Canonical <scp>TGF</scp>‐β Pathway Activity Is a Predictor of <scp>SHH</scp>‐Driven Medulloblastoma Survival and Delineates Putative Precursors in Cerebellar Development

Aref, Donya; Moffatt, C. J. C.; Agnihotri, Sameer; Ramaswamy, Vijay; Dubuc, Adrian M.; Northcott, Paul A.; Taylor, Michael D.; Perry, Arie; Olson, James M.; Eberhart, Charles G.; Croul, Sidney

doi:10.1111/j.1750-3639.2012.00631.x

Cited by 27 publications

(21 citation statements)

References 54 publications

(154 reference statements)

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“…S7). This is in agreement with results previously described in human and mouse models of MDB and mouse models of MDB (Aref et al, 2013; Guessous et al, 2008; Rodini et al, 2010). Smad3/TGFβ activity continued to be sustained till 30 dpf with a very slow decrease.…”

Section: Resultssupporting

confidence: 93%

Zebrafish reporter lines reveal in vivo signaling pathway activities involved in pancreatic cancer

Schiavone

Rampazzo

Casari

et al. 2014

Disease Models &Amp; Mechanisms

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Pancreatic adenocarcinoma, one of the worst malignancies of the exocrine pancreas, is a solid tumor with increasing incidence and mortality in industrialized countries. This condition is usually driven by oncogenic KRAS point mutations and evolves into a highly aggressive metastatic carcinoma due to secondary gene mutations and unbalanced expression of genes involved in the specific signaling pathways. To examine in vivo the effects of KRASG12D during pancreatic cancer progression and time correlation with cancer signaling pathway activities, we have generated a zebrafish model of pancreatic adenocarcinoma in which eGFP-KRASG12D expression was specifically driven to the pancreatic tissue by using the GAL4/UAS conditional expression system. Outcrossing the inducible oncogenic KRASG12D line with transgenic zebrafish reporters, harboring specific signaling responsive elements of transcriptional effectors, we were able to follow TGFβ, Notch, Bmp and Shh activities during tumor development. Zebrafish transgenic lines expressing eGFP-KRASG12D showed normal exocrine pancreas development until 3 weeks post fertilization (wpf). From 4 to 24 wpf we observed several degrees of acinar lesions, characterized by an increase in mesenchymal cells and mixed acinar/ductal features, followed by progressive bowel and liver infiltrations and, finally, highly aggressive carcinoma. Moreover, live imaging analysis of the exocrine pancreatic tissue revealed an increasing number of KRAS-positive cells and progressive activation of TGFβ and Notch pathways. Increase in TGFβ, following KRASG12D activation, was confirmed in a concomitant model of medulloblastoma (MDB). Notch and Shh signaling activities during tumor onset were different between MDB and pancreatic adenocarcinoma, indicating a tissue-specific regulation of cell signaling pathways. Moreover, our results show that a living model of pancreatic adenocarcinoma joined with cell signaling reporters is a suitable tool for describing in vivo the signaling cascades and molecular mechanisms involved in tumor development and a potential platform to screen for novel oncostatic drugs.

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Section: Resultssupporting

confidence: 93%

Zebrafish reporter lines reveal in vivo signaling pathway activities involved in pancreatic cancer

Schiavone

Rampazzo

Casari

et al. 2014

Disease Models &Amp; Mechanisms

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“…Although these results were not statistically significant, the TGF-β responsive gene set was significantly enriched when we combined P4 and P7 cerebella (Fig. 9C) suggesting that this pathway was responsible in part for the reduced proliferation, as previously reported (Aref et al, 2013). …”

