scholarly journals Loss of E-Cadherin Leads to Druggable Vulnerabilities in Sphingolipid Metabolism and Vesicle Trafficking

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 102
Author(s):  
Tom Brew ◽  
Nicola Bougen-Zhukov ◽  
Wilson Mitchell ◽  
Lyvianne Decourtye ◽  
Emily Schulpen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Synthetic Lethality ◽  
Vesicle Trafficking ◽  
Sphingolipid Metabolism ◽  
Mcf10a Cell ◽  
Diffuse Gastric Cancer ◽  
Loss Of Function ◽  
Cancer Syndrome ◽  
Increased Risk ◽  
Mcf10a Cells

Germline inactivating variants of CDH1 are causative of hereditary diffuse gastric cancer (HDGC), a cancer syndrome characterzsed by an increased risk of both diffuse gastric cancer and lobular breast cancer. Because loss of function mutations are difficult to target therapeutically, we have taken a synthetic lethal approach to identify targetable vulnerabilities in CDH1-null cells. We have previously observed that CDH1-null MCF10A cells exhibit a reduced rate of endocytosis relative to wildtype MCF10A cells. To determine whether this deficiency is associated with wider vulnerabilities in vesicle trafficking, we screened isogenic MCF10A cell lines with known inhibitors of autophagy, endocytosis, and sphingolipid metabolism. Relative to wildtype MCF10A cells, CDH1−/− MCF10A cells showed significantly greater sensitivity to several drugs targeting these processes, including the autophagy inhibitor chloroquine, the endocytosis inhibitors chlorpromazine and PP1, and the sphingosine kinase 1 inhibitor PF-543. Synthetic lethality was confirmed in both gastric and mammary organoid models of CDH1 loss, derived from CD44-Cre/Cdh1fl/fl/tdTomato mice. Collectively, these results suggest that both sphingolipid metabolism and vesicle trafficking represent previously unrecognised druggable vulnerabilities in CDH1-null cells and may lead to the development of new therapies for HDGC.

scholarly journals Clinical spectrum and pleiotropic nature of CDH1 germline mutations

2019 ◽  
Vol 56 (4) ◽  
pp. 199-208 ◽  
Author(s):  
Joana Figueiredo ◽  
Soraia Melo ◽  
Patrícia Carneiro ◽  
Ana Margarida Moreira ◽  
Maria Sofia Fernandes ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gastric Cancer ◽  
Genetic Alterations ◽  
Tumour Suppressor Gene ◽  
Diffuse Gastric Cancer ◽  
Loss Of Function ◽  
Lobular Breast Cancer ◽  
Cancer Syndrome ◽  
Risk Of Cancer ◽  
E Cadherin

CDH1 encodes E-cadherin, a key protein in adherens junctions. Given that E-cadherin is involved in major cellular processes such as embryogenesis and maintenance of tissue architecture, it is no surprise that deleterious effects arise from its loss of function. E-cadherin is recognised as a tumour suppressor gene, and it is well established that CDH1 genetic alterations cause diffuse gastric cancer and lobular breast cancer—the foremost manifestations of the hereditary diffuse gastric cancer syndrome. However, in the last decade, evidence has emerged demonstrating that CDH1 mutations can be associated with lobular breast cancer and/or several congenital abnormalities, without any personal or family history of diffuse gastric cancer. To date, no genotype–phenotype correlations have been observed. Remarkably, there are reports of mutations affecting the same nucleotide but inducing distinct clinical outcomes. In this review, we bring together a comprehensive analysis of CDH1-associated disorders and germline alterations found in each trait, providing important insights into the biological mechanisms underlying E-cadherin’s pleiotropic effects. Ultimately, this knowledge will impact genetic counselling and will be relevant to the assessment of risk of cancer development or congenital malformations in CDH1 mutation carriers.

scholarly journals Allosteric AKT Inhibitors Target Synthetic Lethal Vulnerabilities in E-Cadherin-Deficient Cells

