Abstract

Cell adhesion is crucial for maintaining the structural integrity of epithelial tissues, particularly during embryonic development and differentiation. The Cadherin family, with E-cadherin at the forefront, plays a central role in mediating cell-to-cell contact and forming macromolecular complexes essential for adherens junctions (AJs). These complexes, including β-catenin, α-catenin and p120, contribute to the stability of epithelial tissues. Disruptions in the regulatory pathways of E-cadherin structures can lead to the loss of cell adhesion, directly impacting tumor progression. This often involves the reactivation of epithelial-to-mesenchymal transition (EMT), characterized by E-cadherin downregulation and “cadherin switch” leading to N-cadherin expression. N-cadherin facilitates interactions with the extracellular matrix, promoting cellular motility and invasion. Meningioma, a tumor that forms from the cells of the meninges, is particularly noteworthy for its involvement in EMT and the E-cadherin/β-catenin complex. This review explores into the mechanisms disrupting the E-cadherin/β-catenin complex, aiming to clear up the intricate relationship between these disruptions, the EMT process, and their collective impact on tumor progression. Special emphasis is placed on Meningioma, providing insights into specific molecular pathways influencing this tumor type.

Content

Exploring Meningioma Tumorigenesis via the E-Cadherin/β-Catenin Adhesion Odyssey

Flavio Bregu1, Alessandro Beghini1
1Department of Health Sciences, University of Milan, Milan, Italy

Correspondence:
flavio.bregu@studenti.unimi.it
alessandro.beghini@unimi.it

May 2024

Abstract
Cell adhesion is crucial for maintaining the structural integrity of epithelial tissues, particularly during embryonic development and differentiation. The Cadherin family, with E-cadherin at the forefront, plays a central role in mediating cell-to-cell contact and forming macromolecular complexes essential for adherens junctions (AJs). These complexes, including β-catenin, α-catenin and p120, contribute to the stability of epithelial tissues. Disruptions in the regulatory pathways of E-cadherin structures can lead to the loss of cell adhesion, directly impacting tumor progression. This often involves the reactivation of epithelial-to-mesenchymal transition (EMT), characterized by E-cadherin downregulation and “cadherin switch” leading to N-cadherin expression. N-cadherin facilitates interactions with the extracellular matrix, promoting cellular motility and invasion.
Meningioma, a tumor that forms from the cells of the meninges, is particularly noteworthy for its involvement in EMT and the E-cadherin/β-catenin complex. This review explores into the mechanisms disrupting the E-cadherin/β-catenin complex, aiming to clear up the intricate relationship between these disruptions, the EMT process, and their collective impact on tumor progression. Special emphasis is placed on Meningioma, providing insights into specific molecular pathways influencing this tumor type.

 
I.    Introduction
E-cadherin, a pivotal component of adherens junctions (AJs), plays a fundamental role in orchestrating the phenotypic organization of epithelial tissues ¹. Disruptions, such as the downregulation or endocytosis of E-cadherin beyond common structural functions, influences key signaling pathways such as the Hippo, Wnt, and TGF-β pathways ². The convoluted involvement of E-cadherin extends to the regulation of cell division, contributing to the phenomenon of contact inhibition of proliferation (CIP), which ensures the controlled and differentiated development of tissues ³.
In the context of cancer, the disruption of this regulatory mechanism is a common occurrence, impacting the delicate balance maintained by E-cadherin. Numerous studies have shed light on the correlation between E-cadherin dance regulated by the GSK-3β pathway, resulting in the maintenance of low cytoplasmic levels of β-catenin. However, in the presence of Wnt signaling, inhibition of this pathway activates the Wnt/β-catenin signaling cascade, a recognized major pro-tumorigenic pathway ^4,5. This intricate interplay between E-cadherin and β-catenin is not only vital for maintaining tissue homeostasis but also implicated in tumor progression. Loss of E-cadherin expression may lead to reactivation of epithelial-to-mesenchymal transition (EMT) during cancer progression ⁶.
EMT is a marker of various carcinomas, including ovary, breast, colon, and lung cancers; but also in Meningioma, conferring resistance to therapeutic interventions ⁶. Of particular interest is the role of EMT and the E-cadherin/β-catenin complex in the context of Meningioma tumor progression. Numerous studies have illustrated the correlation between E-cadherin expression and the invasiveness of Meningioma, emphasizing the various impact of these molecular processes ^7,8.

