ORCID Profile
0000-0003-2230-9132
Current Organisations
San Francisco General Hospital (now Zuckerberg San Francisco General Hospital)
,
UCSF Medical Center
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Publications
Mechanisms of embryonal tumor initiation: Distinct roles for MycN expression and MYCN amplification
Publisher: Proceedings of the National Academy of Sciences
Date: 16-08-2004
Abstract: The mechanisms causing persistence of embryonal cells that later give rise to tumors is unknown. One tumorigenic factor in the embryonal childhood tumor neuroblastoma is the MYCN protooncogene. Here we show that normal mice developed neuroblast hyperplasia in paravertebral ganglia at birth that completely regressed by 2 weeks of age. In contrast, ganglia from MYCN transgenic ( TH-MYCN ) mice demonstrated a marked increase in neuroblast hyperplasia and MycN expression during week 1. Regression of neuroblast hyperplasia was then delayed and incomplete before neuroblastoma tumor formation at 6 and 13 weeks in homo- and hemizygote mice, respectively. Paravertebral neuronal cells cultured from perinatal TH-MYCN mice exhibited 3- to 10-fold resistance to nerve growth factor (NGF) withdrawal, compared with normal mice. Both low- and high-affinity NGF receptors were expressed in perinatal neuroblast hyperplasia but not in neuroblastoma tumor tissue. MYCN transgene lification was present at low levels in perinatal neuroblast hyperplasia from both homo- and hemizygote TH-MYCN mice. However, only in hemizygous mice did tumor formation correlate with a stepwise increase in the frequency of MYCN lification. These data suggest that inappropriate perinatal MycN expression in paravertebral ganglia cells from TH-MYCN mice initiated tumorigenesis by altering the physiologic process of neural crest cell deletion. Persisting embryonal neural crest cells underwent further changes, such as MYCN lification and repression of NGF receptor expression, during tumor progression. Our studies provide a model for studying perinatal factors influencing embryonal tumor initiation.
Divergent clonal selection dominates medulloblastoma at recurrence
Publisher: Springer Science and Business Media LLC
Date: 2016
DOI: 10.1038/NATURE16478
miR-380-5p represses p53 to control cellular survival and is associated with poor outcome in MYCN-amplified neuroblastoma
Publisher: Springer Science and Business Media LLC
Date: 26-09-2010
DOI: 10.1038/NM.2227
The prenatal origins of cancer
Publisher: Springer Science and Business Media LLC
Date: 06-03-2014
DOI: 10.1038/NRC3679
Intertumoral Heterogeneity within Medulloblastoma Subgroups
Publisher: Elsevier BV
Date: 06-2017
Medulloblastoma Down Under 2013: a report from the third annual meeting of the International Medulloblastoma Working Group
Publisher: Springer Science and Business Media LLC
Date: 22-11-2013
Guidelines for the use and interpretation of assays for monitoring autophagy
Publisher: Informa UK Limited
Date: 04-2012
DOI: 10.4161/AUTO.19496
EAG2 potassium channel with evolutionarily conserved function as a brain tumor target
Publisher: Springer Science and Business Media LLC
Date: 10-08-2015
DOI: 10.1038/NN.4088
Expression of N-myc andMRP genes and their relationship to N-myc gene dosage and tumor formation in a murine neuroblastoma model
Publisher: Wiley
Date: 2000
DOI: 10.1002/1096-911X(20001201)35:6<585::AID-MPO20>3.0.CO;2-P
Abstract: Although the association between N-myc gene lification and poor clinical outcome in neuroblastoma is well established, the mechanism by which lification influences prognosis is not well defined. We used a human N-myc transgenic mouse model to investigate the role of N-myc in neuroblastoma, including its relationship to the multidrug-resistance-associated protein (MRP) gene. We developed a rapid real-time PCR method to distinguish homozygous and hemizygous N-myc mice that is comparable to Southern analysis. A highly significant correlation (P < 0.0001) between N-myc and MRP expression was demonstrated in murine tumors. Amplification of the transgene was observed in the majority of tumors, highlighting the clinical relevance of this model. However, no correlation between N-myc expression and transgene dosage or tumor latency was observed. The data suggest that increased N-myc dosage contributes to increased tumor incidence and decreased latency by mechanisms independent of N-myc expression.
Effects of MYCN antisense oligonucleotide administration on tumorigenesis in a murine model of neuroblastoma
Publisher: Oxford University Press (OUP)
Date: 16-09-2003
DOI: 10.1093/JNCI/DJG045
Abstract: Human MYCN (hMYCN) oncogene lification is a powerful predictor of treatment failure in childhood neuroblastoma, and dysregulation of hMYCN protein expression appears to be critically involved in the pathogenesis of this disease. We used hMYCN antisense (AS) oligonucleotides to investigate, both in vitro and in vivo, the therapeutic potential of inhibiting hMYCN expression. We transiently transfected human neuroblastoma IMR-32 cells, which have an lified hMYCN gene, with fluorescently labeled hMYCN AS or scrambled (SCR) control oligonucleotides and used fluorescence-activated cell sorting to enrich for cell populations containing different levels of the oligonucleotides. We used fluorescence immunocytochemistry or reverse transcription polymerase chain reaction to assay gene expression levels and trypan blue exclusion to assay growth inhibition in the cell populations. We examined the effects of continuous treatment for 6 weeks with AS or SCR oligonucleotides via subcutaneously implanted microosmotic pumps on tumor growth in a transgenic mouse model of hMYCN-induced neuroblastoma (n = 20 mice per group). All statistical tests were two-sided. IMR-32 cells treated with AS oligonucleotides had approximately half as much hMYCN protein and cell proliferation as either SCR oligonucleotide-transfected or mock-transfected controls the differences were statistically significant. Transgenic mice treated with AS oligonucleotides had lower tumor incidence and statistically significantly lower tumor mass than SCR-treated or untreated control mice. Compared with control treatments, AS oligonucleotide treatment in vitro and in vivo was associated with decreased expression of hMYCN and putative hMYCN target genes but not with that of closely related genes. Several AS oligonucleotide-treated mice developed tumors contralateral to the site of oligonucleotide administration, whereas SCR oligonucleotide-treated or untreated mice displayed bilateral tumor growth. Decreased expression of hMYCN protein is achievable with the use of AS oligonucleotide treatment, even in the presence of hMYCN oncogene lification. Antisense strategies targeting the hMYCN oncogene in vivo decrease mouse neuroblastoma tumorigenesis. Investigation of their clinical effect in children with neuroblastoma is warranted.
Involvement of RhoA, ROCK I and myosin II in inverted orientation of epithelial polarity
Publisher: EMBO
Date: 25-07-2008
Related Organisations
University Of California, San Francisco
Location: United States of America
San Francisco General Hospital (now Zuckerberg San Francisco General Hospital)
Location: United States of America
Stanford University School Of Medicine
Location: United States of America
Related Funding Activities
No related grants have been discovered for William Weiss.