Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Merging perspectives: genotype-directed molecular therapy for hereditary diffuse gastric cancer (HDGC) and E-cadherin–EGFR crosstalk

Merging perspectives: genotype-directed molecular therapy for hereditary diffuse gastric cancer... Hereditary diffuse gastric cancer is a cancer predisposition syndrome associated with germline mutations of the E-cadherin gene (CDH1; NM_004360). Male CDH1 germline mutation carriers have by the age of 80 years an esti- mated 70% cumulative incidence of gastric cancer, females of 56% for gastric and of 42% for lobular breast cancer. Metastatic HDGC has a poor prognosis which is worse than for sporadic gastric cancer. To date, there have been no treatment options described tailored to this molecular subtype of gastric cancer. Here we review recent differential drug screening and gene expression results in c.1380del CDH1-mutant HDGC cells which identified drug classes targeting PI3K (phosphoinositide 3-kinase), MEK (mitogen-activated protein kinase), FAK (focal adhesion kinase), PKC (protein kinase C), and TOPO2 (topoisomerase II) as selectively more effective in cells with defective CDH1 function. ERK1-ERK2 (extracellular signal regulated kinase) signaling measured as top enriched network in c.1380delA CDH1- mutant cells. We compared these findings to synthetic lethality and pharmacological screening results in isogenic −/− CDH1 MCF10A mammary epithelial cells with and without CDH1 expression and current knowledge of E-cad- herin/catenin–EGFR cross-talk, and suggest different rationales how loss of E-cadherin function activates PI3K, mTOR, EGFR, or FAK signaling. These leads represent molecularly selected treatment options tailored to the treatment of CDH1-deficient familial gastric cancer. Keywords: Hereditary diffuse gastric cancer (HDGC), Epidermal growth factor receptor (EGFR), E-Cadherin (CDH1), E-Cadherin/catenin–EGFR cross-talk, Pharmacological vulnerabilities cleft lip palate syndrome [2–8]. Lifetime cumulative risk Background for gastric cancer in male CDH1 mutation carriers is 70% Hereditary diffuse gastric cancer (HDGC) is a cancer pre - by age 80; similar risk for female CDH1 mutation car- disposition syndrome which accounts for up to 19–40% riers is 56% for diffuse gastric cancer and 42% for LBC of familial gastric cancers and is associated with an auto- [3]. Overall, the majority of CDH1 germline variants somal-dominant inheritance pattern due to germline are truncating CDH1 mutations, followed by missense CDH1 variants [1–3]. While initially a syndrome used to variants, and variants affecting splice sites [ 3, 9]. While describe familial inheritance of diffuse gastric cancer, it CDH1 variants have been reported to affect each of the is now recognized that the syndrome includes increased 16 exons of the gene, there is a non-random distribution risk for lobular breast cancer (LBC), possibly colorectal with some hotspots reported including the truncating cancer, and non-cancerous but significant conditions like mutations c.1003C>T, c.1212delC, c.1137G>A, 1792C>T, or 2398delC [3, 9]. *Correspondence: rudloffu@mail.nih.gov With recent advances in the understanding of the syn- Thoracic & Gastrointestinal Oncology Branch, National Cancer Institute, drome’s natural history and genetics, detailed guidelines Bethesda, MD, USA have been developed for genetic testing and preventative Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Li et al. Clin Trans Med (2018) 7:7 Page 2 of 6 interventions via endoscopic surveillance, prophylactic effects. In addition, pathway enrichment was derived gastrectomy, and breast imaging [2, 3, 10]. Despite these from differentially expressed gene set(s) (DEG) in heredi - measures, effective systemic therapies for patients who tary c.1380delA HDGC cells in comparison to a panel develop HDGC malignancies remain elusive. Patients of sporadic gastric cancer cell lines. c.1380delA CDH1- with metastatic HDGC typically receive the same, largely mutant cells were selectively sensitive to inhibition of ineffective chemotherapies as patients with sporadic the EGFR effectors PI3K, mTOR, MEK, c-Src, FAK, and gastric cancer; however, HDGC patients experience TOPO2 inhibition. The drug phenotype overlapped with inferior outcomes to sporadic gastric cancer or gastric the top two signaling networks found enriched by Meta- cancer with non-pathogenic CDH1 mutations [10, 11]. Core analysis in c.1380delA cells [12]. The highest-rank - u Th s, there remains a need for identification and selec - ing network predicted to be enriched in c.1380delA cells tion of effective systemic agents for this unique patient included a number of signaling regulators of the enriched subpopulation. epidermal growth factor receptor signaling pathway or inositol triphosphate (IP3)/diacylglyercol (DAG) signal- High‑throughput drug screening in cell‑based ing which directly or indirectly overlapped with the drug models of HDGC phenotype of enhanced sensitivity against MEK, mTOR, As no effective systemic therapies are available for FAK, or PKC activity anti-PKC, c-Src kinase, and FAK HDGC, an initial broad evaluation of potential drug activity. Table 1 lists the drug classes with selective activ- targets is desirable. Our group conducted a differen - ity in gastric cancer cells with hereditary CDH1 mutation tial high-throughput drug screen in gastric cancer cells compared to sporadic gastric cancer cells. derived from a stage IV HDGC patient with a truncating Sensitivity to PI3K, mTOR, and EGFR inhibition was c.1380delA CDH1 germline mutation and gastric cancer independently observed in another sentinel report on cells derived from a liver lesion of a gastric cancer patient this subject conducted in MCF10A cells, a non-tumo- with wild type CDH1 [12]. The drug library utilized for rigenic mammary epithelial cell line [13]. Telford et  al. screening was enriched for oncology compounds and performed a broad, comparative genome-wide siRNA contained multiple compounds per class to detect class screen of isogenic MCF10A cells with and without CDH1 Table 1 Drug sensitivities derived from in vitro models of HDGC CDH1 MCF10A (−/−) CDH1 MCF10A (−/−) [13] c.1380delA CDH1 HDGC c.1380delA CDH1 HDGC [12] [13] [12] qHTS drug phenotype Lethality by siRNA target or qHTS drug phenotype Target kinase in enriched top target ligand