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1359 ◽  
Author(s):  
Nicola Bougen-Zhukov ◽  
Yasmin Nouri ◽  
Tanis Godwin ◽  
Megan Taylor ◽  
Christopher Hakkaart ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Bioinformatic Analysis ◽  
Normal Breast ◽  
Diffuse Gastric Cancer ◽  
Cancer Syndrome ◽  
Gastric Cancer Cells ◽  
Gene Encoding ◽  
Enhanced Sensitivity ◽  
Mcf10a Cells ◽  
E Cadherin

The CDH1 gene, encoding the cell adhesion protein E-cadherin, is one of the most frequently mutated genes in gastric cancer and inactivating germline CDH1 mutations are responsible for hereditary diffuse gastric cancer syndrome (HDGC). Using cell viability assays, we identified that breast (MCF10A) and gastric (NCI-N87) cells lacking CDH1 expression are more sensitive to allosteric AKT inhibitors than their CDH1-expressing isogenic counterparts. Apoptosis priming and total apoptosis assays in the isogenic MCF10A cells confirmed the enhanced sensitivity of E-cadherin-null cells to the AKT inhibitors. In addition, two of these inhibitors, ARQ-092 and MK2206, preferentially targeted mouse-derived gastric Cdh1−/− organoids for growth arrest. AKT protein expression and activation (as measured by phosphorylation of serine 473) were differentially regulated in E-cadherin-null MCF10A and NCI-N87 cells, with downregulation in the normal breast cells, but upregulation in the gastric cancer cells. Bioinformatic analysis of the TCGA STAD dataset revealed that AKT3, but not AKT1 or AKT2, is upregulated in the majority of E-cadherin-deficient gastric cancers. In conclusion, allosteric AKT inhibitors represent a promising class of drugs for chemoprevention and chemotherapy of cancers with E-cadherin loss.

CDH1 germline mutations in healthy individuals from families with the hereditary diffuse gastric cancer syndrome

2021 ◽  
pp. jmedgenet-2021-108226
Author(s):  
Giovanni Corso ◽  
Francesca Magnoni ◽  
Giulia Massari ◽  
Cristina Maria Trovato ◽  
Alessandra Margherita De Scalzi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Healthy Subjects ◽  
Relevant Literature ◽  
Germline Mutations ◽  
Hereditary Diffuse Gastric Cancer ◽  
Diffuse Gastric Cancer ◽  
Missense Mutations ◽  
Healthy Individuals ◽  
Cancer Syndrome ◽  
The Difference

The objective of this study was to determining the frequency of different sub-types of pathogenic CDH1 germline mutations in healthy and asymptomatic individuals from families with the hereditary diffuse gastric cancer (HDGC) syndrome. Relevant literature dating from 1998 to 2019 was systematically searched for data on CDH1 germline mutations. The collected variants were classified according to their subtype into the following classes: missense, non-sense, splicing, insertions and deletions. The χ2 test was used to estimate if the difference observed between patients with gastric cancer (GC) and unaffected individuals was statistically significant. CDH1 genetic screening data were retrieved for 224 patients with GC and 289 healthy individuals. Among the subjects that had tested CDH1 positive, splicing mutations were found in 30.4% of the healthy individuals and in 15.2% of the patients with GC (p=0.0076). Missense mutations were also found to occur in healthy subjects with higher frequency (22.2%) than in GC-affected individuals (18.3%), but the difference was not significant in this case. In families meeting the clinical criteria for the HDGC syndrome, CDH1 splicing and missense germline mutations have been reported to occur with higher frequency in healthy subjects than in patients with cancer. This preliminary observation suggests that not all pathogenic CDH1 germline mutations confer the same risk of developing GC.

