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GSE48275
Homo sapiens
16 Downloadable Samples
Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Since the initial discovery that OCT4, SOX2, KLF4 and c-MYC overexpression sufficed for the induction of pluripotency in somatic cells, methodologies replacing the original factors have enhanced our understanding of the reprogramming process. However, unlike in mouse, OCT4 has not been replaced successfully during reprogramming of human cells. Here we report on a strategy to do so. Through a combination of transcriptome and bioinformatic analysis we have identified factors previously characterized as being lineage specifiers that are able to replace OCT4 and SOX2 in the reprogramming of human fibroblasts. Our results show that is possible to replace OCT4 and SOX2 simultaneously with alternative lineage specifiers in the reprogramming of human cells. At a broader level, they also support a model in which counteracting lineage specification networks underlie the induction of pluripotency,
Publication Title
Reprogramming of human fibroblasts to pluripotency with lineage specifiers.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 18 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
We explored the relationship between Myc activity and PI3K signaling in ESCs. Our data demonstrate that Myc and PI3K signaling function cooperatively for supporting pluripotent property of ESCs. Moreover, our data demonstrate that exposure of ESCs to 2i condition render both Myc and PI3K dispensable for preserving ESC status.
Publication Title
Functional compensation between Myc and PI3K signaling supports self-renewal of embryonic stem cells.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 12 Downloadable Samples
- Affymetrix Mouse Clariom S Array (clariomsmouse)
Description
Under hypoxic conditions, nitroimidazole compounds accumulate in cells in their reduced form and have oxygen-mimetic effects, serving as markers of hypoxia and radiosensitizers. The full potential of their bioreductive metabolism, including cytotoxicity for cancer stem cells, has not been sufficiently explored, however. Here we investigated the changes in gene expression induced by treatment with 2-nitroimidazole doranidazole in murine glioma stem cells, under normoxic or hypoxic conditions.
Publication Title
2-Nitroimidazoles induce mitochondrial stress and ferroptosis in glioma stem cells residing in a hypoxic niche.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 11 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Establishment of human iPSC-based models for the study and targeting of glioma initiating cells.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Homo sapiens
- 11 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Gliomas can originate upon transformation of adult Neural Progenitor Cells (NPCs) to Tumor Initiating Cells (TICs). Studies on human Glioma TICs (GTICs) have focused on the use of primary tumors from which GTICs could be isolated. Therefore investigations on the driver events underlying NPC transformation and human glioma initiation remain limited to the use of human embryonic material. Here we report on the development of strategies for the modeling of human gliomagenesis based on the use of human induced Pluripotent Stem Cells (hiPSCs). Transformation of hiPSC-derived NPCs (iNPCs) by defined genetic alterations led to the establishment of tractable human GTIC models suitable for studying the early steps of gliomagenesis as well as for screening studies. Dysregulation of PI3K, MAPK and p53 signaling in iNPCs led to the acquisition of functional GTIC properties. In vivo transplantation led to the formation of highly aggressive, infiltrative and heterogeneous tumors upon limited dilutions and secondary transplantation, faithfully recapitulating gliomagenesis. Metabolic modulation by chemical approaches compromised GTIC viability. Pilot screening of 101 anti-cancer compounds identified 3 molecules specifically targeting transformed iNPCs and primary GTICs. Together, our results demonstrate the potential of hiPSCs for the functional testing of putative driver mutations underlying human tumorigenesis and pave new avenues for the development of personalized cancer therapeutics.