II.    E-Cadherin/β-Catenin-Complex
E-cadherin, an essential member of the cadherin family, plays a multifaceted role in both embryonic development and the maintenance of adult tissue homeostasis. Within the classical cadherin family (including five classes of proteins characterized by extracellular, transmembrane, and cytoplasmic domains featuring “cadherin repeats”), E-cadherin takes center stage ⁹. These “repeats” facilitate Ca2+-dependent interactions between adjacent cells, a fundamental process for preserving cellular polarity and ensuring the integrity of tissues ¹⁰.

2.1 Architecture of Adherens Junctions (AJs)
Examining the intricate structure of E-cadherin reveals its particular C-terminal catenin-binding domain (CBD), responsible for engaging β-catenin. Simultaneously, the membrane-proximal cadherin juxtamembrane domain (JMD) interacts with p120, another essential member of the catenin family. This dynamic interplay orchestrates the functions of adherens junctions (AJs) and their relationship with the cytoskeleton, contributing to the stability and functionality of epithelia ^11,12.
The molecular choreography continues as β-catenin forms associations with α-catenin, which, in turn, interacts with actin filaments. Notably, the allosteric nature of α-catenin  allows it to bind both the E-cadherin/β-catenin complex and actin, showcasing its versatility in assuming different conformational states. This dynamic interplay involves an ensemble cast of proteins, including vinculins, ZO-1, and EPLIN, collectively participating in the continuous remodeling of the complex's functions ^13,14. [Fig. 1]

Figure 1: The E-Cadherin/β-Catenin Complex Structure (simplified)
E-Cadherins cover the cell surface, endowing it with negative charges (thanks to the presence of oligosaccharide residues), while Ca2+ acts as a "glue" between two cadherins on different cells, allowing their adhesion.
In the absence of Ca2+, the unshielded negative charges of the cadherins would exert mutual electrostatic repulsion, preventing the approach between cells. The adhesion promoted by cadherins is homotypic, meaning it occurs between similar cells. [Figure created by the Authors using www.biorender.com]

2.2 Molecular roles of E-Cadherin/β-catenin
The dynamic nature of the E-cadherin/β-catenin complex extends beyond its structural role. It serves as a crucial hub for signal transduction, mediating diverse cellular pathways. One such pathway is the Hippo pathway, where E-cadherin interacts with Hippo signaling components to regulate cell proliferation and apoptosis. The Wnt pathway and the TGF-β pathway are linked to E-cadherin, influencing migration, invasion, and EMT ^15,16.
The versatile nature of p120 unfolds as it performs a dual role – not only stabilizing cell-to-cell contact by interacting with cytoskeletal components, but also acting as a transcription factor at the nuclear level.
The labyrinthine pathways of p120 and β-catenin reveal a nuclear correlation, underscoring the complex's involvement in different cellular processes, ranging from adhesion to cytoskeletal regulation and proliferation.

III.    From CDH1 gene to E-Cadherin
CDH1, a tumor suppressor gene, is responsible for encoding E-cadherin, and is vital in embryonic development, therefore its knockout can have severe consequences, potentially leading to lethality. The tumor suppressor role of CDH1 is underscored by both germinal and somatic mutations, increasing susceptibility to cancer development ¹⁷.

3.1 Repression of CDH1 (Knudson's two-hit hypothesis)
Notably, cancer cell lines often exhibit mutations in one CDH1 allele, with the second allele succumbing to the two-hit (Knudson’s) hypothesis, solidifying CDH1's significance in maintaining integrity and suppressing tumorigenesis ¹⁸. The transcriptional repression of CDH1, orchestrated by various factors, including SNAIL, ZEB, E12/E47, and SIP1, triggers the tortuous process of epithelial-mesenchymal transition (EMT), a hallmark of tumor progression ^19,20. [Fig. 2]

