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GSE49482
Homo sapiens
6 Downloadable Samples
Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Despite recent advances in the treatment of multiple myeloma (MM), it remains an incurable disease potentially due to the presence of resistant myeloma cancer stem cells (MM-CSC). Although the presence of clonogenic cells in MM was described more than 30 years ago, the phenotype of MM-CSC is still a matter of debate, especially with respect to the expression of syndecan- 1 (CD138). Here, we demonstrate the presence of two subpopulations - CD138++ (95-99%) and CD138low (1-5%) - in eight MM cell lines. To find out possible stem-cell-like features, we have phenotypically, genomic and functionally characterized the two subpopulations. Our results show that the minor CD138low subpopulation is morphologically identical to the CD138++ fraction and does not represent a more immature B-cell compartment (with lack of CD19, CD20 and CD27 surface expression). Moreover, both subpopulations have similar gene expression and genomic profiles. Importantly, both CD138++ and CD138low subpopulations have similar sensitivity to bortezomib, melphalan and doxorubicin. Finally, serial engraftment in SCID mice shows that CD138++ as well as CD138low cells have self-renewal potential and they are also phenotypically interconvertible. Overall, our results differ from previously published data which attribute a B-cell phenotype to MM-CSC and urge the need to explore more reliable markers to discriminate true clonogenic myeloma cells.
Publication Title
Phenotypic, genomic and functional characterization reveals no differences between CD138++ and CD138low subpopulations in multiple myeloma cell lines.
Sample Metadata Fields
Disease, Cell line
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Multiple Myeloma (MM) remains incurable, and new drugs with novel mechanisms of action are still needed. In this report, we have analyzed the action of Zalypsis, an alkaloid analogous to certain natural marine compounds, in MM. Zalypsis turned out to be the most potent antimyeloma agent we have tested so far, with IC50s from picomolar to low nanomolar ranges. It also showed remarkable ex vivo potency in plasma cells from patients and in MM cells in vivo xenografted in mice. Besides the induction of apoptosis and cell cycle arrest, Zalypsis provoked DNA double-strand-breaks (DSB), evidenced by an increase in phospho-Histone-H2AX and phospho-CHK2, followed by a striking overexpression of p53 in p53-wild type cell lines. In addition, in those cell lines in which p53 was mutated, Zalypsis also provoked DSB and induced cell death, although higher concentrations were required. Immunohistochemical studies in tumours also demonstrated Histone-H2AX phosphorylation and p53 overexpression. Gene expression profile studies were concordant with these results, revealing an important deregulation of genes involved in DNA-damage response. The potent in vitro and in vivo antimyeloma activity of Zalypsis uncovers the high sensitivity of tumour plasma cells to DSB, and strongly supports the use of this compound in MM patients.
Publication Title
Zalypsis: a novel marine-derived compound with potent antimyeloma activity that reveals high sensitivity of malignant plasma cells to DNA double-strand breaks.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 135 Downloadable Samples
NextSeq 500
Description
Multiple myeloma (MM), a plasma cell (PC) malignancy, is the second most common blood cancer. Despite extensive research, disease heterogeneity within and between patients is poorly characterized, hampering efforts for early diagnosis and improved treatments. Here, we apply single cell RNA-seq to study the heterogeneity of 40 individuals along the MM progression spectrum. We define malignant PC at single cell resolution, demonstrating high inter-patient variability that can be explained by expression of known MM drivers and additional putative factors. Within newly diagnosed patients, we identify extensive sub-clonal structures for 10/29 patients. In asymptomatic patients with early disease and in minimal residual disease post-treatment, we detect tumor PC for a subset of the patients, with the same drivers of active myeloma. Single cell analysis of rare circulating tumor cells (CTC) allows detection of malignant PC, which reflect the BM disease. Our work establishes scRNA-seq for dissecting blood malignancies and devising detailed molecular characterization of tumor cells in symptomatic and asymptomatic patients. Overall design: The study includes 29 newly diagnosed patients with plasma cell neoplasms and 11 control donors, for which bone marrow plasma cells were single cell sorted by FACS, and their mRNA sequenced. For 11 patients, targeted genomic DNA panel analysis for myeloma was performed.
Publication Title
Single cell dissection of plasma cell heterogeneity in symptomatic and asymptomatic myeloma.
Sample Metadata Fields
Specimen part, Treatment, Subject
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Although new therapies have doubled the survival of multiple myeloma (MM) patients, this remains an incurable disease. It has been postulated that the so-called MM Cancer Stem Cells (MM-CSC) would be responsible for tumor initiation and relapse but their unequivocal identification remains unclear. Here, we investigated in a panel of MM cell lines the presence of CD20+ cells harboring a MM-CSC phenotype. Among the multiple cell lines investigated, only a small population of CD20dim+ cells (0.3%) in the RPMI-8226 cell line was found. CD20dim+ RPMI-8226 cells expressed the plasma cell markers CD38 and CD138 and were CD19-CD27-. Additionally, CD20dim+ RPMI-8226 cells did not exhibit stem-cell markers as shown by gene expression profiling and the aldehyde dehydrogenase (ALDH) assay. Moreover, we demonstrated that CD20dim+ RPMI-8226 cells are not essential for CB17-SCID mice engraftment and show lower self-renewal potential than the CD20- RPMI-8226 cells. These results do not support CD20+ expression for the identification of MM-CSC.
