RNA sequencing-based cell proliferation analysis across 19 cancers identifies a subset of proliferation-informative cancers with a common survival signature

Ramaker, Ryne C.; Lasseigne, Brittany N.; Hardigan, Andrew A.; Palacio, Laura; Gunther, David S.; Kirby, Marie K.; Myers, R; Cooper, Sara J.

doi:10.1101/063057

Cited by 10 publications

(16 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…9a). TrkB.T1 transduced NSCs showed increases in TrkB.T1 RNA and protein and also exhibit increases in gene signatures previously characterized as a marker of a cell's proliferative index 52,53 , compared with TrkB.FL ( Supplementary Fig. 9b).…”

Section: Go Analysis Of Gscs Stratified By Trkbt1 Expressionmentioning

confidence: 67%

A kinase-deficient NTRK2 splice variant predominates in glioma and amplifies several oncogenic signaling pathways

et al. 2020

View full text Add to dashboard Cite

Independent scientific achievements have led to the discovery of aberrant splicing patterns in oncogenesis, while more recent advances have uncovered novel gene fusions involving neurotrophic tyrosine receptor kinases (NTRKs) in gliomas. The exploration of NTRK splice variants in normal and neoplastic brain provides an intersection of these two rapidly evolving fields. Tropomyosin receptor kinase B (TrkB), encoded NTRK2, is known for critical roles in neuronal survival, differentiation, molecular properties associated with memory, and exhibits intricate splicing patterns and post-translational modifications. Here, we show a role for a truncated NTRK2 splice variant, TrkB.T1, in human glioma. TrkB.T1 enhances PDGF-driven gliomas in vivo, augments PDGF-induced Akt and STAT3 signaling in vitro, while next generation sequencing broadly implicates TrkB.T1 in the PI3K signaling cascades in a ligandindependent fashion. These TrkB.T1 findings highlight the importance of expanding upon whole gene and gene fusion analyses to include splice variants in basic and translational neuro-oncology research.

show abstract

Section: Go Analysis Of Gscs Stratified By Trkbt1 Expressionmentioning

confidence: 67%

A kinase-deficient NTRK2 splice variant predominates in glioma and amplifies several oncogenic signaling pathways

et al. 2020

View full text Add to dashboard Cite

show abstract

“…In addition to immune-related terms, there was an enrichment for terms that implied a possible role for cellular proliferation, such as ribosome biogenesis and DNA replication. To assess this contribution to mtOXPHOS-nuOXPHOS correlation, we used the expression data to infer a measure of active proliferation, the Proliferative Index (PI) (Ramaker, Lasseigne et al 2017), for all GTEx samples. Despite a significant relationship, the PI explained a tiny fraction of the variance across tissues in OXPHOS correlation (R 2 = 0.00759, p < 2.2 x 10 -16 )(Fig 5b).…”

Section: Nf-kb Expression Is Correlated With Oxphos Co-ordination In Healthy Tissuesmentioning

confidence: 99%

Malignancy and NF-kB signalling strengthen coordination between the expression of mitochondrial and nuclear-encoded oxidative phosphorylation genes

Perez

Sarkies

2021

Preprint

View full text Add to dashboard Cite

Mitochondria are ancient endosymbiotic organelles crucial to eukaryotic growth and metabolism. Mammalian mitochondria carry a small genome containing thirteen protein-coding genes with the remaining mitochondrial proteins encoded by the nuclear genome. Little is known about how coordination between the two sets of genes is achieved. Correlation analysis of RNA-seq expression data from large publicly-available datasets is a common method to leverage genetic diversity to infer gene co-expression modules. Here we use this method to investigate nuclear-mitochondrial gene expression coordination. We identify a pitfall in correlation analysis that results from the large variation in the proportion of transcripts from the mitochondrial genome in RNA-seq data. Commonly used normalization techniques based on total read count (such as FPKM or TPM) produce artefactual negative correlations between mitochondrial- and nuclear-encoded transcripts. This also results in artefactual correlations between pairs of nuclear-encoded genes, thus having important consequences for inferring co-expression modules beyond mitochondria. We show that these effects can be overcome by normalizing using the median-ratio normalization (MRN) or trimmed mean of M values (TMM) methods. Using these normalizations, we find only weak and inconsistent correlations between mitochondrial and nuclear-encoded mitochondrial genes in the majority of healthy human tissues from the GTEx database. However, a subset of healthy tissues with high expression of NFkB show significant coordination supporting a role for NFkB in retrograde signalling. Contrastingly, most cancer types show robust coordination of nuclear and mitochondrial OXPHOS gene expression, identifying this as a feature of gene regulation in cancer.

show abstract

“…Although primarily studied in post‐mitotic neurons in the central nervous system (CNS), both RELN and DAB1 are also expressed in a variety of tissues outside of the CNS . In a cancer context, it has been shown that RELN is involved in the regulation of invasion and proliferation of breast cancer . Moreover, RELN was found to inhibit both migration and invasion of pancreatic cancer cells .…”

Section: Introductionmentioning

confidence: 99%

RELN signaling modulates glioblastoma growth and substrate‐dependent migration

et al. 2018

View full text Add to dashboard Cite

Glioblastoma (GBM) represents the most common and most malignant type of primary brain tumor and significantly contributes to cancer morbidity and mortality. Invasion into the healthy brain parenchyma is a major feature of glioblastoma aggressiveness. Reelin (RELN) is a large secreted extracellular matrix glycoprotein that regulates neuronal migration and positioning in the developing brain and sustains functionality in the adult brain. We here show that both RELN and its main downstream effector DAB1 are silenced in glioblastoma as compared to non-neoplastic tissue and mRNA expression is inversely correlated with malignancy grade. Furthermore, RELN expression is positively correlated with patient survival in two large, independent clinically annotated datasets. RELN silencing occurs via promoter hypermethylation as shown by both database mining and bisulfite sequencing of the RELN promoter. Consequently, treatment with 5'-Azacytidine and trichostatin A induced RELN expression in vitro. On the functional level, we found RELN to regulate glioblastoma cell migration both in a DAB1 (tyrosine phosphorylation)-dependent and -independent fashion, depending on the substrate provided. Moreover, stimulation of RELN signaling strongly reduced proliferation in glioblastoma cells. This phenotype depends on DAB1 stimulation by RELN, as a mutant that lacks all RELN induced tyrosine phosphorylation sites (DAB1-5F) failed to induce a growth arrest. Proteomic analyzes revealed that these effects are mediated by a reduction in E2F targets and dephosphorylation of ERK1/2. Taken together, our data establish a relevance of RELN signaling in glioblastoma pathology and thereby might unearth novel, yet unrecognized treatment options.

show abstract

RNA sequencing-based cell proliferation analysis across 19 cancers identifies a subset of proliferation-informative cancers with a common survival signature

Cited by 10 publications

References 57 publications

A kinase-deficient NTRK2 splice variant predominates in glioma and amplifies several oncogenic signaling pathways

A kinase-deficient NTRK2 splice variant predominates in glioma and amplifies several oncogenic signaling pathways

Malignancy and NF-kB signalling strengthen coordination between the expression of mitochondrial and nuclear-encoded oxidative phosphorylation genes

RELN signaling modulates glioblastoma growth and substrate‐dependent migration

Contact Info

Product

Resources

About