Comprehensive multi-omics analysis revealed WEE1 as a synergistic lethal target with hyperthermia through CDK super-activation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA944942 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23868570_1.fastq.gz | Fastqsanger.gz | |||
| SRR23868570_2.fastq.gz | Fastqsanger.gz | |||
| SRR23868571_1.fastq.gz | Fastqsanger.gz | |||
| SRR23868571_2.fastq.gz | Fastqsanger.gz | |||
| SRR24982377.fastq.gz | Fastqsanger.gz |
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Project description:The role of hyperthermic intraperitoneal chemotherapy (HIPEC) in epithelial ovarian cancer (EOC) is still controversial partly because of the poorly understood mechanism of action. Further an understanding of the underlying mechanisms could identify potential combination therapies. Here, we conduct a comprehensive multi-omics study (transcriptiome, proteome, and phosphoproteome) upon hyperthermia (HT) in ovarian cancer cells. Unbiased trans-omics approach deciphered a unique hyperthermia- induced molecular panorama and demonstrated rapid alterations in protein phosphorylation as the primary cell response upon HT. Based on the phospho-signature, we identified CDK kinases to be hyperactivated and responsible for the global signaling landscape upon HT. Molecular and functional experiments demonstrated the dynamic and reversible CDK activity, subsequent replication arrest, and early mitotic entry after HT. A follow-up drug screen identified WEE1 inhibition to synergistically kills cancer cells with HT. An in-house developed miniaturized devise delivered proof-of-concept that the combination of hyperthermia with WEE1i leads to dramatic anti-tumor responses in vivo. These findings provide new insights into how to improve the effectiveness of HIPEC in EOC.
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Project description:To explore the translational expression on mRNA levels after hyperthermia，we exposed OVCAR8 cells to hyperthemia (42℃) for 90 mins.
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Project description:we performed a genome-wide synthetic lethal screen, using CRISPR-Cas9 genome editing, to identify potential therapeutic targets specific for ATRX-mutated cancers. In isogenic hepatocellular carcinoma (HCC) cell lines engineered for ATRX loss, we identified 58 genes, including the checkpoint kinase WEE1, uniquely required for the cell growth of ATRX null cells. Treatment with the WEE1 inhibitor AZD1775 robustly inhibited the growth of several ATRX-deficient HCC cell lines in vitro, as well as xenografts in vivo. The increased sensitivity to the WEE1 inhibitor was caused by accumulated DNA damage induced apoptosis. AZD1775 also selectively inhibited the proliferation of patient-derived primary cell lines from gliomas with naturally occurring ATRX mutations, indicating that the synthetic lethal relationship between WEE1 and ATRX could be exploited in a broader spectrum of human tumors. As WEE1 inhibitors have been investigated in several phase II clinical trials, our discovery provides the basis for an easily clinically testable therapeutic strategy specific for cancers deficient in ATRX.
2019-10-23 | GSE114035 | GEO
Project description:Synthetic lethal screen reveals selective vulnerability of ATRX-mutant cancers to WEE1 inhibition
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Project description:The current standard-of-care for advanced liver cancer is limited. Therefore, there is an urgent need for development of novel molecular targeted therapy. Increase of WEE1 kinase activity through an epigenetic regulation plays an important role in the development of hepatocellular carcinoma (HCC). Here we demonstrated that WEE1 siRNA silencing caused inhibition of HCC cell growth through blockade of cell cycle progression and induction of apoptosis. The anti-proliferative effects were driven by a subset of molecular alterations including the upregulation of cdk inhibitor p21 and the downregulation of AKT1, CDK2, cyclin B1 (CCNB1), PARP1 and GPAM which are functionally involved in control of cell cycle, apoptosis and lipid metabolism. Systemic delivery of a modified WEE1 siRNA encapsulated in lipid nanoparticles significantly inhibited human HCC growth in murine xenograft models, and increased mice survival. Wee1 silencing in tumor cells also resulted in a strong inhibition of lipogenesis (SREBP1C, FAS) and caused a marked decrease in fat accumulation. Of importance, knockdown of WEE1 dramatically reduced the portion of liver cancer stem cells (CSCs) population through co-downregulation of cancer stemness genes and weakened the capacity of sphere formation and the ability of cancer cell migration. Our findings suggest that the epigenetic modifier WEE1 functionally involve to HCC lipid metabolism and CSC-like phenotype maintenance and that molecular targeting of WEE1 may be an effective systemic therapy for prevention of tumor recurrence via elimination of CSCs in liver tumor microenvironment.