Outcomes of Surveillance Endoscopy in the Hereditary Diffuse Gastric Cancer Syndrome

2017 ◽  
Vol 152 (5) ◽  
pp. S553-S554
Author(s):  
Tomer Adar ◽  
Devanshi Patel ◽  
John T. Mullen ◽  
Gregory Y. Lauwers ◽  
Daniel C. Chung
Keyword(s):  
Gastric Cancer ◽  
Hereditary Diffuse Gastric Cancer ◽  
Diffuse Gastric Cancer ◽  
Cancer Syndrome ◽  
Surveillance Endoscopy

Hereditary Diffuse Gastric Cancer: Approaches to Screening, Surveillance, and Treatment

2020 ◽  
Vol 72 (1) ◽  
Author(s):  
Nastazja Dagny Pilonis ◽  
Marc Tischkowitz ◽  
Rebecca C. Fitzgerald ◽  
Massimiliano di Pietro
Keyword(s):  
Gastric Cancer ◽  
Hereditary Diffuse Gastric Cancer ◽  
Prophylactic Surgery ◽  
Future Research ◽  
Annual Review ◽  
Publication Date ◽  
Diffuse Gastric Cancer ◽  
Cancer Syndrome ◽  
Pathogenic Variants ◽  
History Of

Hereditary diffuse gastric cancer (HDGC) is a cancer syndrome associated with a significant lifetime risk of diffuse gastric cancer (DGC), a malignancy characterized by late clinical presentation and poor prognosis, as well as lobular breast cancer. HDGC is linked to germline pathogenic variants in the E-cadherin gene ( CDH1) that are inherited in an autosomal dominant pattern; however, in many families with DGC clustering, no genetic cause has been identified. This review discusses key elements that allow risk assessment of potential inherited DGC susceptibility. We provide a practical overview of the recommendations for surveillance and treatment of individuals at risk and patients with early disease. The review also outlines future research avenues to improve our understanding of the genetic background and natural history of the disease, the endoscopic detection of early lesions, and the outcome of prophylactic surgery in young individuals. Expected final online publication date for the Annual Review of Medicine, Volume 72 is January 27, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Role of endoscopy in the management of hereditary diffuse gastric cancer syndrome

2019 ◽  
Vol 25 (23) ◽  
pp. 2878-2886 ◽  
Author(s):  
Shria Kumar ◽  
Jessica M Long ◽  
Gregory G Ginsberg ◽  
Bryson W Katona
Keyword(s):  
Gastric Cancer ◽  
Hereditary Diffuse Gastric Cancer ◽  
Diffuse Gastric Cancer ◽  
Cancer Syndrome

scholarly journals Family’s History Based on the CDH1 Germline Variant (c.360delG) and a Suspected Hereditary Gastric Cancer Form

2020 ◽  
Vol 21 (14) ◽  
pp. 4904
Author(s):  
Laura Caggiari ◽  
Mara Fornasarig ◽  
Mariangela De Zorzi ◽  
Renato Cannizzaro ◽  
Agostino Steffan ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Susceptibility ◽  
Stop Codon ◽  
Case Reports ◽  
Premature Stop Codon ◽  
Diffuse Gastric Cancer ◽  
Cancer Syndrome ◽  
The Family ◽  
Hereditary Gastric Cancer ◽  
E Cadherin

Hereditary diffuse gastric cancer (HDGC) is a cancer susceptibility syndrome caused by germline pathogenic variant in CDH1, the gene encoding E-cadherin. The germline loss-of-function variants are the only proven cause of the cancer syndrome HDGC, occurring in approximately 10–18% of cases and representing a helpful tool in genetic counseling. The current case reports the family history based on a CDH1 gene variant, c.360delG, p.His121Thr in a suspected family for hereditary gastric cancer form. This frameshift deletion generates a premature stop codon at the amino acid 214, which leads to a truncated E-cadherin protein detecting it as a deleterious variant. The present study expands the mutational spectra of the family with the CDH1 variant. Our results highlight the clinical impact of the reported CDH1 variant running in gastric cancer families.

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