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A Machine-learning approach to define and predict the therapeutic landscape of pan-cancer Hippo pathway dependency

ABSTRACT: A Machine-learning approach to define and predict the therapeutic landscape of pan-cancer Hippo pathway dependency

PROVIDER: PRJNA675152 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13001200.fastq.gz	Fastqsanger.gz
	SRR13001201.fastq.gz	Fastqsanger.gz
	SRR13001202.fastq.gz	Fastqsanger.gz
	SRR13001203.fastq.gz	Fastqsanger.gz
	SRR13001204.fastq.gz	Fastqsanger.gz

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A Machine-learning approach to define and predict the therapeutic landscape of pan-cancer Hippo pathway dependency (ATAC-seq)

Project description:One challenge of cancer precision medicine is the heterogeneity of genetic and non-genetic alterations that result in dysfunctional molecular pathways. As an emerging drug discovery effort, dysregulation in Hippo pathway signaling is known to drive oncogenesis across numerous cancer types but lacks recurrent mutation(s) that are often found in other canonical signaling pathways. Here, we use first principles approach to develop a machine-learning framework to identify a robust, lineage-independent gene expression signature to quantify Hippo pathway dependency in cancers. Through integrating data from multi-omics platforms, this data-driven approach has enabled identifying a proposed combination with MAPK inhibition for direct targeting of Hippo pathway dependent cancers for which we then elucidate the underlying molecular mechanism. The results underscore how a multifaceted approach, computational models combined with laboratory efforts, can accelerate precision medicine efforts toward co-targeting Hippo and MAPK pathways, an approach that can be generalized to other key cancer signaling pathways to define therapeutic strategies.

2021-01-26 | GSE161018 | GEO

A Machine-learning approach to define and predict the therapeutic landscape of pan-cancer Hippo pathway dependency (RNA-seq)

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A Machine-learning approach to define and predict the therapeutic landscape of pan-cancer Hippo pathway dependency (ATAC-seq)

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A Machine-learning approach to define and predict the therapeutic landscape of pan-cancer Hippo pathway dependency (RNA-seq)

Project description:A Machine-learning approach to define and predict the therapeutic landscape of pan-cancer Hippo pathway dependency (RNA-seq)

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A Machine-learning approach to define and predict the therapeutic landscape of pan-cancer Hippo pathway dependency

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-01-26 | GSE161019 | GEO

Pan-caspase inhibition during normothermic machine perfusion of discarded livers mitigates ischemia-reperfusion injury

Project description:Access to liver transplantation is limited by a significant organ shortage. The recent introduction of machine perfusion technology allows surgeons to monitor and assess ex situ liver function prior to transplantation. However, many donated organs are of inadequate quality for transplant, though opportunities exist to rehabilitate organ function with adjunct therapeutics during normothermic machine perfusion. In this preclinical study, we targeted the apoptosis pathway as a potential method of improving hepatocellular function. Treatment of discarded human livers during normothermic perfusion with an irreversible pan-caspase inhibitor, emricasan, resulted in significant mitigation of ischemia-reperfusion injury at both the transcriptional and protein level. This was evidenced by significantly decreased circulating levels of the pro-inflammatory cytokines, interleukin-6, interleukin-8, and interferon-gamma, compared to control livers. Untreated livers also demonstrated transcriptional changes notable for enrichment in pathways involved in innate immunity, leukocyte migration, and cytokine-mediated signaling. Targeting of unregulated apoptosis may represent a viable therapeutic intervention for rehabilitating liver hepatocellular function during machine perfusion.

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Transcriptional targets of Hippo signaling in mammalian cells

Project description:The Hippo pathway is an emerging signaling cascade involved in the regulation of organ size control. It consists of evolutionally conserved protein kinases that are sequentially phosphorylated and activated. The active Hippo pathway subsequently phosphorylates a transcription coactivator, YAP, which precludes its nuclear localization and transcriptional activation. Identification of transcriptional targets of YAP in diverse cellular contexts is therefore critical to the understanding of the molecular mechanisms in which the Hippo pathway restricts tissue growth. We used microarrays to profile the gene expression patterns upon acute siRNA knockdown of Hippo pathway components in multiple mammalian cell lines and identified a set of genes representing immediate transcriptional targets of the Hippo/Yap signaling pathway. Three mammalian cell lines (HEK293T, HepG2, HaCaT) were transfected with scramble siRNA controls or siRNAs against NF2 and LATS2, two core components of the Hippo pathway, simultaneously. Total RNAs were harvested four days after transfection to reveal the gene expression pattern unsing microarry. YAP and TAZ siRNAs were also transfected along with NF2 and LATS2 siRNAs to identify YAP/TAZ-dependent transcriptional targets upon loss of NF2/LATS2.

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Project description:The Hippo pathway is a commonly altered signaling pathway involved in cancer initiation and progression; however, exactly how this pathway becomes dysregulated to promote human cancer development has not been fully understood. In this study, we systematically analyzed the Hippo somatic mutations derived from human cancer genome and functionally annotated their roles in targeting the Hippo pathway. We identified a total of 85 driver missense mutations for the major Hippo pathway genes and elucidated the mechanisms by which these mutations altered their functions in the Hippo pathway. Through these analyses, we revealed zinc-finger domain (ZNF) as an integral structure required for MOB1 function, whose driver mutations promoted head and neck cancer development. Moreover, we discovered that the schwannoma/meningioma-derived NF2 driver mutations gained an oncogenic role by activating the VANGL-JNK pathway. Taken together, our study offers a rich somatic mutation resource for further investigating the Hippo pathway in human cancer, providing a molecular basis for the development of Hippo-related personalized cancer therapy.

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Hippo kinase screen

Project description:In vitro kinase screen of the Hippo kinase STK3 and 4.

2016-11-04 | MSV000080315 | MassIVE