network Drug class PI3K inhibitor Yes PIK3CA, PIK3CG, PIK3R5, Yes No PIK3CB, PIK3CD, PIK3C2B AKT1 No AKT1 No No mTOR inhibitor Yes Yes Yes EGFR and PDGFR family Yes PDGFD, EGFR, ERBB3, NRG1 No Yes inhibitor Src kinase inhibitor Yes No Yes FAK inhibitor ? Yes Yes ALK/ROS1-like tyrosine kinase Yes ROS1, ALK Yes No inhibitor JAK family inhibitor Yes JAK2 No No BCL2 inhibitor Yes BCL2 No No Aurora kinase inhibitor Yes Yes No HDAC inhibitor Yes HDAC3, HDAC9, SIN3A, RERE No ROCK inhibitor No Yes No Protein kinase C inhibitor No Yes Yes −/− Quantitative high-throughput drug screening of MCF10A mammary epithelial cells vs isogenic CDH1 MCF10A cells and hereditary c.1380del CDH1 gastric cancer −/− cells vs sporadic CDH1 wild type SB.msgc-1 cells. Listed are vulnerabilities selective in CDH1 -mutant MCF10A and c.1380del CDH1 cells, shared drug classes are highlighted in italics Active in both c.1380delA CDH1 mutant hereditary SB.mhdgc-1 and control CDH1 wild type SB.msgc-1 gastric cancer cells Li et al. Clin Trans Med (2018) 7:7 Page 3 of 6 expression. G-Protein-coupled receptor (GPCR) signal- E‑Cadherin/catenin–EGFR cross talk and potential ing proteins and cytoskeletal proteins were selectively mechanisms for pharmacologic targeting −/− lethal upon siRNA-mediated knockdown in the CDH1 Early broad pharmacologic screens in in  vitro mod- null MCF10A cells. These genetic vulnerabilities over - els of diffuse gastric cancer indicate that dysregulated lapped with selective drug response profiles derived from EGFR receptor and downstream effector signaling may a 4057 drug screen in the CDH1 isogenic MCF10A cell be involved in aberrant signal transduction selective for lines. Drugs and drug classes with increased sensitivity CDH1-deficient gastric cancer cells. While c-Src kinase −/− in the CDH1 null MCF10A compared to CDH1 wild and FAK activation might be a direct result of elevated type cells included HDAC, PI3K, mTOR, JAK, BCL2, or GPCR signaling, activation of ERK signaling in addition aurora kinase inhibitors. Thus, when aligning drug phe - to enhanced PI3K and mTOR sensitivity suggest activa- notypes derived from both in  vitro models of HDGC, tion of upstream receptor tyrosinase kinase signaling in −/− CDH1 null MCF10A and c.1380delA CDH1 HDGC HDGC cells. Thus, how is E-cadherin/catenin complex cells, gastric cancer cells with defective CDH1 function dysfunction able to activate EGFR signaling and how can showed selective overlapping sensitivity to PI3K, mTOR, loss of CDH1 function explain above signal perturbation ALK/ROS-1 like tyrosine, and aurora kinase inhibition and drug phenotype? E-Cadherin/catenin signaling has in both systems. Table  1 list selective genetic and phar- long been known a downstream effector of EGFR sign - −/− macological vulnerabilities in CDH1 null MCF10A aling [15–18]. Upon ligand activation, EGFR promotes and drug phenotype and enriched gene expression aber- loss of cellular adhesion and increased migration and rations in c.1380delA HDGC cells. Differences in line - invasion, among other mechanisms, through phospho- age and evolvement of screened cells, like pre-neoplastic rylation of E-cadherin bound β-catenin, plakoglobin primary mammary epithelial MCF10A cells versus meta- (γ-catenin) and p120ctn (δ-catenin 1), leading to destabi- static cells derived from the ascites of a CDH1 germline lization of the E-cadherin/catenin/actin complex (Fig.  1) mutation carrier with stage IV gastric cancer, or different [17, 19–21]. As suggested by observed co-localization coverages of the used drug libraries, might explain dif- and cooperativity of the EGFR and E-cadherin/catenin ferences in observed drug phenotype like lack of HDAC complexes in the cell membrane of epithelial cells, phos- inhibition, anti-Bcl2, and anti-XIAP sensitivity in the phorylated EGFR directly interacts with both β- and c.1380delA CDH1 cells or lack of sensitivity to MEK inhi- δ-catenins [22–25]. −/− bition in the CDH1 null MCF10A cells. Recently, there is increased appreciation of reverse Indications of potential vulnerability to PI3KmTOR, E-cadherin/catenin–EGFR cross-talk as part of a bidirec- or FAK inhibition are, in part, also corroborated by tis- tional signaling axis in cancer pathogenesis. Inhibition of sue studies on early T1a stage and  >  T2 lesions from ligand-activated EGFR signaling by E-cadherin is hereby CDH1-mutation carriers. Detailed pathology analysis of dependent on the integrity of the extracellular domains the early, non-proliferative intramucosal T1a lesions in of E-cadherin and independent of β-catenin or p120ctn prophylactic gastrectomy specimens of multiple family binding [26]. CDH1 missense mutant cell lines derived members with a c.1008G>T CDH1 germline mutation from families with missense mutations in the extracel- showed as the earliest, disease-initiating change reduced lular domains of E-cadherin were correspondingly less or absent expression of β-actin, p120 catenin, and Lin-7 able to suppress EGFR signaling than cell lines with wild compared to surrounding mucosa with general loss of type E-cadherin [27–29]. Similarly, deleting mutations organization of adherens junctions; [14]. Loss of adhe- (exons 8 and 9 of CDH1) affecting the extracellular cad - sion function in the intramucosal stage was followed herin-binding domains of E-cadherin show increased upon progression towards  >  T2 lesions by activation of EGFR activation [30]. Hence, loss of suppression of EGFR c-Src kinase and FAK activation, and epithelial to mes- signaling by lack of E-cadherin/catenin–EGFR interac- enchymal transition (EMT). β-Catenin activation (as a tion in HDGC families with CDH1 germline mutations result of p120 loss; measured by nuclear catenin stain- might explain the increased sensitivity to EGFR and PI3K ing) and mTOR activation (measured by staining with kinase inhibition in CDH1-deficient HDGC (Fig. 1). anti-phospho-mTOR Ser2448) was also observed in The increased sensitivity to FAK inhibition, or to the T1a lesions isolated in gastrectomy specimens of CDH1 c-Src kinase inhibitor saracatinib and the selective loss of −/− mutation carriers with del124_126CCCinsT, c.521dupA, viability upon GPCR knockdown in C DH1 MCF10A and c.1565+1G>A variants [9]. These observations of mutant cells, might be explained by increased GPCR activation of the c-Src–FAK axis, catenin and mTOR signaling. GPCR