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"Warden, Charles"
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Glioma IL13Rα2 Is Associated with Mesenchymal Signature Gene Expression and Poor Patient Prognosis
A major challenge for successful immunotherapy against glioma is the identification and characterization of validated targets. We have taken a bioinformatics approach towards understanding the biological context of IL-13 receptor α2 (IL13Rα2) expression in brain tumors, and its functional significance for patient survival. Querying multiple gene expression databases, we show that IL13Rα2 expression increases with glioma malignancy grade, and expression for high-grade tumors is bimodal, with approximately 58% of WHO grade IV gliomas over-expressing this receptor. By several measures, IL13Rα2 expression in patient samples and low-passage primary glioma lines most consistently correlates with the expression of signature genes defining mesenchymal subclass tumors and negatively correlates with proneural signature genes as defined by two studies. Positive associations were also noted with proliferative signature genes, whereas no consistent associations were found with either classical or neural signature genes. Probing the potential functional consequences of this mesenchymal association through IPA analysis suggests that IL13Rα2 expression is associated with activation of proinflammatory and immune pathways characteristic of mesenchymal subclass tumors. In addition, survival analyses indicate that IL13Rα2 over-expression is associated with poor patient prognosis, a single gene correlation ranking IL13Rα2 in the top ~1% of total gene expression probes with regard to survival association with WHO IV gliomas. This study better defines the functional consequences of IL13Rα2 expression by demonstrating association with mesenchymal signature gene expression and poor patient prognosis. It thus highlights the utility of IL13Rα2 as a therapeutic target, and helps define patient populations most likely to respond to immunotherapy in present and future clinical trials.
Journal Article
Identification of a common mesenchymal stromal progenitor for the adult haematopoietic niche
Microenvironment cues received by haematopoietic stem cells (HSC) are important in regulating the choice between self-renewal and differentiation. On the basis of the differential expression of cell-surface markers, here we identify a mesenchymal stromal progenitor hierarchy, where CD45
−
Ter119
−
CD31
−
CD166
−
CD146
−
Sca1
+
(Sca1
+
) progenitors give rise to CD45
−
Ter119
−
CD31
−
CD166
−
CD146
+
(CD146
+
) intermediate and CD45
−
Ter119
−
CD31
−
CD166
+
CD146
−
(CD166
+
) mature osteo-progenitors. All three progenitors preserve HSC long-term multi-lineage reconstitution capability
in vitro
; however, their
in vivo
fates are different. Post-transplantation, CD146
+
and CD166
+
progenitors form bone only. While Sca1
+
progenitors produce CD146
+
, CD166
+
progenitors, osteocytes and CXCL12-producing stromal cells. Only Sca1
+
progenitors are capable of homing back to the marrow post-intravenous infusion. Ablation of Sca1
+
progenitors results in a decrease of all three progenitor populations as well as haematopoietic stem/progenitor cells. Moreover, suppressing production of KIT-ligand in Sca1
+
progenitors inhibits their ability to support HSCs. Our results indicate that Sca1
+
progenitors, through the generation of both osteogenic and stromal cells, provide a supportive environment for hematopoiesis.
How the environment of the niche regulates haematopoietic stem cells (HSC) is unclear. Here, the authors identify a mesenchymal stromal progenitor hierarchy and identify Sca1+ cells as common progenitors for mesenchymal stromal cells in the adult niche that provide a supportive environment for hematopoiesis.
Journal Article
CCNE1 amplification is associated with poor prognosis in patients with triple negative breast cancer
Background
Triple negative breast cancer (TNBC) is aggressive with limited treatment options upon recurrence. Molecular discordance between primary and metastatic TNBC has been observed, but the degree of biological heterogeneity has not been fully explored. Furthermore, genomic evolution through treatment is poorly understood. In this study, we aim to characterize the genomic changes between paired primary and metastatic TNBCs through transcriptomic and genomic profiling, and to identify genomic alterations which may contribute to chemotherapy resistance.
