Reprogramming Medulloblastoma-Propagating Cells by a Combined Antagonism of Sonic Hedgehog and CXCR4

Ward, Stacey; Warrington, Nicole M.; Taylor, Sara; Kfoury, Najla; Luo, Jingqin; Rubin, Joshua B.

doi:10.1158/0008-5472.can-16-0847

Cited by 15 publications

(17 citation statements)

References 41 publications

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“…To determine whether ATOH1 can directly activate transcription of GLI2 target regions, we performed a luciferase reporter assay using GLI2/ATOH1-bound regions from two candidate genes: intron 2 of Ptch1 and an element 26 kb downstream of Cxcr4. CXCR4, the receptor for chemokine CXCL12, has been implicated in cerebellar patterning (Zou et al, 1998), and MB tumorigenesis (Ward et al, 2017). The promoter of human CXCR4 was shown to be a direct target of GLI1 (Inaguma et al, 2015).…”

Section: Gli2 and Atoh1 Synergistically Activate Gli2 Target Genesmentioning

confidence: 99%

Dual Regulatory Functions of SUFU and Targetome of GLI2 in SHH Subgroup Medulloblastoma

Yin

Satkunendran

et al. 2019

Developmental Cell

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Graphical Abstract Highlights d Sufu exerts tumor-promoting and -suppressive functions in SHH medulloblastoma d Sufu;Spop double knockout medulloblastoma mouse model unveils GLI2 targetome d ATOH1 and GLI2 cooperate to activate target genes in SHH medulloblastoma SUMMARY SUFU alterations are common in human Sonic Hedgehog (SHH) subgroup medulloblastoma (MB). However, its tumorigenic mechanisms have remained elusive. Here, we report that loss of Sufu alone is unable to induce MB formation in mice, due to insufficient Gli2 activation. Simultaneous loss of Spop, an E3 ubiquitin ligase targeting Gli2, restores robust Gli2 activation and induces rapid MB formation in Sufu knockout background. We also demonstrated a tumor-promoting role of Sufu in Smo-activated MB ($60% of human SHH MB) by maintaining robust Gli activity. Having established Gli2 activation as a key driver of SHH MB, we report a comprehensive analysis of its targetome. Furthermore, we identified Atoh1 as a target and molecular accomplice of Gli2 that activates core SHH MB signature genes in a synergistic manner. Overall, our work establishes the dual role of SUFU in SHH MB and provides mechanistic insights into transcriptional regulation underlying Gli2-mediated SHH MB tumorigenesis. (C) Survival is normal in Sufu KO mice, while Ptch1 KO mice rapidly succumb to MBs. (D) Gene expression profiling by cDNA microarray reveals downregulation of several Gli target genes and moderate expression of some Hh pathway components and MB signature genes in Sufu KO cerebellum at P13, while Ptch1 KO MBs displays upregulation of Hh component genes and full-blown MB signature. See also Figure S1.

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Section: Gli2 and Atoh1 Synergistically Activate Gli2 Target Genesmentioning

confidence: 99%

Dual Regulatory Functions of SUFU and Targetome of GLI2 in SHH Subgroup Medulloblastoma

Yin

Satkunendran

et al. 2019

Developmental Cell

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“…For phenotypic effect screening, the 36 compounds were tested by a spheroid invasion assay (SIA, Figure a, b) using a cell‐based model of sonic hedgehog medulloblastoma tumors, which express high levels of CXCR4 (Figure S4) and depend on CXCR4 function for tumor propagation . The SIA revealed a significant invasion‐activating effect of compounds 1 and 3 – 5 on DAOY medulloblastoma cells (Figure c).…”

Section: Resultsmentioning

confidence: 99%

Identification of Synthetic Activators of Cancer Cell Migration by Hybrid Deep Learning

et al. 2019

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Deep convolutional neural networks (CNNs) are a method of choice for image recognition. Herein a hybrid CNN approach is presented for molecular pattern recognition in drug discovery. Using self‐organizing map images of molecular pharmacophores as input, CNN models were trained to identify chemokine receptor CXCR4 modulators with high accuracy. This machine learning classifier identified first‐in‐class synthetic CXCR4 full agonists. The receptor‐activating effects were confirmed by intracellular cAMP response and in a phenotypic spheroid invasion assay of medulloblastoma cell invasion. Additional macromolecular targets of the small molecules were predicted in silico and tested in vitro, revealing modulatory effects on dopamine receptors and CCR1. These results positively advocate the applicability of molecular image recognition by CNNs to ligand‐based virtual compound screening, and demonstrate the complementarity of machine intelligence and human expert knowledge.