Figure 2: CDH1 mutations: E-Cadherin Silencing
The CDH1 gene is located on the short arm of chromosome 16 (16q22.1). Its multiple exons are transcribed into mRNA, which is then translated into the E-cadherin protein, which is involved in Adherens Junctions. Whereas EMT transcription factors, led by SNAIL proteins (but also by other factors, as shown on the right part of the figure), which initiate the transition by binding to specific regions on the CDH1 promoter. Furthermore, The Polycomb repressive complex 2 (PCR2), reinforces E-cadherin repression and activates mesenchymal genes. In detail, PCR2 methylates histone proteins in the shown region, contributing to the epigenetic regulation that underlies the epithelial-to-mesenchymal transition (EMT) process. [Figure created by the Authors using www.biorender.com]
3.2 E-cadherin and Growth Factors (GFs)
The dynamic interplay between E-cadherin and the epidermal growth factor receptor EGFR reveals a built association where E-cadherin acts as an inhibitor of the EGF maturation factor rhomboid protease , thereby exerting control over stem cell proliferation ²¹. Dysregulation of this delicate balance is implicated in tissue dysmorphogenesis and tumorigenesis, particularly in epithelial tumors characterized by elevated EGFR and E-cadherin levels. The reciprocal influence of growth factors (GFs) on E-cadherin levels further emphasizes the multifaceted nature of their interaction, impacting cell-to-cell contact and initiating events associated with the epithelial-mesenchymal transition (EMT) ^22,23.

IV.    Epithelia Mesenchymal Transition
Downregulation of E-cadherin culminates in the tortuous process of epithelial-mesenchymal transition (EMT), in which epithelial cells acquire a motile, mesenchymal phenotype. This transformative event is marked by the “cadherin switch”, distinctly characterized by the upregulation of N-cadherin expression, reflecting extensive gene reprogramming and convergence of signaling pathways crucial for tumor progression ^24,25.
4.1 The Cadherin Switch: Dynamics and Implications
Epithelial-mesenchymal transition (EMT) is a dynamic cellular program central to embryonic development and often pathologically reactivated in various diseases, especially cancer. One of its defining features is the cadherin switch, a molecular event characterized by the downregulation of E-cadherin and the upregulation of N-cadherin. This transition reflects extensive gene reprogramming and converging signaling pathways that significantly impact tissue homeostasis and facilitates tumorigenesis ^26,27.
Understanding the cadherin switch involves investigating the intricate regulation of E-cadherin and the emergence of N-cadherin. EMT transcription factors (EMT-TFs), SNAIL proteins represent the main molecules, orchestrate this switch by binding to specific regions on the CDH1 promoter. The recruitment of the Polycomb repressive complex 2 PCR2 further solidifies the repression of E-cadherin and activates mesenchymal genes. SNAIL1, a prominent member of the SNAIL family, is subject to regulation by diverse pathways, including Notch, β-catenin/TCF signaling, and growth factors, underscoring the complexity of the regulatory landscape governing the cadherin switch ^28-31.
Moreover, the cadherin switch is not a binary event but a spectrum, with cells exhibiting varying degrees of both epithelial and mesenchymal characteristics. This plasticity highlights the dynamic nature of EMT and its importance in developmental processes and disease progression. The implications of the cadherin switch, when explored in greater detail, provide valuable insights into the potential therapeutic interventions that can modulate EMT, offering avenues for precision medicine in cancer treatment ³².

4.2 SNAIL Transcription Factors: Conductors of the Cadherin Switch
In the realm of EMT regulation, SNAIL transcription factors (encoded by SNAI1 and SNAI2  genes) emerge as crucial players driving the repression of CDH1 and initiating the cascade of events leading to mesenchymal transformation. SNAIL1, in particular, exhibits a versatile role in orchestrating the cadherin switch. By binding to specific motifs on the CDH1 promoter, SNAIL1 initiates the recruitment of the Polycomb repressive complex 2 (PCR2), resulting in the epigenetic silencing of E-cadherin ³³.
The regulation of SNAIL1 expression is a finely tuned process involving diverse signaling pathways. The Notch pathway, known for its role in cell fate determination, influences SNAI1 expression, providing a link between developmental signaling and EMT. Additionally, the β-catenin/TCF signaling pathway and growth factors contribute to the upregulation of SNAIL1, further emphasizing the intricate network of interactions governing EMT ³⁴.

4.3 β-Catenin/TCF Signaling: Cellular Dynamics
The multifaceted role played by β-catenin introduces intricate layers of complexity to the regulatory dynamics of epithelial-mesenchymal transition (EMT). Its involvement in the Wnt signaling pathway establishes a crucial link between the extracellular microenvironment and the intracellular events of EMT ³⁵. Upon Wnt pathway activation, the inhibition of glycogen-synthase-kinase-3β (GSK-3β) prevents the degradation of β-catenin. Consequently, β-catenin translocates to the nucleus, where it interacts with transcription factors like T-cell factor and lymphoid enhancer factor (TCF/LEF), initiating the transcription of genes associated with cell proliferation, survival, and EMT ³⁶.