Publication Title
CD20 positive cells are undetectable in the majority of multiple myeloma cell lines and are not associated with a cancer stem cell phenotype.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 129 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
The gastrointestinal (GI) tract can have significant impact on the regulation of the whole body metabolism and may contribute to the development of obesity and diabetes. To systemically elucidate the role of the GI tract in obesity, we performed a transcriptomic analyses in different parts of the GI tract of two obese mouse models: ob/ob and high-fat diet (HFD) fed mice. Compared to their lean controls, both obese mouse groups had significant amount of gene expression changes in the stomach (ob/ob: 959; HFD: 542), much more than the number of changes in the intestine. Despite the difference in genetic background, the two mouse models shared 296 similar gene expression changes in the stomach. Among those genes, some had known associations to obesity, diabetes and insulin resistance. In addition, the gene expression profile strongly suggested an increased gastric acid secretion in both obese mouse models, probably through an activation of the gastrin pathway. In conclusion, our data reveal a previously unknown dominant connection between the stomach and obesity.
Publication Title
Significant obesity-associated gene expression changes occur in the stomach but not intestines in obese mice.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 12 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
BACKGROUND: p53 is an important tumor suppressor with a known role in the later stages of colorectal cancer, but its relevance to the early stages of neoplastic initiation remains somewhat unclear. Although p53-dependent regulation of Wnt signalling activity is known to occur, the importance of these regulatory mechanisms during the early stages of intestinal neoplasia has not been demonstrated.
Publication Title
A limited role for p53 in modulating the immediate phenotype of Apc loss in the intestine.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 9 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
To characterize how symbiotic bacteria affect the lolecular and cellular mechanisms of epithelial homeostasis, human colonic Caco-2 cells
Publication Title
Epithelial cell proliferation arrest induced by lactate and acetate from Lactobacillus casei and Bifidobacterium breve.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus, Homo sapiens
- 10 Downloadable Samples
- Affymetrix Human Gene 2.0 ST Array (hugene20st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
The kinesin spindle protein inhibitor filanesib enhances the activity of pomalidomide and dexamethasone in multiple myeloma.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Mus musculus
- 9 Downloadable Samples
- Affymetrix Human Gene 2.0 ST Array (hugene20st)
Description
Kinesin spindle protein (KSP) inhibition is known to be an effective therapeutic approach in several malignancies. Filanesib (Arry-520), a KSP inhibitor, has demonstrated activity in heavily pretreated multiple myeloma (MM) patients. The aim of this work was to investigate the activity of filanesib in combination with an IMiDs plus dexamethasone backbone, and the mechanisms underlying the potential synergistic effect. Results: Filanesib showed in vitro and in vivo synergy with all IMiDs plus dexamethasone treatment, particularly with the pomalidomide combination (PDF). Importantly, the in vivo synergy observed in this combination was more evident in large, highly proliferative tumors, and it was shown to be mediated by impairment of mitosis transcriptional control, an increase in monopolar spindles, cell cycle arrest and the induction of apoptosis in cells in proliferative phases. In addition, PDF increased the activation of the proapoptotic protein Bax, which has been previously associated with sensitivity to filanesib, and could potentially be used as a predictive biomarker of response to this combination. Conclusions: Our results provide preclinical evidence for the potential benefit of the combination of filanesib with pomalidomide and dexamethasone and es-tablished the basis for a recently activated trial being conducted by the Spanish MM group investigating this combination in relapsed MM patients.
Publication Title
The kinesin spindle protein inhibitor filanesib enhances the activity of pomalidomide and dexamethasone in multiple myeloma.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 1 Downloadable Sample
- Affymetrix Human Gene 2.0 ST Array (hugene20st)
Description
Kinesin spindle protein (KSP) inhibition is known to be an effective therapeutic approach in several malignancies. Filanesib (Arry-520), a KSP inhibitor, has demonstrated activity in heavily pretreated multiple myeloma (MM) patients. The aim of this work was to investigate the activity of filanesib in combination with an IMiDs plus dexamethasone backbone, and the mechanisms underlying the potential synergistic effect. Results: Filanesib showed in vitro and in vivo synergy with all IMiDs plus dexamethasone treatment, particularly with the pomalidomide combination (PDF). Importantly, the in vivo synergy observed in this combination was more evident in large, highly proliferative tumors, and it was shown to be mediated by impairment of mitosis transcriptional control, an increase in monopolar spindles, cell cycle arrest and the induction of apoptosis in cells in proliferative phases. In addition, PDF increased the activation of the proapoptotic protein Bax, which has been previously associated with sensitivity to filanesib, and could potentially be used as a predictive biomarker of response to this combination. Conclusions: Our results provide preclinical evidence for the potential benefit of the combination of filanesib with pomalidomide and dexamethasone and es-tablished the basis for a recently activated trial being conducted by the Spanish MM group investigating this combination in relapsed MM patients.
Publication Title
The kinesin spindle protein inhibitor filanesib enhances the activity of pomalidomide and dexamethasone in multiple myeloma.
Sample Metadata Fields
Cell line, Treatment
View Samples