Publication Title
Establishment of human iPSC-based models for the study and targeting of glioma initiating cells.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Mus musculus
- 12 Downloadable Samples
Illumina HiSeq 2500
Description
Cancer originates as the progressive accumulation of genetic mutations in proto-oncogenes and tumor suppressors. However, the early events underlying tumor initiation remain largely elusive, mostly due to the general lack of information regarding the cells-of-origin responsible for tumor formation as well as the precise impacts of genetic insults on tumor initiation in vivo. Here, we demonstrate that Sox2-positive (Sox2+) adult stem cells are responsible for epithelial squamous tumor formation. Conditional expression of oncogenic Kras (KrasG12D) and knockout of p53 (also known as Trp53) in Sox2+ cells quickly and specifically resulted in the formation of squamous tumors in the forestomach and esophagus. GFP-based lineage tracing experiments demonstrated that Sox2+ cells are the cells-of-origin of squamous tumors in the esophagus and forestomach. Of note, our data showed that p53 deletion alone did not suffice for tumor initiation. On the contrary, tumor initiation was observed upon KrasG12D activation whereas p53 deletion further contributed to the malignancy of the generated tumors, pointing out distinct roles for Kras activation and p53 deletion in squamous tumor formation and progression, to which a multihit carcinogenesis model can be applied. Global gene expression analysis revealed secreting factors upregulated in the generated tumors induced by oncogenic Kras, which contribute to tumor progression. Taken together, these results demonstrate that epithelial squamous tumors can specifically originate as a consequence of defined genetic mutations in a Sox2+ cell population and highlight the connections between proliferative stem cells and tumor development in vivo. Overall design: Expression profiling of mouse tissues with genetically induced tumors by RNA-Seq
Publication Title
Mutations in foregut SOX2<sup>+</sup> cells induce efficient proliferation via CXCR2 pathway.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Recent studies have shown that stem cell memory T (TSCM) cell-like properties are important for the successful adoptive immune therapy by the chimeric antigen receptor-engineered-T (CAR-T) cells. We previously reported that both human and murine activated T cells are converted into stem cell memory-like T (iTSCM) cells by co-culture with stromal OP9 cells expressing the NOTCH-ligand. However, the mechanism of NOTCH-mediated iTSCM reprogramming remains to be elucidated. Here, we report that the NOTCH/OP9 system efficiently converts conventional human CAR-T cells into TSCM-like CAR-T, “CAR-iTSCM” cells, and that the mitochondrial metabolic reprogramming plays a key role in this conversion. The NOTCH signals promote mitochondrial biogenesis and fatty acid synthesis during iTSCM formation, which are essential for the properties of iTSCM cells. We identified fork head box M1 (FOXM1) as a downstream target of NOTCH, which is responsible for these metabolic changes and the subsequent iTSCM differentiation. Like NOTCH-induced CAR-iTSCM cells, FOXM1-induced CAR-iTSCM cells possess superior antitumor potential compared to conventional CAR-T cells. We propose that the NOTCH- or FOXM1-driven CAR-iTSCM formation is an effective strategy for improving cancer immunotherapy.
Publication Title
The NOTCH-FOXM1 Axis Plays a Key Role in Mitochondrial Biogenesis in the Induction of Human Stem Cell Memory-like CAR-T Cells.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 16 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
c-Myc is one of key players that are crucially involved in maintaining the undifferentiated state and the self-renewal of ESCs. To understand the mechanism by which c-Myc helps preserve these prominent characteristics of ESCs, we generated null-ES cells for the Max gene, which encodes the best characterized partner protein for all Myc family proteins. Although Myc/Max complexes have been widely regarded as crucial regulators of the ESC status, our data reveal that ESCs do not absolutely require these complexes in so-called ground state or related conditons and that this requirement is restricted to conventional ES culture conditions without using a MAPK inhibitor.
Publication Title
Indefinite self-renewal of ESCs through Myc/Max transcriptional complex-independent mechanisms.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 4 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Ablation of expression of the Max gene encoding a Myc protein partner in ES cells provoked two major phenomena, i.e. loss of pluripotency and apoptotic cell death. We found that nicotinamide (Nam) significantly alleviates these Max expression ablation-coupled phenotypes in ES cells. To see the alleviation effect of Nam on the overall expression profile of Max-null ES cells whose Max expression is controlled by the tet-off system, we eliminated Max expression by adding doxycycline (Dox) in the presence of Nam.
Publication Title
Sirt1, p53, and p38(MAPK) are crucial regulators of detrimental phenotypes of embryonic stem cells with Max expression ablation.
Sample Metadata Fields
Sex, Specimen part, Treatment
View Samples- Mus musculus
- 14 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Partial induced pluripotent cells (iPSCs) are cell lines strayed from normal route from somatic cells to iPSCs and are immortalized. Mouse partial iPSCs are able to convert to real iPSCs by the exposure to 2i condition using MAPK and GSK3? inhibitors. However, the molecular mechanisms of this conversion are totally not known. Our piggyback vector mediated genome-wide screen revealed that Cnot2, one of core components of Ccr4-Not complex participates in this conversion. Subsequent analyses revealed other core components, i.e., Cnot1 and Cnot3 and Trim28 which is known to extensively share genomic binding sites with Cnot3 contribute to this conversion as well. Our bioinformatics analyses indicate that the major role of these factors in the conversion is the down-regulation of developmental genes in partial iPSCs.
Publication Title
Identification of Ccr4-not complex components as regulators of transition from partial to genuine induced pluripotent stem cells.
Sample Metadata Fields
Sex, Specimen part
View Samples