Section: Resultssupporting

confidence: 56%

“…In agreement with these reports, we found, by GSEA analysis, that the TGF-β pathway was upregulated in the cerebella of miR-17∼92 cKO; miR-106b∼25 KO mice. TGF-β pathway is associated with SHH-MB pathogenesis with high levels connoting a good prognosis (Aref et al, 2013). Our results are in agreement with a study suggesting that miR-17∼92 cluster downregulates two different signaling pathways, Bmp and TGF-β pathways (Brock et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Role of the miR-17∼92 cluster family in cerebellar and medulloblastoma development

et al. 2014

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The miR-17∼92 cluster family is composed of three members encoding microRNAs that share seed sequences. To assess their role in cerebellar and medulloblastoma (MB) development, we deleted the miR-17∼92 cluster family in Nestin-positive neural progenitors and in mice heterozygous for the Sonic Hedgehog (SHH) receptor Patched 1 (Ptch1+/−). We show that mice in which we conditionally deleted the miR-17∼92 cluster (miR-17∼92floxed/floxed; Nestin-Cre+) alone or together with the complete loss of the miR-106b∼25 cluster (miR-106b∼25−/−) were born alive but with small brains and reduced cerebellar foliation. Remarkably, deletion of the miR-17∼92 cluster abolished the development of SHH-MB in Ptch1+/− mice. Using an orthotopic transplant approach, we showed that granule neuron precursors (GNPs) purified from the cerebella of postnatal day 7 (P7) Ptch1+/−; miR-106b∼25−/− mice and overexpressing Mycn induced MBs in the cortices of naïve recipient mice. In contrast, GNPs purified from the cerebella of P7 Ptch1+/−; miR-17∼92floxed/floxed; Nestin-Cre+ animals and overexpressing Mycn failed to induce tumors in recipient animals. Taken together, our findings demonstrate that the miR-17∼92 cluster is dispensable for cerebellar development, but required for SHH-MB development.

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“…Consistent with our results, increasing TGF-β signaling with BMP2/4 addition or Smad5 overexpression in the presence of Shh stimulation reduces CGNP proliferation 42, 43 . Furthermore, increased nuclear Smad3 in SHH-related human medulloblastomas is correlated with a more favorable prognosis 38 .…”

Section: Resultsmentioning

confidence: 99%

ASC deficiency suppresses proliferation and prevents medulloblastoma incidence

et al. 2014

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Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is silenced by promoter methylation in many types of tumors, yet ASC’s role in most cancers remains unknown. Here, we show that ASC is highly expressed in a model of medulloblastoma, the most common malignant pediatric brain cancer; ASC is also expressed in human medulloblastomas. Importantly, while ASC deficiency did not affect normal cerebellar development, ASC knock-out mice on the Smoothened (ND2:SmoA1) transgenic model of medulloblastoma exhibited a profound reduction in medulloblastoma incidence and a delayed tumor onset. A similar decrease in tumorigenesis with ASC deficiency was also seen in the hGFAP-Cre:SmoM2 mouse model of medulloblastoma. Interestingly, hyperproliferation of the external granule layer (EGL) was comparable at P20 in both the wildtype and ASC-deficient SmoA1 mice. However, while the apoptosis and differentiation markers remained unchanged at this age, proliferation makers were decreased, and the EGL was reduced in thickness and area by P60. This reduction in proliferation with ASC deficiency was also seen in isolated SmoA1 cerebellar granule precursor cells in vitro, indicating that the effect of ASC deletion on proliferation was cell autonomous. Interestingly, ASC deficient SmoA1 cerebella exhibited disrupted expression of genes in the TGF-β pathway and increased level of nuclear Smad3. Together, these results demonstrate an unexpected role for ASC in Sonic hedgehog-driven medulloblastoma tumorigenesis, thus identifying ASC as a promising novel target for anti-tumor therapy.

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Canonical TGF‐β Pathway Activity Is a Predictor of SHH‐Driven Medulloblastoma Survival and Delineates Putative Precursors in Cerebellar Development

Cited by 27 publications

References 54 publications

Zebrafish reporter lines reveal in vivo signaling pathway activities involved in pancreatic cancer

Zebrafish reporter lines reveal in vivo signaling pathway activities involved in pancreatic cancer

Role of the miR-17∼92 cluster family in cerebellar and medulloblastoma development

ASC deficiency suppresses proliferation and prevents medulloblastoma incidence

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