Methods
Genomic alterations and mRNA expression of 10 paired primary and metastatic TNBCs were determined through targeted sequencing, microarray analysis, and RNA sequencing. Commonly mutated genes, as well as differentially expressed and co-expressed genes were identified. We further explored the clinical relevance of differentially expressed genes between primary and metastatic tumors to patient survival using large public datasets.
Results
Through gene expression profiling, we observed a shift in TNBC subtype classifications between primary and metastatic TNBCs. A panel of eight cancer driver genes (
CCNE1, TPX2, ELF3, FANCL, JAK2, GSK3B, CEP76,
and
SYK
) were differentially expressed in recurrent TNBCs, and were also overexpressed in TCGA and METABRIC.
CCNE1
and
TPX2
were co-overexpressed in TNBCs. DNA mutation profiling showed that multiple mutations occurred in genes comprising a number of potentially targetable pathways including PI3K/AKT/mTOR, RAS/MAPK, cell cycle, and growth factor receptor signaling, reaffirming the wide heterogeneity of mechanisms driving TNBC.
CCNE1
amplification was associated with poor overall survival in patients with metastatic TNBC.
Conclusions
CCNE1
amplification may confer resistance to chemotherapy and is associated with poor overall survival in TNBC.
Journal Article
Deleterious effects of endocrine disruptors are corrected in the mammalian germline by epigenome reprogramming
Exposure to environmental endocrine-disrupting chemicals during pregnancy reportedly causes transgenerationally inherited reproductive defects. We hypothesized that to affect the grandchild, endocrine-disrupting chemicals must alter the epigenome of the germ cells of the in utero-exposed G1 male fetus. Additionally, to affect the great-grandchild, the aberration must persist in the germ cells of the unexposed G2 grandchild.
Here, we treat gestating female mice with vinclozolin, bisphenol A, or di-(2-ethylhexyl)phthalate during the time when global de novo DNA methylation and imprint establishment occurs in the germ cells of the G1 male fetus. We map genome-wide features in purified G1 and G2 prospermatogonia, in order to detect immediate and persistent epigenetic aberrations, respectively. We detect changes in transcription and methylation in the G1 germline immediately after endocrine-disrupting chemicals exposure, but changes do not persist into the G2 germline. Additional analysis of genomic imprints shows no persistent aberrations in DNA methylation at the differentially methylated regions of imprinted genes between the G1 and G2 prospermatogonia, or in the allele-specific transcription of imprinted genes between the G2 and G3 soma.
Our results suggest that endocrine-disrupting chemicals exert direct epigenetic effects in exposed fetal germ cells, which are corrected by reprogramming events in the next generation. Avoiding transgenerational inheritance of environmentally-caused epigenetic aberrations may have played an evolutionary role in the development of dual waves of global epigenome reprogramming in mammals.
Journal Article
Prognostic and therapeutic significance of ribonucleotide reductase small subunit M2 in estrogen-negative breast cancers
Background
Ribonucleotide reductase (RR) is an essential enzyme involved in DNA synthesis. We hypothesized that RR subunit M2 (
RRM2
) might be a novel prognostic and predictive biomarker for estrogen receptor (ER)-negative breast cancers.
Methods
Individual and pooled survival analyses were conducted on six independent large-scale breast cancer microarray data sets; and findings were validated on a human breast tissue set (ZJU set).
Results
Gene set enrichment analysis revealed that
RRM2
-high breast cancers were significantly enriched for expression of gene sets that increased in proliferation, invasiveness, undifferentiation, embryonic stem/progenitor-like phenotypes, and poor patient survival (p < 0.01). Independent and pooled analyses verified that increased
RRM2
mRNA levels were associated with poor patient outcome in a dose-dependent manner. The prognostic power of
RRM2
mRNA was comparable to multiple gene signatures, and it was superior to TNM stage. In ER-negative breast cancers,
RRM2
showed more prognostic power than that in ER-positive breast cancers. Further analysis indicated that
RRM2
was a more accurate prognostic biomarker for ER-negative breast cancers than the pathoclinical indicators and
uPA
. A new RR inhibitor, COH29, could significantly enhance the chemosensitivity to doxorubicin in ER-negative MDA-MB-231 cells, but not in ER-positive MCF-7 cells.