signaling directly activates c-Src, and signaling in clinical specimens appears to be in line with increased GPCR signaling has been suggested by ele- the drug phenotypes derived from the in vitro models. vated intracellular phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate Li et al. Clin Trans Med (2018) 7:7 Page 4 of 6 Fig. 1 Bidirectional E-cadherin/catenin–EGFR cross talk in epithelial biology. Protein–protein interaction with the extracellular cadherin-binding domains of E-cadherin inhibits ligand-mediated activation of EGFR signaling (right); loss of E-cadherin–EGFR interaction leads to increased activa- tion of PI3K, c-Src, and MAPK kinase pathway activation and phosphorylation and destabilization of the E-cadherin/catenin complex (left) (PIP3) levels (second messenger intermediates of GPCR cytoplasmatic PI3K-AKT signaling promoting tumor cell signaling) in c.del1380 CHH1 HDGC cells. Of note, acti- growth (Fig.  2). A similar reciprocal relation of reduced vation of the c-Src kinase and FAK system was inferred E-cadherin expression levels and increased PI3K-AKT after loss of adherens function including reduced levels activation was seen in T1a lesions in prophylactic gas- of actin, p120ctn, or Lin in the progression of intramu- trectomy specimens from CDH1-mutation carriers; T1a cosal T1a lesions in CDH1 germline mutation carriers lesions from three out of four CDH1 mutation carriers [14]. Loss of p120ctn is a pro-tumorigenic driver event from different HDGC families with different truncating in epithelial cancers with augmentation of EGFR signal- CDH1 mutations harbored activation of mTOR (meas- ing in breast cancer, elevated levels and activation states ured by staining with anti-phospho-mTOR Ser2448) and of c-Src kinase and FAK have been found to be associ- catenin (measured by increased nuclear catenin staining) ated with accelerated progression and shorter survival in [9]. Thus, activation of PI3K-mTOR signaling in CDH1- epithelial malignancies including gastric cancer [31–33]. deficient gastric cancer cells might be the result of mul - Inhibition of the Src kinase–FAK pathway can restore cell tiple signal transduction aberrations including lack of adhesion, reduce cell migration, and promote an epithe- suppression of ligand-mediated EGFR activation (Fig.  1) lial phenotype [34]. or lack of negative feedback inhibition of the PI3K–Akt Activation of the EGFR downstream PI3K-mTOR axis via reduced PTEN levels (Fig. 2). pathway in CDH1-mutant cells may also be caused by the disruption of a negative feedback group of β-catenin Conclusions −/− and PTEN [35]. E-Cadherin loss is associated with Drug screening studies in isogenic CDH1 -mutant enhanced nuclear β-catenin translocation, suppression mammary epithelial MCF10A and c.1380delA CDH1- of nuclear expression of EGR-1 and PTEN, and increased mutant gastric cancer cells show considerable overlap in Li et al. Clin Trans Med (2018) 7:7 Page 5 of 6 E-Cadherin exerts direct and indirect negative regulation onto EGFR signaling, supporting blockade of the EGFR– PI3K kinase axis as therapy in this molecular subtype of gastric cancer. Considering that both anti-mTOR, anti- PI3K, and anti-EGFR therapies are already in routine clinical use or in late clinical development for a number of other cancer histologies, these observations suggest that PI3K and mTOR inhibitors may be considered for molecular-targeted therapies within clinical studies for patients with HDGC in the near future. Abbreviations ALK: anaplastic lymphoma receptor tyrosine kinase; CDH1: E-cadherin; DAG: diacylglycerol; EGFR: epidermal growth factor receptor; EMT: epithelial–mes- enchymal transition; ERK: extracellular signal regulated kinase; FAK: focal adhe- sion kinase; HDGC: hereditary diffuse gastric cancer; IP3: inositol trisphosphate; JAK: janus kinase; MEK: mitogen-activated protein kinase; mTOR: mammalian target of rapamycin; PI3K: phosphatidylinositol 3-kinase; PKC: protein kinase C; STAT3: signal transducer and activator of transcription 3; TOPO2: topoisomer- ase II. Authors’ contributions DL conducted previous experiment with c.1380delA CDH1-mutant gastric cancer cells. DL, WL, and UR conceived and designed the clinical and transla- tional perspectives of drug screening, compiled the figures, and wrote paper. All authors read and approved the final manuscript. Author details Thoracic & Gastrointestinal Oncology Branch, National Cancer Institute, Bethesda, MD, USA. Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA. Acknowledgements We would like to thank Ms. Erina He, MScBMC Medical Illustrator and NIH Medical Arts for compilation of the illustrations. Competing interests The authors declare that they have no competing interests. Consent for publication Not applicable. Fig. 2 E-Cadherin/catenin–PI3K/AKT crosstalk. Release of nega- Ethics approval and consent to participate tive feedback inhibition of PI3K/AKT signaling via reduced PTEN Not applicable. expression through elevated nuclear β-catenin levels. Disruption of the E-cadherin/catenin complex induces nuclear translocation of β-catenin repressing Egr-1-mediated PTEN expression leading to Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- increased AKT activation lished maps and institutional affiliations. Received: 28 December 2017 Accepted: 31 January 2018 sensitivity to PI3K, mTOR, or ALK/ROS-1 like tyrosine kinase inhibition. These pharmacological vulnerabilities are supported by comparative synthetic lethality, gene expression, and correlative tissue studies in clinical speci- References 1. Kaurah P, MacMillan A, Boyd N et al (2007) Founder and recurrent CDH1 mens of CDH1 mutation carriers, which indicate select mutations in families with hereditary diffuse gastric cancer. JAMA perturbations of GPCR, actin-related, ERK1–ERK2, or 297:2360–2372 FAK and c-Src kinase activity as signaling alterations and 2. van der Post RS, Vogelaar IP, Carneiro F et al (2015) Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline possible targets selective for CDH1-mutant gastric can- CDH1 mutation carriers. J Med Genet 52:361–374 cer cells. These pharmacological vulnerabilities are also 3. Hansford S, Kaurah P, Li-Chang H et al (2015) Hereditary diffuse gastric supported by an improved understanding of the bidirec- cancer syndrome: CDH1 mutations and beyond. JAMA Oncol 1:23–32 tional cross-talk between