4.4 TGFβ/SMAD Signaling: Central Nexus in EMT Development
The Transforming Growth Factor β TGFβ emerges as a central player in supporting EMT during tumorigenesis. Operating through SMAD complexes, TGFβ influences various cellular processes, including the intricate regulation of E-cadherin expression and the promotion of mesenchymal traits ³⁷. The TGFβ/SMAD signaling pathway enhances the transcription of SNAI1, a pivotal EMT transcription factor, and collaborates with SMAD2-3/SMAD4 to transcriptionally repress CDH1 ³⁸. This synergy between SMAD proteins and EMT-transcription factors underscores the adaptable nature of EMT regulation ³⁹.
4.5 Intersections in EMT: Navigating the Regulatory Network
EMT does not arise from isolated signaling pathways but rather results from complex
influencing CDH1 repression and EMT development ^40,41. [Fig. 3]

Figure 3: Main Signaling Pathways leading to EMT
TGFβ signaling is a key player in EMT. Activation of TGF-β receptors leads to the phosphorylation of Smad proteins, which then translocate into the nucleus and regulate the transcription of EMT-related genes. TGF-β can also cooperate with Wnt/β-catenin and EGFR signaling to promote EMT.
Wnt/β-catenin signaling induces EMT-related transcription factors (e.g., Snail, Slug, Twist, Zeb), leading to the repression of E-Cadherin and activation of genes associated with a mesenchymal phenotype.
EGFR, a receptor tyrosine kinase, activates downstream pathways (such as Ras/Raf/MEK/ERK in orange, and PI3K/AKT/mTORC2 in green) upon ligand binding. Crosstalk between EGFR and Wnt/β-catenin pathways (in blue) can stabilize β-catenin, promoting its nuclear translocation and enhancing the transcription of EMT-related genes. Wnt signaling, a crucial regulator of the E-Cadherin/β-catenin pathway, controls β-catenin stability. In the absence of Wnt signaling, β-catenin undergoes ubiquitination and degradation. Upon Wnt ligand binding, the destruction complex is inhibited, allowing β-catenin to accumulate in the cytoplasm.
Accumulated β-catenin translocates to the nucleus, where it associates with T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors. This complex activates target genes, influencing cell proliferation, survival, and promoting EMT. Activation of Wnt/β-catenin signaling is linked to E-Cadherin downregulation. β-catenin, by disrupting interactions with E-Cadherin at adherens junctions, contributes to E-Cadherin loss.
In the E-Cadherin/β-catenin/Wnt pathway, β-catenin acts as a key adaptor, linking E-cadherin to the actin cytoskeleton and functioning prominently in Wnt signaling regulation. Under physiological conditions, β-catenin is kept inactive by the APC/GSK3β/Axin/CK1 degradation complex. Wnt signaling inhibits this degradation, leading to β-catenin translocation into the nucleus, inducing uncontrolled cell proliferation and growth. In the absence of E-Cadherin, excess un-sequestered cytoplasmic β-catenin can enter the nucleus, potentially activating Wnt pathway and repressing PTEN expression. E-Cadherin also influences EGFR/RAS/RAF/MEK pathways, inhibiting EGFR signaling. Loss of E-Cadherin correlates with increased nuclear translocation of β-catenin and activation of pro-tumorigenic pathways.
[Figure created by the Authors using www.biorender.com]

V.    Dysfunctions in Meningioma
Meningioma, a very frequent intracranial tumor, unveils a various landscape of polygenic factors contributing to its pathogenesis. Among these factors, dysfunction in the E-cadherin/β-catenin complex emerges as a key player, intricately linked to the progression of this tumor ^42,43.
This section delves into the foggy facets of Meningioma, shedding light on the main features that define its molecular landscape and drive its tumorigenic potential.

5.1 Chromosome 22 Deletions and NF2’s LOH
At its core, meningioma is characterized by distinct genetic aberrations, prominently featuring chromosome 22 deletions and neurofibromatosis type 2 NF2  gene’s loss of heterozygosity (LOH). The Merlin protein, a regulator of the E-cadherin/β-catenin complex, assumes a central role in maintaining the delicate balance of this adhesion complex. The inactivation of NF2 disrupts this equilibrium, contributing significantly to the dysregulation of cell adhesion and, consequently, the progression of meningiomas ^44,45.