Conclusion
RRM2
appears to be a promising prognostic biomarker and therapeutic target for ER-negative breast cancer patients.
Journal Article
Downregulation of TLX induces TET3 expression and inhibits glioblastoma stem cell self-renewal and tumorigenesis
Glioblastomas have been proposed to be maintained by highly tumorigenic glioblastoma stem cells (GSCs) that are resistant to current therapy. Therefore, targeting GSCs is critical for developing effective therapies for glioblastoma. In this study, we identify the regulatory cascade of the nuclear receptor TLX and the DNA hydroxylase Ten eleven translocation 3 (TET3) as a target for human GSCs. We show that knockdown of TLX expression inhibits human GSC tumorigenicity in mice. Treatment of human GSC-grafted mice with viral vector-delivered TLX shRNA or nanovector-delivered TLX siRNA inhibits tumour development and prolongs survival. Moreover, we identify TET3 as a potent tumour suppressor downstream of TLX to regulate the growth and self-renewal in GSCs. This study identifies the TLX-TET3 axis as a potential therapeutic target for glioblastoma.
TLX
is a nuclear receptor essential for neural stem cell self-renewal and recently involved in glioblastoma development. In this study, the authors show that inhibition of
TLX
expression, achieved using a dendrimer nanovector-delivered siRNAs or viral vector-delivered shRNAs, reduces glioblastoma stem cells self renewal and
in vivo
tumour growth through activation of TET3.
Journal Article
Altered Expression of Polycomb Group Genes in Glioblastoma Multiforme
The Polycomb group (PcG) proteins play a critical role in histone mediated epigenetics which has been implicated in the malignant evolution of glioblastoma multiforme (GBM). By systematically interrogating The Cancer Genome Atlas (TCGA), we discovered widespread aberrant expression of the PcG members in GBM samples compared to normal brain. The most striking differences were upregulation of EZH2, PHF19, CBX8 and PHC2 and downregulation of CBX7, CBX6, EZH1 and RYBP. Interestingly, changes in EZH2, PHF19, CBX7, CBX6 and EZH1 occurred progressively as astrocytoma grade increased. We validated the aberrant expression of CBX6, CBX7, CBX8 and EZH2 in GBM cell lines by Western blotting and qRT-PCR, and further the aberrant expression of CBX6 in GBM tissue samples by immunohistochemical staining. To determine if there was functional significance to the diminished CBX6 levels in GBM, CBX6 was overexpressed in GBM cells resulting in decreased proliferative capacity. In conclusion, aberrant expression of PcG proteins in GBMs may play a role in the development or maintenance of the malignancy.
Journal Article
A Human Embryonic Stem Cell Model of Aβ-Dependent Chronic Progressive Neurodegeneration
We describe construction and phenotypic analysis of a human embryonic stem cell model of progressive Abeta-dependent neurodegeneration (ND) with potential relevance to Alzheimer’s disease (AD). We modified one allele of the normal APP locus to directly express a secretory form of Abeta40 or Abeta42, eliminating the need for amyloidogenic APP proteolysis. Following neuronal differentiation edited cell lines specifically accumulate aggregated/oligomeric Abeta, exhibit a synaptic deficit and have an abnormal accumulation of endolysosomal vesicles. Edited cultures progress to a stage of overt ND. All phenotypes appear at earlier culture times for Abeta42 relative to Abeta40. Whole transcriptome RNA-Seq analysis identified 23 up and 70 down regulated genes (DEGs) with similar directional fold change but larger absolute values in the Abeta42 samples suggesting common underlying pathogenic mechanisms. Pathway/annotation analysis suggested that down regulation of extracellular matrix and cilia functions are significantly overrepresented. This cellular model could be useful for uncovering mechanisms directly linking Abeta to neuronal death and as a tool to screen for new therapeutic agents that slow or prevent human ND.
Journal Article