E-cadherin/catenin and EGFR. Li et al. Clin Trans Med (2018) 7:7 Page 6 of 6 4. Pharoah PD, Guilford P, Caldas C (2001) Incidence of gastric cancer and 20. Seton-Rogers SE, Lu Y, Hines LM et al (2004) Cooperation of the ErbB2 breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary receptor and transforming growth factor beta in induction of migra- diffuse gastric cancer families. Gastroenterology 121:1348–1353 tion and invasion in mammary epithelial cells. Proc Natl Acad Sci USA 5. Benusiglio PR, Malka D, Rouleau E et al (2013) CDH1 germline mutations 101:1257–1262 and the hereditary diffuse gastric and lobular breast cancer syndrome: a 21. Lilien J, Balsamo J (2005) The regulation of cadherin-mediated adhesion multicentre study. J Med Genet 50:486–489 by tyrosine phosphorylation/dephosphorylation of beta-catenin. Curr 6. Richards FM, McKee SA, Rajpar MH et al (1999) Germline E-cadherin gene Opin Cell Biol 17:459–465 (CDH1) mutations predispose to familial gastric cancer and colorectal 22. Shiozaki H, Kadowaki T, Doki Y et al (1995) Eec ff t of epidermal growth cancer. Hum Mol Genet 8:607–610 factor on cadherin-mediated adhesion in a human oesophageal cancer 7. Frebourg T, Oliveira C, Hochain P et al (2006) Cleft lip/palate and CDH1/E- cell line. Br J Cancer 71:250–258 cadherin mutations in families with hereditary diffuse gastric cancer. J 23. Jones JL, Royall JE, Walker RA (1996) E-cadherin relates to EGFR expres- Med Genet 43:138–142 sion and lymph node metastasis in primary breast carcinoma. Br J Cancer 8. Benusiglio PR, Caron O, Consolino E et al (2013) Cleft lip, cleft palate, 74:1237–1241 hereditary diffuse gastric cancer and germline mutations in CDH1. Int J 24. Hoschuetzky H, Aberle H, Kemler R (1994) Beta-catenin mediates the Cancer 132:2470 interaction of the cadherin-catenin complex with epidermal growth fac- 9. Sabesan AZB, Lo W, Wu HH, Powers A, Sorber RA, Ravichandran R, Chen I, tor receptor. J Cell Biol 127:1375–1380 McDuffie LA, Quadri HS, Beane JD, Calzone K, Miettinen MK, Hewitt SM, 25. Bae GY, Choi SJ, Lee JS et al (2013) Loss of E-cadherin activates EGFR- Koh C, Heller T, Wacholder S, Rudloff U (2017) Association of CDH1 ger - MEK/ERK signaling, which promotes invasion via the ZEB1/MMP2 axis in mline variant location and cancer phenotype in families with hereditary non-small cell lung cancer. Oncotarget 4:2512–2522 diffuse gastric cancer (HDGC). J Med Genet (under review) 26. Qian X, Karpova T, Sheppard AM et al (2004) E-Cadherin-mediated adhe- 10. van der Post RS, Vogelaar IP, Manders P et al (2015) Accuracy of hereditary sion inhibits ligand-dependent activation of diverse receptor tyrosine diffuse gastric cancer testing criteria and outcomes in patients with a kinases. EMBO J 23:1739–1748 germline mutation in CDH1. Gastroenterology 149(897–906):e19 27. Mateus AR, Seruca R, Machado JC et al (2007) EGFR regulates RhoA-GTP 11. Corso G, Carvalho J, Marrelli D et al (2013) Somatic mutations and dele- dependent cell motility in E-cadherin mutant cells. Hum Mol Genet tions of the E-cadherin gene predict poor survival of patients with gastric 16:1639–1647 cancer. J Clin Oncol 31:868–875 28. Mateus AR, Simoes-Correia J, Figueiredo J et al (2009) E-Cadherin muta- 12. Chen I, Mathews-Greiner L, Li D et al (2017) Transcriptomic profiling and tions and cell motility: a genotype-phenotype correlation. Exp Cell Res quantitative high-throughput (qHTS) drug screening of CDH1 deficient 315:1393–1402 hereditary diffuse gastric cancer (HDGC) cells identify treatment leads for 29. Figueiredo J, Soderberg O, Simoes-Correia J et al (2013) The impor- familial gastric cancer. J Transl Med 15:92 tance of E-cadherin binding partners to evaluate the pathogenicity of 13. Telford BJ, Chen A, Beetham H et al (2015) Synthetic lethal screens E-cadherin missense mutations associated to HDGC. Eur J Hum Genet identify vulnerabilities in GPCR signaling and cytoskeletal organization in 21:301–309 E-cadherin-deficient cells. Mol Cancer Ther 14:1213–1223 30. Bremm A, Walch A, Fuchs M et al (2008) Enhanced activation of epider- 14. Humar B, Fukuzawa R, Blair V et al (2007) Destabilized adhesion in the mal growth factor receptor caused by tumor-derived E-cadherin muta- gastric proliferative zone and c-Src kinase activation mark the develop- tions. Cancer Res 68:707–714 ment of early diffuse gastric cancer. Cancer Res 67:2480–2489 31. Park JH, Lee BL, Yoon J et al (2010) Focal adhesion kinase (FAK) gene 15. Hazan RB, Norton L (1998) The epidermal growth factor receptor modu- amplification and its clinical implications in gastric cancer. Hum Pathol lates the interaction of E-cadherin with the actin cytoskeleton. J Biol 41:1664–1673 Chem 273:9078–9084 32. Lai IR, Chu PY, Lin HS et al (2010) Phosphorylation of focal adhesion 16. Ozawa M, Kemler R (1998) Altered cell adhesion activity by pervanadate kinase at Tyr397 in gastric carcinomas and its clinical significance. Am J due to the dissociation of alpha-catenin from the E-cadherin–catenin Pathol 177:1629–1637 complex. J Biol Chem 273:6166–6170 33. Schackmann RC, Klarenbeek S, Vlug EJ et al (2013) Loss of p120-catenin 17. Roura S, Miravet S, Piedra J et al (1999) Regulation of E-cadherin/catenin induces metastatic progression of breast cancer by inducing anoikis association by tyrosine phosphorylation. J Biol Chem 274:36734–36740 resistance and augmenting growth factor receptor signaling. Cancer Res 18. Yasmeen A, Bismar TA, Al Moustafa AE (2006) ErbB receptors and 73:4937–4949 epithelial-cadherin–catenin complex in human carcinomas. Future Oncol 34. Zhang S, Yu D (2012) Targeting Src family kinases in anti-cancer therapies: 2:765–781 turning promise into triumph. Trends Pharmacol Sci 33:122–128 19. Lu Z, Ghosh S, Wang Z et al (2003) Downregulation of caveolin-1 function 35. Lau MT, Klausen C, Leung PC (2011) E-Cadherin inhibits tumor cell by EGF leads to the loss of E-cadherin, increased transcriptional activity of growth by suppressing PI3K/Akt signaling via beta-catenin-Egr1-medi- beta-catenin, and enhanced tumor cell invasion. Cancer Cell 4:499–515 ated PTEN expression. Oncogene 30:2753–2766 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical and Translational Medicine Springer Journals

Merging perspectives: genotype-directed molecular therapy for hereditary diffuse gastric cancer (HDGC) and E-cadherin–EGFR crosstalk

Loading next page...