5.2 E-Cadherin Rates Across Meningioma Grades
The E-cadherin/β-catenin complex orchestrates a dynamic role in the development of meningiomas, presenting varying incidence rates across different tumor grades. Notably, higher-grade meningiomas exhibit a marked decrease in E-cadherin positivity, a phenomenon that holds implications for the tumor's aggressiveness ⁴⁶. Studies further underscore the correlation between reduced E-cadherin levels and heightened cellular proliferation and invasiveness, underlining the crosstalk between various molecular networks. The convergence of TGFβ, β-catenin, and other pathways creates a dynamic regulatory landscape, influencing the development and stability of EMT. The interplay between TGFβ and β-catenin is particularly notable, with TGFβ enhancing β-catenin's nuclear activity, showcasing their collaboration in orchestrating EMT. Additionally, GSK-3β interacts with SNAIL1, illustrating the interconnectedness of diverse regulatory elements in driving EMT. The PI3K/AKT/mTOR complex, known for its role in cell survival and proliferation, modulates GSK-3β stability, thereby strong interplay between cell adhesion dynamics and meningioma progression.
 
5.3 EMT, Cadherin Switch, and Wnt Pathway Activation in Meningioma
The intricate molecular ballet within Meningioma includes the “Cadherin-Switch”, a hallmark of epithelial-mesenchymal transition (EMT), as seen in more detail in section IV. This transition involves heightened N-cadherin expression and the involvement of several transcription factors. Moreover, the activation of the Wnt pathway in meningiomas is actively linked to increased β-catenin function, a focal player in stimulating cell proliferation and oncogene synthesis ⁴⁷. This activation is further associated with increased β-catenin expression, potentially impeding apoptosis ³⁵.
Reviewing and understanding these molecular intricacies not only enhances our understanding of meningioma molecular biology, but also presents potential avenues for targeted therapeutic interventions aimed at modulating these deregulated signaling pathways associated with aggressive tumor phenotypes. [Fig. 4]

Figure 4: ETM stages in Meningioma (from microscopic to macroscopic)
We investigated the expression of E-Cadherin, and EMT-related transcription factors in meningiomas to explore their association with this tumor. In aggressive meningiomas displayed altered expression (loss of E-Cadherin, increased SNAIL1/2, Zeb-1/2, Twist, Slug), leads, as seen in the previous figure, to molecular features of EMT. TGFβ induced EMT by increasing EMT-related transcription factors.
Before this molecular changes occur, we have a physiological situation in the epithelia (stage 0 in the figure).
Within Meningioma, a complex molecular ballet unfolds, featuring the prominent “Cadherin-Switch”, involving also other cellular protein related to membrane-junctions, such as occludin, claudin, connexin and integin (stage 1 in the figure). This transformative process involves heightened expression of N-cadherin (in yellow) and the repression of E-Cadherin (in light-blue) due to various transcription factors. Furthermore, after the complete “switch” of N-cadherin instead of E-cadherin, the cell is considerable mesenchymal as it has occurred a “complete” ETM (stage 2 in the figure). It may, unfortunaly, lead to metastasis (stage 3 in the figure) and diffusion in the cranial theca, reaching and growing (usually) in particular regions (shown on the upper left part of the figure).
[Figure created by the Authors using www.biorender.com]

VI.    CONCLUSIONS
In summary, the E-cadherin/β-catenin complex emerges as a anchor in maintaining the delicate equilibrium of epithelial homeostasis, orchestrating different cellular pathways. The distinguishable cadherin switch, essentially an indication of Epithelial-to-Mesenchymal Transition (EMT), opens a setting of heightened invasiveness and metastatic potential, underscoring the complex's profound impact on cellular behavior.
Digging into the realm of Meningioma, the perturbations within the E-cadherin/β-catenin complex manifest as critical determinants of tumor progression.
Explaining the molecular reasons of E-cadherin/β-catenin dysregulation not only enriches our understanding of meningioma but also provides a roadmap for innovative treatment modalities. Future research avenues may explore the therapeutic potential of modulating this complex, offering promising prospects for mitigating the impact of meningioma and, perhaps, extending to other tumors sharing similar molecular substructure.
 