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“…CXCR4 and SHH pathways are therapeutic targets validated in many cancer types, including MB. Ward, Warrington [98] verified that inhibition of the SHH and CXCR4 pathways exerts potent antitumor effects in a murine model of SHH-MB subgroup. Moreover, this study provides a rationale to evaluate combinatorial inhibition of SHH and CXCR4 in patients with MB as well as other cancers driven by SHH that co-express high levels of CXCR4.…”

Section: Sonic Hedgehog (Shh) Pathway and Cxcl12/cxcr4 Axis In Mbmentioning

confidence: 95%

“…There are several CXCR4 inhibitors, such as AMD3100 (plerixafor, nonpeptidic CXCR4 antagonist), AMD3465 (non-peptidic CXCR4 antagonist) and CTCE-9908 (CXCL12 peptidic analogue) [119]. Although these molecules act by direct inhibition of CXCR4 ( Figure 1) and show efficacy when compared to other chemotherapeutic agents, their toxic effects are not well understood yet [98].…”

Section: Sonic Hedgehog (Shh) Pathway and Cxcl12/cxcr4 Axis In Mbmentioning

confidence: 99%

“…Recently, Ward, Warrington [98] reported that dual inhibition of SHH and CXCR4 pathways with GDC-0449 and AMD3100, respectively, showed synergistic effects in a murine model of SHH-subgroup of MB, with more potent antitumor activity than each inhibition alone. This finding is of Induces apoptosis in mice tumor cells (HDAC1/HDAC2 inhibitor) [53] Benzylphthalazines ÃÃ Inhibits growth of MB allograft in mice [116] Plerixafor ÃÃ (AMD 3100)…”

Section: Sonic Hedgehog (Shh) Pathway and Cxcl12/cxcr4 Axis In Mbmentioning

confidence: 99%

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Potential use of CXCL12/CXCR4 and sonic hedgehog pathways as therapeutic targets in medulloblastoma

et al. 2018

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Medulloblastoma (MB) is the most common malignant brain tumor occurring in children, and although high long-term survival rates have been reached with current therapeutic protocols, several neurological injuries are still observed among survivors. It has been shown that the development of MB is highly dependent on the microenvironment surrounding it and that the CXCL12 chemokine and its receptor, CXCR4 and the Sonic Hedgehog (SHH) pathway are crucial for cerebellar development, coordinating proliferation and migration of embryonic cells and malfunctions in these axes can lead to MB development. Indeed, the concomitant overactivation of these axes was suggested to define a new MB molecular subgroup. New molecules are being studied, aiming to inhibit either CXCR4 or the SHH pathways and have been tested in preclinical settings for the treatment of cancers. The use of these molecules could improve MB treatment and save patients from aggressive surgery, chemotherapy and radiotherapy regimens, which are responsible for severe neurological consequences. This review aims to summarize current data about the experimental inhibition of CXCR4 and SHH pathways in MB and its potential implications in treatment of this cancer.

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Reprogramming Medulloblastoma-Propagating Cells by a Combined Antagonism of Sonic Hedgehog and CXCR4

Cited by 15 publications

References 41 publications

Dual Regulatory Functions of SUFU and Targetome of GLI2 in SHH Subgroup Medulloblastoma

Dual Regulatory Functions of SUFU and Targetome of GLI2 in SHH Subgroup Medulloblastoma

Identification of Synthetic Activators of Cancer Cell Migration by Hybrid Deep Learning

Potential use of CXCL12/CXCR4 and sonic hedgehog pathways as therapeutic targets in medulloblastoma

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