1
 
/lp/springer_journal/merging-perspectives-genotype-directed-molecular-therapy-for-W7a7n9jM2v

References (35)

Publisher
Springer Journals
Copyright
Copyright © 2018 by The Author(s)
Subject
Medicine & Public Health; Medicine/Public Health, general
eISSN
2001-1326
DOI
10.1186/s40169-018-0184-7
Publisher site
See Article on Publisher Site

Abstract

Hereditary diffuse gastric cancer is a cancer predisposition syndrome associated with germline mutations of the E-cadherin gene (CDH1; NM_004360). Male CDH1 germline mutation carriers have by the age of 80 years an esti- mated 70% cumulative incidence of gastric cancer, females of 56% for gastric and of 42% for lobular breast cancer. Metastatic HDGC has a poor prognosis which is worse than for sporadic gastric cancer. To date, there have been no treatment options described tailored to this molecular subtype of gastric cancer. Here we review recent differential drug screening and gene expression results in c.1380del CDH1-mutant HDGC cells which identified drug classes targeting PI3K (phosphoinositide 3-kinase), MEK (mitogen-activated protein kinase), FAK (focal adhesion kinase), PKC (protein kinase C), and TOPO2 (topoisomerase II) as selectively more effective in cells with defective CDH1 function. ERK1-ERK2 (extracellular signal regulated kinase) signaling measured as top enriched network in c.1380delA CDH1- mutant cells. We compared these findings to synthetic lethality and pharmacological screening results in isogenic −/− CDH1 MCF10A mammary epithelial cells with and without CDH1 expression and current knowledge of E-cad- herin/catenin–EGFR cross-talk, and suggest different rationales how loss of E-cadherin function activates PI3K, mTOR, EGFR, or FAK signaling. These leads represent molecularly selected treatment options tailored to the treatment of CDH1-deficient familial gastric cancer. Keywords: Hereditary diffuse gastric cancer (HDGC), Epidermal growth factor receptor (EGFR), E-Cadherin (CDH1), E-Cadherin/catenin–EGFR cross-talk, Pharmacological vulnerabilities cleft lip palate syndrome [2–8]. Lifetime cumulative risk Background for gastric cancer in male CDH1 mutation carriers is 70% Hereditary diffuse gastric cancer (HDGC) is a cancer pre - by age 80; similar risk for female CDH1 mutation car- disposition syndrome which accounts for up to 19–40% riers is 56% for diffuse gastric cancer and 42% for LBC of familial gastric cancers and is associated with an auto- [3]. Overall, the majority of CDH1 germline variants somal-dominant inheritance pattern due to germline are truncating CDH1 mutations, followed by missense CDH1 variants [1–3]. While initially a syndrome used to variants, and variants affecting splice sites [ 3, 9]. While describe familial inheritance of diffuse gastric cancer, it CDH1 variants have been reported to affect each of the is now recognized that the syndrome includes increased 16 exons of the gene, there is a non-random distribution risk for lobular breast cancer (LBC), possibly colorectal with some hotspots reported including the truncating cancer, and non-cancerous but significant conditions like mutations c.1003C>T, c.1212delC, c.1137G>A, 1792C>T, or 2398delC [3, 9]. *Correspondence: rudloffu@mail.nih.gov With recent advances in the understanding of the syn- Thoracic & Gastrointestinal Oncology Branch, National Cancer Institute, drome’s natural history and genetics, detailed guidelines Bethesda, MD, USA have been developed for genetic testing and preventative Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Li et al. Clin Trans Med (2018) 7:7 Page 2 of 6 interventions via endoscopic surveillance, prophylactic effects. In addition, pathway enrichment was derived gastrectomy, and breast imaging [2, 3, 10]. Despite these from differentially expressed gene set(s) (DEG) in heredi - measures, effective systemic therapies for patients who tary c.1380delA HDGC cells in comparison to a panel develop HDGC malignancies remain elusive. Patients of sporadic gastric cancer cell lines. c.1380delA CDH1- with metastatic HDGC typically receive the same, largely mutant cells were selectively sensitive to inhibition of ineffective chemotherapies as patients with sporadic the EGFR effectors PI3K, mTOR, MEK, c-Src, FAK, and gastric cancer; however, HDGC patients experience TOPO2 inhibition. The drug phenotype overlapped with inferior outcomes to sporadic gastric cancer or gastric the top two signaling networks found enriched by Meta- cancer with non-pathogenic CDH1 mutations [10, 11]. Core analysis in c.1380delA cells [12]. The highest-rank - u Th s, there remains a need for identification and selec - ing network predicted to be enriched in c.1380delA cells tion of effective systemic agents for this unique patient included a number of signaling regulators of the enriched subpopulation. epidermal growth factor receptor signaling pathway or inositol triphosphate (IP3)/diacylglyercol (DAG) signal- High‑throughput drug screening in cell‑based ing which directly or indirectly overlapped with the drug models of HDGC phenotype of enhanced sensitivity against MEK, mTOR, As no effective systemic therapies are available for FAK, or PKC activity anti-PKC, c-Src kinase, and FAK HDGC, an initial broad evaluation of potential drug activity. Table 1 lists the drug classes with selective activ- targets is desirable. Our group conducted a differen - ity in gastric cancer cells with hereditary CDH1 mutation tial high-throughput drug screen in gastric cancer cells compared to sporadic gastric cancer cells. derived from a stage IV HDGC patient with a truncating Sensitivity to PI3K, mTOR, and EGFR inhibition was c.1380delA CDH1 germline mutation and gastric cancer independently observed in another sentinel report on cells derived from a liver lesion of a gastric cancer patient this subject conducted in MCF10A cells, a non-tumo- with wild type CDH1 [12]. The drug library utilized for rigenic mammary epithelial cell line [13]. Telford et  al. screening was enriched for oncology compounds and performed a broad, comparative genome-wide siRNA contained multiple compounds per class to detect class screen of isogenic MCF10A cells with and without CDH1 Table 1 Drug sensitivities derived from in vitro models of HDGC CDH1 MCF10A (−/−) CDH1 MCF10A (−/−) [13] c.1380delA CDH1 HDGC c.1380delA CDH1 HDGC [12] [13] [12] qHTS drug phenotype Lethality