VII.    REFERENCES:

[1] Mendonsa AM, Na TY, Gumbiner BM. E-cadherin in contact inhibition and cancer. Oncogene. 2018 Aug;37(35):4769-4780. doi: 10.1038/s41388-018-0304-2. Epub 2018 May 21. PMID: 29780167; PMCID: PMC6119098.

[2] Lin WH, Cooper LM, Anastasiadis PZ. Cadherins and catenins in cancer: connecting cancer pathways and tumor microenvironment. Front Cell Dev Biol. 2023 May 15;11:1137013. doi: 10.3389/fcell.2023.1137013. PMID: 37255594; PMCID: PMC10225604..

[3] McClatchey AI, Yap AS. Contact inhibition (of proliferation) redux. Curr Opin Cell Biol. 2012 Oct;24(5):685-94. doi: 10.1016/j.ceb.2012.06.009. Epub 2012 Jul 24. PMID: 22835462.

[4] Balamurugan K, Poria DK, Sehareen SW, Krishnamurthy S, Tang W, McKennett L, Padmanaban V, Czarra K, Ewald AJ, Ueno NT, Ambs S, Sharan S, Sterneck E. Stabilization of E-cadherin adhesions by COX-2/GSK3β signaling is a targetable pathway in metastatic breast cancer. JCI Insight. 2023 Mar 22;8(6):e156057. doi: 10.1172/jci.insight.156057. PMID: 36757813; PMCID: PMC10070121.

[5] Ng LF, Kaur P, Bunnag N, Suresh J, Sung ICH, Tan QH, Gruber J, Tolwinski NS. WNT Signaling in Disease. Cells. 2019 Aug 3;8(8):826. doi: 10.3390/cells8080826. PMID: 31382613; PMCID: PMC6721652.

[6] Kaszak I, Witkowska-Piłaszewicz O, Niewiadomska Z, Dworecka-Kaszak B, Ngosa Toka F, Jurka P. Role of Cadherins in Cancer-A Review. Int J Mol Sci. 2020 Oct 15;21(20):7624. doi: 10.3390/ijms21207624. PMID: 33076339; PMCID: PMC7589192.

[7] Mohamed H, Haglund C, Jouhi L, Atula T, Hagström J, Mäkitie A. Expression and Role of E-Cadherin, β-Catenin, and Vimentin in Human Papillomavirus-Positive and Human Papillomavirus-Negative Oropharyngeal Squamous Cell Carcinoma. J Histochem Cytochem. 2020 Sep;68(9):595-606. doi: 10.1369/0022155420950841. Epub 2020 Aug 14. PMID: 32794417; PMCID: PMC7469711.

[8] Nives Pecina-Slaus,  Tatjana Cicvara-Pecina,  Anja Kafka. Epithelial-to-mesenchymal transition: possible role in meningiomas. Front. Biosci. (Elite Ed) 2012, 4(3), 889-896

[9] Sisto, M.; Ribatti, D.; Lisi, S. E-Cadherin Signaling in Salivary Gland Development and Autoimmunity. J. Clin. Med. 2022, 11, 2241. https://doi.org/10.3390/jcm11082241 (link available on 8th of January 2024)

[10] Kong D, Großhans J. Planar Cell Polarity and E-Cadherin in Tissue-Scale Shape Changes in Drosophila Embryos. Front Cell Dev Biol. 2020 Dec 23;8:619958. doi: 10.3389/fcell.2020.619958. PMID: 33425927; PMCID: PMC7785826.

[11] Kourtidis A, Ngok SP, Anastasiadis PZ. p120 catenin: an essential regulator of cadherin stability, adhesion-induced signaling, and cancer progression. Prog Mol Biol Transl Sci. 2013;116:409-32. doi: 10.1016/B978-0-12-394311-8.00018-2. PMID: 23481205; PMCID: PMC4960658.

[12] Shapiro L, Weis WI. Structure and biochemistry of cadherins and catenins. Cold Spring Harb Perspect Biol. 2009 Sep;1(3):a003053. doi: 10.1101/cshperspect.a003053. PMID: 20066110; PMCID: PMC2773639.

[13] Knudsen KA, Soler AP, Johnson KR, Wheelock MJ. Interaction of alpha-actinin with the cadherin/catenin cell-cell adhesion complex via alpha-catenin. J Cell Biol. 1995 Jul;130(1):67-77. doi: 10.1083/jcb.130.1.67. PMID: 7790378; PMCID: PMC2120515.

