment with existing modalities. Identification of novel therapies is a high priority in high-risk neuroblastoma, and the combination of genetic analysis with increased mechanistic understanding—including identification of key signaling and developmental events—provides optimism for the future. This focused review highlights several recent findings concerning chromosomes 1p, 2p, and 11q, which link genetic aberrations with aberrant molecular signaling output. These novel molecular insights contribute important knowledge towards more effective treatment strategies for neuroblastoma.

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11q Deletion or ALK Activity Curbs DLG2 Expression to Maintain an Undifferentiated State in Neuroblastoma

Abstract: Highlights d ALK-ERK-SP1 signaling promotes an undifferentiated state in neuroblastoma cells d ALK signaling suppresses DLG2 transcription d DLG2 expression drives differentiation of neuroblastoma cells d 11q deletion neuroblastomas exhibit genetic lesions in the DLG2 locus

Cited by 30 publications

References 71 publications

ATR inhibition enables complete tumour regression in ALK-driven NB mouse models

ATR inhibition enables complete tumour regression in ALK-driven NB mouse models

Defining Pathological Activities of ALK in Neuroblastoma, a Neural Crest-Derived Cancer

Chromosome Imbalances in Neuroblastoma—Recent Molecular Insight into Chromosome 1p-deletion, 2p-gain, and 11q-deletion Identifies New Friends and Foes for the Future

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