by siRNA target or qHTS drug phenotype Target kinase in enriched top target ligand network Drug class PI3K inhibitor Yes PIK3CA, PIK3CG, PIK3R5, Yes No PIK3CB, PIK3CD, PIK3C2B AKT1 No AKT1 No No mTOR inhibitor Yes Yes Yes EGFR and PDGFR family Yes PDGFD, EGFR, ERBB3, NRG1 No Yes inhibitor Src kinase inhibitor Yes No Yes FAK inhibitor ? Yes Yes ALK/ROS1-like tyrosine kinase Yes ROS1, ALK Yes No inhibitor JAK family inhibitor Yes JAK2 No No BCL2 inhibitor Yes BCL2 No No Aurora kinase inhibitor Yes Yes No HDAC inhibitor Yes HDAC3, HDAC9, SIN3A, RERE No ROCK inhibitor No Yes No Protein kinase C inhibitor No Yes Yes −/− Quantitative high-throughput drug screening of MCF10A mammary epithelial cells vs isogenic CDH1 MCF10A cells and hereditary c.1380del CDH1 gastric cancer −/− cells vs sporadic CDH1 wild type SB.msgc-1 cells. Listed are vulnerabilities selective in CDH1 -mutant MCF10A and c.1380del CDH1 cells, shared drug classes are highlighted in italics Active in both c.1380delA CDH1 mutant hereditary SB.mhdgc-1 and control CDH1 wild type SB.msgc-1 gastric cancer cells Li et al. Clin Trans Med (2018) 7:7 Page 3 of 6 expression. G-Protein-coupled receptor (GPCR) signal- E‑Cadherin/catenin–EGFR cross talk and potential ing proteins and cytoskeletal proteins were selectively mechanisms for pharmacologic targeting −/− lethal upon siRNA-mediated knockdown in the CDH1 Early broad pharmacologic screens in in  vitro mod- null MCF10A cells. These genetic vulnerabilities over - els of diffuse gastric cancer indicate that dysregulated lapped with selective drug response profiles derived from EGFR receptor and downstream effector signaling may a 4057 drug screen in the CDH1 isogenic MCF10A cell be involved in aberrant signal transduction selective for lines. Drugs and drug classes with increased sensitivity CDH1-deficient gastric cancer cells. While c-Src kinase −/− in the CDH1 null MCF10A compared to CDH1 wild and FAK activation might be a direct result of elevated type cells included HDAC, PI3K, mTOR, JAK, BCL2, or GPCR signaling, activation of ERK signaling in addition aurora kinase inhibitors. Thus, when aligning drug phe - to enhanced PI3K and mTOR sensitivity suggest activa- notypes derived from both in  vitro models of HDGC, tion of upstream receptor tyrosinase kinase signaling in −/− CDH1 null MCF10A and c.1380delA CDH1 HDGC HDGC cells. Thus, how is E-cadherin/catenin complex cells, gastric cancer cells with defective CDH1 function dysfunction able to activate EGFR signaling and how can showed selective overlapping sensitivity to PI3K, mTOR, loss of CDH1 function explain above signal perturbation ALK/ROS-1 like tyrosine, and aurora kinase inhibition and drug phenotype? E-Cadherin/catenin signaling has in both systems. Table  1 list selective genetic and phar- long been known a downstream effector of EGFR sign - −/− macological vulnerabilities in CDH1 null MCF10A aling [15–18]. Upon ligand activation, EGFR promotes and drug phenotype and enriched gene expression aber- loss of cellular adhesion and increased migration and rations in c.1380delA HDGC cells. Differences in line - invasion, among other mechanisms, through phospho- age and evolvement of screened cells, like pre-neoplastic rylation of E-cadherin bound β-catenin, plakoglobin primary mammary epithelial MCF10A cells versus meta- (γ-catenin) and p120ctn (δ-catenin 1), leading to destabi- static cells derived from the ascites of a CDH1 germline lization of the E-cadherin/catenin/actin complex (Fig.  1) mutation carrier with stage IV gastric cancer, or different [17, 19–21]. As suggested by observed co-localization coverages of the used drug libraries, might explain dif- and cooperativity of the EGFR and E-cadherin/catenin ferences in observed drug phenotype like lack of HDAC complexes in the cell membrane of epithelial cells, phos- inhibition, anti-Bcl2, and anti-XIAP sensitivity in the phorylated EGFR directly interacts with both β- and c.1380delA CDH1 cells or lack of sensitivity to MEK inhi- δ-catenins [22–25]. −/− bition in the CDH1 null MCF10A cells. Recently, there is increased appreciation of reverse Indications of potential vulnerability to PI3KmTOR, E-cadherin/catenin–EGFR cross-talk as part of a bidirec- or FAK inhibition are, in part, also corroborated by tis- tional signaling axis in cancer pathogenesis. Inhibition of sue studies on early T1a stage and  >  T2 lesions from ligand-activated EGFR signaling by E-cadherin is hereby CDH1-mutation carriers. Detailed pathology analysis of dependent on the integrity of the extracellular domains the early, non-proliferative intramucosal T1a lesions in of E-cadherin and independent of β-catenin or p120ctn prophylactic gastrectomy specimens of multiple family binding [26]. CDH1 missense mutant cell lines derived members with a c.1008G>T CDH1 germline mutation from families with missense mutations in the extracel- showed as the earliest, disease-initiating change reduced lular domains of E-cadherin were correspondingly less or absent expression of β-actin, p120 catenin, and Lin-7 able to suppress EGFR signaling than cell lines with wild compared to surrounding mucosa with general loss of type E-cadherin [27–29]. Similarly, deleting mutations organization of adherens junctions; [14]. Loss of adhe- (exons 8 and 9 of CDH1) affecting the extracellular cad - sion function in the intramucosal stage was followed herin-binding domains of E-cadherin show increased upon progression towards  >  T2 lesions by activation of EGFR activation [30]. Hence, loss of suppression of EGFR c-Src kinase and FAK activation, and epithelial to mes- signaling by lack of E-cadherin/catenin–EGFR interac- enchymal transition (EMT). β-Catenin activation (as a tion in HDGC families with CDH1 germline mutations result of p120 loss; measured by nuclear catenin stain- might explain the increased sensitivity to EGFR and PI3K ing) and mTOR activation (measured by staining with kinase inhibition in CDH1-deficient HDGC (Fig. 1). anti-phospho-mTOR Ser2448) was also observed in The increased sensitivity to FAK inhibition, or to the T1a lesions isolated in gastrectomy specimens of CDH1 c-Src kinase inhibitor saracatinib and the selective loss of −/− mutation carriers with del124_126CCCinsT, c.521dupA, viability upon GPCR knockdown in C DH1 MCF10A and c.1565+1G>A variants [9]. These observations of mutant cells, might