Identification of MYCN non-amplified neuroblastoma subgroups points towards molecular signatures for precision prognosis and therapy stratification

2021 ◽  
Author(s):  
Xiaoxiao Hu ◽  
Yilu Zhou ◽  
Charlotte Hill ◽  
Kai Chen ◽  
Yeming Wu ◽  
...  
Keyword(s):  
Molecular Subtypes ◽  
Aurora Kinase ◽  
Gene Signature ◽  
Extensive Study ◽  
Clinical Implications ◽  
Molecular Signatures ◽  
Expression Data ◽  
Aurora Kinase A ◽  
Investigational Therapies ◽  
Therapy Stratification

Abstract Despite the extensive study of MYCN-amplified neuroblastomas, there is a significant unmet clinical need in MYCN non-amplified neuroblastomas. In particular, the extent of heterogeneity within the MYCN non-amplified population is unknown. Here, we investigate whether transcriptional subtyping of MYCN non-amplified neuroblastomas can identify molecular subtypes with discrete prognosis and therapeutic vulnerabilities. Using tumour expression data and ConsensusClusterPlus, we demonstrate that MYCN non-amplified neuroblastomas are heterogeneous and can be classified into 3 subgroups based on their transcriptional signatures. Within these groups, subgroup 2 has the worst prognosis and this group shows a "MYCN" signature that is potentially induced by the overexpression of Aurora Kinase A (AURKA); whilst subgroup 3 is characterised by an "inflamed" gene signature. The clinical implications of this subtype classification are significant, as each subtype demonstrates unique prognosis and vulnerability to investigational therapies. We propose that matching baseline tumour subtype to therapy may enhance precision prognosis and therapy stratification for patients with MYCN non-amplified neuroblastomas.

Die Expression der Aurora Kinase A korreliert mit dem Wnt-Modulator RACGAP1 im Magenkarzinom

2015 ◽  
Vol 53 (08) ◽  
Author(s):  
J Bornschein ◽  
J Nielitz ◽  
I Drozdov ◽  
M Selgrad ◽  
T Wex ◽  
...  
Keyword(s):  
Aurora Kinase ◽  
Aurora Kinase A ◽  
Kinase A

On the limits of active module identification

2021 ◽  
Author(s):  
Olga Lazareva ◽  
Jan Baumbach ◽  
Markus List ◽  
David B Blumenthal
Keyword(s):  
Gene Expression ◽  
Gene Expression Data ◽  
Small Diameter ◽  
Extensive Study ◽  
Biological Knowledge ◽  
Expression Data ◽  
Module Identification ◽  
Ppi Networks ◽  
Novel Algorithms ◽  
Context Specific

Abstract In network and systems medicine, active module identification methods (AMIMs) are widely used for discovering candidate molecular disease mechanisms. To this end, AMIMs combine network analysis algorithms with molecular profiling data, most commonly, by projecting gene expression data onto generic protein–protein interaction (PPI) networks. Although active module identification has led to various novel insights into complex diseases, there is increasing awareness in the field that the combination of gene expression data and PPI network is problematic because up-to-date PPI networks have a very small diameter and are subject to both technical and literature bias. In this paper, we report the results of an extensive study where we analyzed for the first time whether widely used AMIMs really benefit from using PPI networks. Our results clearly show that, except for the recently proposed AMIM DOMINO, the tested AMIMs do not produce biologically more meaningful candidate disease modules on widely used PPI networks than on random networks with the same node degrees. AMIMs hence mainly learn from the node degrees and mostly fail to exploit the biological knowledge encoded in the edges of the PPI networks. This has far-reaching consequences for the field of active module identification. In particular, we suggest that novel algorithms are needed which overcome the degree bias of most existing AMIMs and/or work with customized, context-specific networks instead of generic PPI networks.

