| Title |
E-cadherin-deficient cells have synthetic lethal vulnerabilities in plasma membrane organisation, dynamics and function
|
|---|---|
| Published in |
Gastric Cancer, July 2018
|
| DOI | 10.1007/s10120-018-0859-1 |
| Pubmed ID | |
| Authors |
Tanis D. Godwin, S. Thomas Kelly, Tom P. Brew, Nicola M. Bougen-Zhukov, Andrew B. Single, Augustine Chen, Cassie E. Stylianou, Lawrence D. Harris, Sophie K. Currie, Bryony J. Telford, Henry G. Beetham, Gary B. Evans, Michael A. Black, Parry J. Guilford |
| Abstract |
The E-cadherin gene (CDH1) is frequently mutated in diffuse gastric cancer and lobular breast cancer, and germline mutations predispose to the cancer syndrome Hereditary Diffuse Gastric Cancer. We are taking a synthetic lethal approach to identify druggable vulnerabilities in CDH1-mutant cancers. Density distributions of cell viability data from a genome-wide RNAi screen of isogenic MCF10A and MCF10A-CDH1-/- cells were used to identify protein classes affected by CDH1 mutation. The synthetic lethal relationship between selected protein classes and E-cadherin was characterised by drug sensitivity assays in both the isogenic breast MCF10A cells and CDH1-isogenic gastric NCI-N87. Endocytosis efficiency was quantified using cholera toxin B uptake. Pathway metagene expression of 415 TCGA gastric tumours was statistically correlated with CDH1 expression. MCF10A-CDH1-/- cells showed significantly altered sensitivity to RNAi inhibition of groups of genes including the PI3K/AKT pathway, GPCRs, ion channels, proteosomal subunit proteins and ubiquitinylation enzymes. Both MCF10A-CDH1-/- and NCI-N87-CDH1-/- cells were more sensitive than wild-type cells to compounds that disrupted plasma membrane composition and trafficking, but showed contrasting sensitivities to inhibitors of actin polymerisation and the chloride channel inhibitor NS3728. The MCF10A-CDH1-/- cell lines showed reduced capacity to endocytose cholera toxin B. Pathway metagene analysis identified 20 Reactome pathways that were potentially synthetic lethal in tumours. Genes involved in GPCR signalling, vesicle transport and the metabolism of PI3K and membrane lipids were strongly represented amongst the candidate synthetic lethal genes. E-cadherin loss leads to disturbances in receptor signalling and plasma membrane trafficking and organisation, creating druggable vulnerabilities. |
X Demographics
The data shown below were collected from the profiles of 5 X users who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| New Zealand | 2 | 40% |
| Unknown | 3 | 60% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Scientists | 3 | 60% |
| Members of the public | 2 | 40% |
Mendeley readers
The data shown below were compiled from readership statistics for 26 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 26 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Researcher | 6 | 23% |
| Student > Ph. D. Student | 6 | 23% |
| Student > Master | 2 | 8% |
| Student > Bachelor | 2 | 8% |
| Student > Doctoral Student | 1 | 4% |
| Other | 2 | 8% |
| Unknown | 7 | 27% |
| Readers by discipline | Count | As % |
|---|---|---|
| Biochemistry, Genetics and Molecular Biology | 12 | 46% |
| Medicine and Dentistry | 5 | 19% |
| Psychology | 1 | 4% |
| Agricultural and Biological Sciences | 1 | 4% |
| Unknown | 7 | 27% |
Attention Score in Context
This research output has an Altmetric Attention Score of 3. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 17 July 2019.
All research outputs
#12,911,138
of 23,098,660 outputs
Outputs from Gastric Cancer
#240
of 603 outputs
Outputs of similar age
#153,983
of 329,833 outputs
Outputs of similar age from Gastric Cancer
#7
of 13 outputs
Altmetric has tracked 23,098,660 research outputs across all sources so far. This one is in the 43rd percentile – i.e., 43% of other outputs scored the same or lower than it.
So far Altmetric has tracked 603 research outputs from this source. They receive a mean Attention Score of 3.0. This one has gotten more attention than average, scoring higher than 60% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 329,833 tracked outputs that were published within six weeks on either side of this one in any source. This one has gotten more attention than average, scoring higher than 52% of its contemporaries.
We're also able to compare this research output to 13 others from the same source and published within six weeks on either side of this one. This one is in the 46th percentile – i.e., 46% of its contemporaries scored the same or lower than it.