be explained by increased GPCR activation of the c-Src–FAK axis, catenin and mTOR signaling. GPCR signaling directly activates c-Src, and signaling in clinical specimens appears to be in line with increased GPCR signaling has been suggested by ele- the drug phenotypes derived from the in vitro models. vated intracellular phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate Li et al. Clin Trans Med (2018) 7:7 Page 4 of 6 Fig. 1 Bidirectional E-cadherin/catenin–EGFR cross talk in epithelial biology. Protein–protein interaction with the extracellular cadherin-binding domains of E-cadherin inhibits ligand-mediated activation of EGFR signaling (right); loss of E-cadherin–EGFR interaction leads to increased activa- tion of PI3K, c-Src, and MAPK kinase pathway activation and phosphorylation and destabilization of the E-cadherin/catenin complex (left) (PIP3) levels (second messenger intermediates of GPCR cytoplasmatic PI3K-AKT signaling promoting tumor cell signaling) in c.del1380 CHH1 HDGC cells. Of note, acti- growth (Fig.  2). A similar reciprocal relation of reduced vation of the c-Src kinase and FAK system was inferred E-cadherin expression levels and increased PI3K-AKT after loss of adherens function including reduced levels activation was seen in T1a lesions in prophylactic gas- of actin, p120ctn, or Lin in the progression of intramu- trectomy specimens from CDH1-mutation carriers; T1a cosal T1a lesions in CDH1 germline mutation carriers lesions from three out of four CDH1 mutation carriers [14]. Loss of p120ctn is a pro-tumorigenic driver event from different HDGC families with different truncating in epithelial cancers with augmentation of EGFR signal- CDH1 mutations harbored activation of mTOR (meas- ing in breast cancer, elevated levels and activation states ured by staining with anti-phospho-mTOR Ser2448) and of c-Src kinase and FAK have been found to be associ- catenin (measured by increased nuclear catenin staining) ated with accelerated progression and shorter survival in [9]. Thus, activation of PI3K-mTOR signaling in CDH1- epithelial malignancies including gastric cancer [31–33]. deficient gastric cancer cells might be the result of mul - Inhibition of the Src kinase–FAK pathway can restore cell tiple signal transduction aberrations including lack of adhesion, reduce cell migration, and promote an epithe- suppression of ligand-mediated EGFR activation (Fig.  1) lial phenotype [34]. or lack of negative feedback inhibition of the PI3K–Akt Activation of the EGFR downstream PI3K-mTOR axis via reduced PTEN levels (Fig. 2). pathway in CDH1-mutant cells may also be caused by the disruption of a negative feedback group of β-catenin Conclusions −/− and PTEN [35]. E-Cadherin loss is associated with Drug screening studies in isogenic CDH1 -mutant enhanced nuclear β-catenin translocation, suppression mammary epithelial MCF10A and c.1380delA CDH1- of nuclear expression of EGR-1 and PTEN, and increased mutant gastric cancer cells show considerable overlap in Li et al. Clin Trans Med (2018) 7:7 Page 5 of 6 E-Cadherin exerts direct and indirect negative regulation onto EGFR signaling, supporting blockade of the EGFR– PI3K kinase axis as therapy in this molecular subtype of gastric cancer. Considering that both anti-mTOR, anti- PI3K, and anti-EGFR therapies are already in routine clinical use or in late clinical development for a number of other cancer histologies, these observations suggest that PI3K and mTOR inhibitors may be considered for molecular-targeted therapies within clinical studies for patients with HDGC in the near future. Abbreviations ALK: anaplastic lymphoma receptor tyrosine kinase; CDH1: E-cadherin; DAG: diacylglycerol; EGFR: epidermal growth factor receptor; EMT: epithelial–mes- enchymal transition; ERK: extracellular signal regulated kinase; FAK: focal adhe- sion kinase; HDGC: hereditary diffuse gastric cancer; IP3: inositol trisphosphate; JAK: janus kinase; MEK: mitogen-activated protein kinase; mTOR: mammalian target of rapamycin; PI3K: phosphatidylinositol 3-kinase; PKC: protein kinase C; STAT3: signal transducer and activator of transcription 3; TOPO2: topoisomer- ase II. Authors’ contributions DL conducted previous experiment with c.1380delA CDH1-mutant gastric cancer cells. DL, WL, and UR conceived and designed the clinical and transla- tional perspectives of drug screening, compiled the figures, and wrote paper. All authors read and approved the final manuscript. Author details Thoracic & Gastrointestinal Oncology Branch, National Cancer Institute, Bethesda, MD, USA. Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA. Acknowledgements We would like to thank Ms. Erina He, MScBMC Medical Illustrator and NIH Medical Arts for compilation of the illustrations. Competing interests The authors declare that they have no competing interests. Consent for publication Not applicable. Fig. 2 E-Cadherin/catenin–PI3K/AKT crosstalk. Release of nega- Ethics approval and consent to participate tive feedback inhibition of PI3K/AKT signaling via reduced PTEN Not applicable. expression through elevated nuclear β-catenin levels. Disruption of the E-cadherin/catenin complex induces nuclear translocation of β-catenin repressing Egr-1-mediated PTEN expression leading to Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- increased AKT activation lished maps and institutional affiliations. Received: 28 December 2017 Accepted: 31 January 2018 sensitivity to PI3K, mTOR, or ALK/ROS-1 like tyrosine kinase inhibition. These pharmacological vulnerabilities are supported by comparative synthetic lethality, gene expression, and correlative tissue studies in clinical speci- References 1. Kaurah P, MacMillan A, Boyd N et al (2007) Founder and recurrent CDH1 mens of CDH1 mutation carriers, which indicate select mutations in families with hereditary diffuse gastric cancer. JAMA perturbations of GPCR, actin-related, ERK1–ERK2, or 297:2360–2372 FAK and c-Src kinase activity as signaling alterations and 2. van der Post RS, Vogelaar IP, Carneiro F et al (2015) Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline possible targets selective for CDH1-mutant gastric can- CDH1 mutation carriers. J Med Genet 52:361–374 cer cells. These pharmacological vulnerabilities are also 3. Hansford S, Kaurah P, Li-Chang H et al (2015) Hereditary diffuse gastric supported by an improved