2017-05-31 | GSE68778 | GEO
Project description:Tumor Treating Fields (TTFields) disturbs mitosis and consequently leads to cell cycle arrest and cell death. Mild hyperthermia induces cancer cell death by apoptosis,leading to DNA damage and disturbing DNA repair. Thus, when mild hyperthermia is combined with TTFields, the anti-tumor effect could be augmented. This prompted the hypothesis for the present thesis: TTFields and mild hyperthermia as synergistic modalities in Pancreatic ductal adenocarcinoma (PDAC) treatment could probably enhance antitumor efficacy and abate individual toxic effects through distinct and overlapping mechanisms target the tumor cell. Our established PDAC cell line (Bx-GEM) was treated with TTFields and TTFields with mild hyperthermia and was examined by microarray. 500 ng mRNA was checked for quality control and the concentration was measured again. Subsequently, gene expression profiling was performed using human HuGene-2_0-st-type array from Affymetrix.
2021-03-17 | E-MTAB-10270 | biostudies-arrayexpress
Project description:The G2 DNA damage checkpoint inhibits Cdc2 and mitotic entry through the dual regulation of Wee1 and Cdc25 by the Chk1 effector kinase. Up-regulation of Chk1 by mutation or overexpression bypasses the requirement for up-stream regulators or DNA damage to promote a G2 cell cycle arrest. We screened in fission yeast for mutations that rendered cells resistant to overexpressed Chk1. We identified a mutation in tra1, which encodes one of two homologs of TRRAP, an ATM/R-related pseudokinase that scaffolds several histone acetyltransferase (HAT) complexes. Inhibition of histone deacetylases reverts the resistance to overexpressed Chk1, suggesting this phenotype is due to a HAT activity, though expression of checkpoint and cell cycle genes is not greatly affected. Cells with mutant or deleted tra1 activate Chk1 normally and are checkpoint proficient. However, these cells are semi-wee even when overexpressing Chk1, and accumulate inactive Wee1 protein. The Cdr (changed division response) kinases Cdr1 and Cdr2 are negative regulators of Wee1, and while best characterized in the cellular response to limited nutrition, we show that they are required for the Tra1-dependent alterations to Wee1 function. This identifies Tra1 as another component controlling the timing of entry into mitosis via Cdc2 activation. Two and three independent microaaray experiments were done for wild type and the mutant (tra1-1) respectively.
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Project description:A deeper mechanistic understanding of response to hyperthermia in cancer cells in comparison between hyperthermia sensitive and resistant ovarian cancer cell lines
2016-12-31 | GSE77310 | GEO
Project description:Replication stress is a common feature of cancer cells, and thus a potentially important therapeutic target. Here we show that CDK-induced replication stress is synthetic lethal with mutations disrupting dNTP homeostasis in fission yeast. Wee1 inactivation leads to increased dNTP demand and replication stress through CDK-induced firing of dormant replication origins. Subsequent dNTP depletion leads to inefficient DNA replication, Mus81- dependent DNA damage, and to genome instability. Cells respond to this replication stress by increasing dNTP supply through Set2-dependent MBFinduced expression of Cdc22, the catalytic subunit of ribonucleotide reductase (RNR). Disrupting dNTP synthesis following Wee1 inactivation, through loss of Set2-dependent H3K36 tri-methylation, results in further dNTP depletion due to reduced RNR expression, leading to replication catastrophe and cell death. This lethality can be rescued by increasing dNTP levels. Similarly, we find loss of the DNA integrity checkpoint results in synthetic lethality with Wee1 inactivation, which is also associated with replication collapse through critically low dNTP levels. Together, these findings support a ‘dNTP supply and demand’ model in which maintaining dNTP homeostasis is essential in preventing replication catastrophe in response to CDK-induced replication stress.
2018-05-26 | GSE113747 | GEO
Project description:The G2 DNA damage checkpoint inhibits Cdc2 and mitotic entry through the dual regulation of Wee1 and Cdc25 by the Chk1 effector kinase. Up-regulation of Chk1 by mutation or overexpression bypasses the requirement for up-stream regulators or DNA damage to promote a G2 cell cycle arrest. We screened in fission yeast for mutations that rendered cells resistant to overexpressed Chk1. We identified a mutation in tra1, which encodes one of two homologs of TRRAP, an ATM/R-related pseudokinase that scaffolds several histone acetyltransferase (HAT) complexes. Inhibition of histone deacetylases reverts the resistance to overexpressed Chk1, suggesting this phenotype is due to a HAT activity, though expression of checkpoint and cell cycle genes is not greatly affected. Cells with mutant or deleted tra1 activate Chk1 normally and are checkpoint proficient. However, these cells are semi-wee even when overexpressing Chk1, and accumulate inactive Wee1 protein. The Cdr (changed division response) kinases Cdr1 and Cdr2 are negative regulators of Wee1, and while best characterized in the cellular response to limited nutrition, we show that they are required for the Tra1-dependent alterations to Wee1 function. This identifies Tra1 as another component controlling the timing of entry into mitosis via Cdc2 activation.
2010-04-11 | GSE12674 | GEO