Unknown,Transcriptomics,Genomics,Proteomics

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Cancers originate preferentially in adult tissue stem cells

ABSTRACT: Stem cells have long been regarded as a potential origin of cancer. But cancers could also arise from mutated, differentiated cells that reacquire stem cell properties. Here, in mice harboring conditional oncogenic and lineage tracing alleles, we show that cancers develop from Prom1+ (CD133) cells, only in organs where these cells operate as stem cells. Allograft assays demonstrated that these cancers are not necessarily propagated by Prom1+ cancer stem cells, even when initiated in Prom1-lineages that maintain the normal organ. Normal and transformed Prom1+ stem cells in our mice, maintained the gastric mucosa and gastric adenocarcinomas, respectively. Comparison of these cells identified the latent sodium channel gene Nalcn as a novel gastric cancer suppressor that regulates the differentiation of stomach stem cell daughters. Our data provide new evidence that cancers are initiated preferentially within stem cells, and important insights into how these cells are deregulated to initiate and maintain cancers Prom1 conditional mutants in mice that develped tumors and normal from cells various tissues in mice are compared. 117 samples were studied.

ORGANISM(S): Mus musculus

SUBMITTER: David Finkelstein

PROVIDER: E-GEOD-40634 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:We examined the transformation susceptibility of different cerebellar stem/progenitors by developing several new Group3 medulloblastoma murine models using orthotopic transplantation and in utero electroporation (EP)-based in vivo gene transfer with Cre/LoxP-mediated conditional Myc gene activation and loss of Trp53 function. We used microarrays to compared the transcriptome of these novel Group3 medulloblastoma mouse models to existing mouse models of medulloblastoma subgroups and used cross-species analysis to compare these models to human medulloblastoma subgroups This study aimed to investigate the cell of origin of Group3 MB using our orthotopical MYC model followed by a novel electroporation approach. Orthotopic cell-lineage specific MYC tumors were generated by enforced Myc expression in P6 GNPs isolated from P0-1 tamoxifen treated [Atoh1-CreER;Trp53fl/-] and [Prom1-CreER;Trp53fl/-] mice followed by cortical implants in immunocompromised mice. These tumors are referred to as Atoh1ER-MYC [dka072-075], Prom1-CreER [dka077-081]. The first Group3 MB models in which tumors developed in situ were generated by electroporation of plasmids containing Myc and dominant negative Trp53 flanked by loxP sites into the fourth ventricle of E13.5 Blbp-Cre [dka081, 087, 089, 090, 091 and blm121], Gad2-IRES-Cre [blm128-130 and blm134] and Ptf1a-Cre [blm135-137] mouse embryos. The gene expression profile of these tumors were compared to our previously published Group3 MB model as well as SHH and WNT models of medulloblastoma. For SHH subgroup medulloblastoma, [dka001-005, 009, 033 and 034] and [dka050-057], spontaneous medulloblastomas from [Cdkn2c-/-; Trp53Fl/Fl; Nestin-Cre] and [Cdkn2c-/-; Ptch1+/-] (Uziel et al.,2005 Genes Dev) were used, respectively. For Group3 medulloblastomas, [dka013-16, 049 and 065-067], in which Myc was overexpressed in Cdkn2c-/-, Trp53-/- cerebellar cells and implanted into the cortices of immunocompromised nude mice prior to tumor isolation. For WNT subgroup medulloblastomas [pgr003, 016 and 066], spontaneously developed tumors from CTNNB1+/lox (ex3); BLBP-Cre; Trp53Fl/Fl (Gibson et al., 2010, Nature) were removed for RNA extraction.

Project description:Throughout postnatal life in mammals, neural stem cells (NSCs) are located in the subventricular zone (SVZ) of the lateral ventricles. The greatest diversity of neuronal and glial lineages they generate occurs during early postnatal life in a region-specific manner. In order to evaluate potential heterogeneity in the NSC pool, we microdissected the dorsal and lateral SVZ at different postnatal ages and isolated NSCs and their immediate progeny based on their expression of Hes5-EGFP/Prominin1 and Ascl1-EGFP, respectively. Whole genome comparative transcriptome analysis revealed transcriptional regulators as major hallmarks that sustain postnatal SVZ regionalization. Manipulation of single genes encoding for locally enriched transcription factors influenced NSC specification indicating that the fate of regionalized postnatal SVZ NSCs can be readily modified . These findings reveal functional heterogeneity of NSCs in the postnatal SVZ and provide targets to recruit region-specific lineages in regenerative contexts. Microarrays of neural stem cells, early progenitors and the tissue from subregions of the subventricular zone were compiled to screen for the full extent of heterogeneity in this region during postnatal life. Spatially distinct regions of the developing forebrain subventricular zone (SVZ) aged at P4, P8 and P11 were microdissected in RNAse free/sterile conditions. Mice expressing Ascl1-EGFP in the SVZ were used to aid accurate microdissection of the dorsal and lateral wall of each of the studied time points as per our previous publications characterizing this method. As well as at the whole microdomain level, additionally, NSCs (Hes5-EGFP+/Prom1+) and early progenitors (Ascl1-EGFP+) from each microdomain were further isolated by FAC sorting methods. This was to provide a comprehensive gene expression analysis at the tissue level and at the cellular level. Generally, 1 litter was used to yield 1 'n' number of replicates. A total of 23 affymetrix analysis were performed.

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Cancers originate preferentially in adult tissue stem cells

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