understanding of the bidirec- cancer syndrome: CDH1 mutations and beyond. JAMA Oncol 1:23–32 tional cross-talk between E-cadherin/catenin and EGFR. Li et al. Clin Trans Med (2018) 7:7 Page 6 of 6 4. Pharoah PD, Guilford P, Caldas C (2001) Incidence of gastric cancer and 20. Seton-Rogers SE, Lu Y, Hines LM et al (2004) Cooperation of the ErbB2 breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary receptor and transforming growth factor beta in induction of migra- diffuse gastric cancer families. Gastroenterology 121:1348–1353 tion and invasion in mammary epithelial cells. Proc Natl Acad Sci USA 5. Benusiglio PR, Malka D, Rouleau E et al (2013) CDH1 germline mutations 101:1257–1262 and the hereditary diffuse gastric and lobular breast cancer syndrome: a 21. Lilien J, Balsamo J (2005) The regulation of cadherin-mediated adhesion multicentre study. J Med Genet 50:486–489 by tyrosine phosphorylation/dephosphorylation of beta-catenin. Curr 6. Richards FM, McKee SA, Rajpar MH et al (1999) Germline E-cadherin gene Opin Cell Biol 17:459–465 (CDH1) mutations predispose to familial gastric cancer and colorectal 22. Shiozaki H, Kadowaki T, Doki Y et al (1995) Eec ff t of epidermal growth cancer. Hum Mol Genet 8:607–610 factor on cadherin-mediated adhesion in a human oesophageal cancer 7. Frebourg T, Oliveira C, Hochain P et al (2006) Cleft lip/palate and CDH1/E- cell line. Br J Cancer 71:250–258 cadherin mutations in families with hereditary diffuse gastric cancer. J 23. Jones JL, Royall JE, Walker RA (1996) E-cadherin relates to EGFR expres- Med Genet 43:138–142 sion and lymph node metastasis in primary breast carcinoma. Br J Cancer 8. Benusiglio PR, Caron O, Consolino E et al (2013) Cleft lip, cleft palate, 74:1237–1241 hereditary diffuse gastric cancer and germline mutations in CDH1. Int J 24. Hoschuetzky H, Aberle H, Kemler R (1994) Beta-catenin mediates the Cancer 132:2470 interaction of the cadherin-catenin complex with epidermal growth fac- 9. Sabesan AZB, Lo W, Wu HH, Powers A, Sorber RA, Ravichandran R, Chen I, tor receptor. J Cell Biol 127:1375–1380 McDuffie LA, Quadri HS, Beane JD, Calzone K, Miettinen MK, Hewitt SM, 25. Bae GY, Choi SJ, Lee JS et al (2013) Loss of E-cadherin activates EGFR- Koh C, Heller T, Wacholder S, Rudloff U (2017) Association of CDH1 ger - MEK/ERK signaling, which promotes invasion via the ZEB1/MMP2 axis in mline variant location and cancer phenotype in families with hereditary non-small cell lung cancer. Oncotarget 4:2512–2522 diffuse gastric cancer (HDGC). J Med Genet (under review) 26. Qian X, Karpova T, Sheppard AM et al (2004) E-Cadherin-mediated adhe- 10. van der Post RS, Vogelaar IP, Manders P et al (2015) Accuracy of hereditary sion inhibits ligand-dependent activation of diverse receptor tyrosine diffuse gastric cancer testing criteria and outcomes in patients with a kinases. EMBO J 23:1739–1748 germline mutation in CDH1. Gastroenterology 149(897–906):e19 27. Mateus AR, Seruca R, Machado JC et al (2007) EGFR regulates RhoA-GTP 11. Corso G, Carvalho J, Marrelli D et al (2013) Somatic mutations and dele- dependent cell motility in E-cadherin mutant cells. Hum Mol Genet tions of the E-cadherin gene predict poor survival of patients with gastric 16:1639–1647 cancer. J Clin Oncol 31:868–875 28. Mateus AR, Simoes-Correia J, Figueiredo J et al (2009) E-Cadherin muta- 12. Chen I, Mathews-Greiner L, Li D et al (2017) Transcriptomic profiling and tions and cell motility: a genotype-phenotype correlation. Exp Cell Res quantitative high-throughput (qHTS) drug screening of CDH1 deficient 315:1393–1402 hereditary diffuse gastric cancer (HDGC) cells identify treatment leads for 29. Figueiredo J, Soderberg O, Simoes-Correia J et al (2013) The impor- familial gastric cancer. J Transl Med 15:92 tance of E-cadherin binding partners to evaluate the pathogenicity of 13. Telford BJ, Chen A, Beetham H et al (2015) Synthetic lethal screens E-cadherin missense mutations associated to HDGC. Eur J Hum Genet identify vulnerabilities in GPCR signaling and cytoskeletal organization in 21:301–309 E-cadherin-deficient cells. Mol Cancer Ther 14:1213–1223 30. Bremm A, Walch A, Fuchs M et al (2008) Enhanced activation of epider- 14. Humar B, Fukuzawa R, Blair V et al (2007) Destabilized adhesion in the mal growth factor receptor caused by tumor-derived E-cadherin muta- gastric proliferative zone and c-Src kinase activation mark the develop- tions. Cancer Res 68:707–714 ment of early diffuse gastric cancer. Cancer Res 67:2480–2489 31. Park JH, Lee BL, Yoon J et al (2010) Focal adhesion kinase (FAK) gene 15. Hazan RB, Norton L (1998) The epidermal growth factor receptor modu- amplification and its clinical implications in gastric cancer. Hum Pathol lates the interaction of E-cadherin with the actin cytoskeleton. J Biol 41:1664–1673 Chem 273:9078–9084 32. Lai IR, Chu PY, Lin HS et al (2010) Phosphorylation of focal adhesion 16. Ozawa M, Kemler R (1998) Altered cell adhesion activity by pervanadate kinase at Tyr397 in gastric carcinomas and its clinical significance. Am J due to the dissociation of alpha-catenin from the E-cadherin–catenin Pathol 177:1629–1637 complex. J Biol Chem 273:6166–6170 33. Schackmann RC, Klarenbeek S, Vlug EJ et al (2013) Loss of p120-catenin 17. Roura S, Miravet S, Piedra J et al (1999) Regulation of E-cadherin/catenin induces metastatic progression of breast cancer by inducing anoikis association by tyrosine phosphorylation. J Biol Chem 274:36734–36740 resistance and augmenting growth factor receptor signaling. Cancer Res 18. Yasmeen A, Bismar TA, Al Moustafa AE (2006) ErbB receptors and 73:4937–4949 epithelial-cadherin–catenin complex in human carcinomas. Future Oncol 34. Zhang S, Yu D (2012) Targeting Src family kinases in anti-cancer therapies: 2:765–781 turning promise into triumph. Trends Pharmacol Sci 33:122–128 19. Lu Z, Ghosh S, Wang Z et al (2003) Downregulation of caveolin-1 function 35. Lau MT, Klausen C, Leung PC (2011) E-Cadherin inhibits tumor cell by EGF leads to the loss of E-cadherin, increased transcriptional activity of growth by suppressing PI3K/Akt signaling via beta-catenin-Egr1-medi- beta-catenin, and enhanced tumor cell invasion. Cancer Cell 4:499–515 ated PTEN expression. Oncogene 30:2753–2766

Journal

Clinical and Translational MedicineSpringer Journals

Published: Feb 22, 2018

There are no references for this article.