scholarly journals Therapeutically actionable signaling node to rescue AURKA driven loss of primary cilia in VHL-deficient cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Pratim Chowdhury ◽  
Dimuthu Perera ◽  
Reid T. Powell ◽  
Tia Talley ◽  
Durga Nand Tripathi ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Primary Cilia ◽  
Mtor Inhibitor ◽  
E3 Ubiquitin Ligase ◽  
Xenograft Model ◽  
Aurora Kinase ◽  
Tumor Burden ◽  
Aurora Kinase A ◽  
Von Hippel Lindau ◽  
In Cells

AbstractLoss of primary cilia in cells deficient for the tumor suppressor von Hippel Lindau (VHL) arise from elevated Aurora Kinase A (AURKA) levels. VHL in its role as an E3 ubiquitin ligase targets AURKA for degradation and in the absence of VHL, high levels of AURKA result in destabilization of the primary cilium. We identified NVP-BEZ235, a dual PI3K/AKT and mTOR inhibitor, in an image-based high throughput screen, as a small molecule that restored primary cilia in VHL-deficient cells. We identified the ability of AKT to modulate AURKA expression at the transcript and protein level. Independent modulation of AKT and mTOR signaling decreased AURKA expression in cells confirming AURKA as a new signaling node downstream of the PI3K cascade. Corroborating these data, a genetic knockdown of AKT in cells deficient for VHL rescued the ability of these cells to ciliate. Finally, inhibition of AKT/mTOR using NVP-BEZ235 was efficacious in reducing tumor burden in a 786-0 xenograft model of renal cell carcinoma. These data highlight a previously unappreciated signaling node downstream of the AKT/mTOR pathway via AURKA that can be targeted in VHL-null cells to restore ciliogenesis.

scholarly journals Molecular Tumor Subtypes of HPV-Positive Head and Neck Cancers: Biological Characteristics and Implications for Clinical Outcomes

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2721
Author(s):  
Tingting Qin ◽  
Shiting Li ◽  
Leanne E. Henry ◽  
Siyu Liu ◽  
Maureen A. Sartor
Keyword(s):  
Head And Neck ◽  
Stromal Cells ◽  
Clinical Characteristics ◽  
Molecular Subtypes ◽  
Squamous Cell Carcinomas ◽  
Head And Neck Cancers ◽  
Molecular Signatures ◽  
Tumor Subtypes ◽  
Mesenchymal Differentiation ◽  
High Incidence

Until recently, research on the molecular signatures of Human papillomavirus (HPV)-associated head and neck cancers mainly focused on their differences with respect to HPV-negative head and neck squamous cell carcinomas (HNSCCs). However, given the continuing high incidence level of HPV-related HNSCC, the time is ripe to characterize the heterogeneity that exists within these cancers. Here, we review research thus far on HPV-positive HNSCC molecular subtypes, and their relationship with clinical characteristics and HPV integration into the host genome. Different omics data including host transcriptomics and epigenomics, as well as HPV characteristics, can provide complementary viewpoints. Keratinization, mesenchymal differentiation, immune signatures, stromal cells and oxidoreductive processes all play important roles.

scholarly journals Targeting Aurora kinase A and JAK2 prevents GVHD while maintaining Tregand antitumor CTL function

2017 ◽  
Vol 9 (372) ◽  
pp. eaai8269 ◽  
Author(s):  
Brian C. Betts ◽  
Anandharaman Veerapathran ◽  
Joseph Pidala ◽  
Hua Yang ◽  
Pedro Horna ◽  
...  
Keyword(s):  
Aurora Kinase ◽  
Aurora Kinase A ◽  
Kinase A

Inhibition of Aurora Kinase A enhances chemosensitivity of medulloblastoma cell lines

2010 ◽  
Vol 55 (1) ◽  
pp. 35-41 ◽  
Author(s):  
Ayman El-Sheikh ◽  
Rong Fan ◽  
Diane Birks ◽  
Andrew Donson ◽  
Nicholas K Foreman ◽  
...  
Keyword(s):  
Cell Lines ◽  
Aurora Kinase ◽  
Aurora Kinase A ◽  
Medulloblastoma Cell ◽  
Kinase A ◽  
Medulloblastoma Cell Lines
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