[14] Rubtsova SN, Zhitnyak IY, Gloushankova NA. Dual role of E-cadherin in cancer cells. Tissue Barriers. 2022 Oct 2;10(4):2005420. doi: 10.1080/21688370.2021.2005420. Epub 2021 Nov 25. PMID: 34821540; PMCID: PMC9621038.

[15] Wu G, Huang H, Garcia Abreu J, He X. Inhibition of GSK3 phosphorylation of beta-catenin via phosphorylated PPPSPXS motifs of Wnt coreceptor LRP6. PLoS One. 2009;4(3):e4926. doi: 10.1371/journal.pone.0004926. Epub 2009 Mar 18. PMID: 19293931; PMCID: PMC2654145.

[16] Qin K, Yu M, Fan J, Wang H, Zhao P, Zhao G, Zeng W, Chen C, Wang Y, Wang A, Schwartz Z, Hong J, Song L, Wagstaff W, Haydon RC, Luu HH, Ho SH, Strelzow J, Reid RR, He TC, Shi LL. Canonical and noncanonical Wnt signaling: Multilayered mediators, signaling mechanisms and major signaling crosstalk. Genes Dis. 2023 Mar 24;11(1):103-134. doi: 10.1016/j.gendis.2023.01.030. PMID: 37588235; PMCID: PMC10425814..

[17] Berx G, Becker KF, Höfler H, van Roy F. Mutations of the human E-cadherin (CDH1) gene. Hum Mutat. 1998;12(4):226-37. doi: 10.1002/(SICI)1098-1004(1998)12:4<226::AID-HUMU2>3.0.CO;2-D. PMID: 9744472.

[18] Luo W, Fedda F, Lynch P, Tan D. CDH1 Gene and Hereditary Diffuse Gastric Cancer Syndrome: Molecular and Histological Alterations and Implications for Diagnosis and Treatment. Front Pharmacol. 2018 Dec 5;9:1421. doi: 10.3389/fphar.2018.01421. PMID: 30568591; PMCID: PMC6290068.

[19] Bolós V, Peinado H, Pérez-Moreno MA, Fraga MF, Esteller M, Cano A. The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors. J Cell Sci. 2003 Feb 1;116(Pt 3):499-511. doi: 10.1242/jcs.00224. Erratum in: J Cell Sci. 2016 Mar 15;129(6):1283. PMID: 12508111.

[20] Wang Y, Shi J, Chai K, Ying X, Zhou BP. The Role of Snail in EMT and Tumorigenesis. Curr Cancer Drug Targets. 2013 Nov;13(9):963-972. doi: 10.2174/15680096113136660102. PMID: 24168186; PMCID: PMC4004763.

[21] Rübsam M, Mertz AF, Kubo A, et al. E-cadherin integrates mechanotransduction and EGFR signaling to control junctional tissue polarization and tight junction positioning. Nature Communications. 2017 Nov;8(1):1250. DOI: 10.1038/s41467-017-01170-7. PMID: 29093447; PMCID: PMC5665913.

[22] Adrain C, Strisovsky K, Zettl M, Hu L, Lemberg MK, Freeman M. Mammalian EGF receptor activation by the rhomboid protease RHBDL2. EMBO Rep. 2011 May;12(5):421-7. doi: 10.1038/embor.2011.50. Epub 2011 Apr 15. PMID: 21494248; PMCID: PMC3090019.

[23] Arnaud T, Rodrigues-Lima F, Viguier M, Deshayes F. Interplay between EGFR, E-cadherin, and PTP1B in epidermal homeostasis. Tissue Barriers. 2023 Jul 3;11(3):2104085. doi: 10.1080/21688370.2022.2104085. Epub 2022 Jul 24. PMID: 35875939; PMCID: PMC10364651.

[24] Ramírez Moreno M, Bulgakova NA. The Cross-Talk Between EGFR and E-Cadherin. Front Cell Dev Biol. 2022 Jan 20;9:828673. doi: 10.3389/fcell.2021.828673. PMID: 35127732; PMCID: PMC8811214.

[25] Aban CE, Lombardi A, Neiman G, Biani MC, La Greca A, Waisman A, Moro LN, Sevlever G, Miriuka S, Luzzani C. Downregulation of E-cadherin in pluripotent stem cells triggers partial EMT. Sci Rep. 2021 Jan 21;11(1):2048. doi: 10.1038/s41598-021-81735-1. PMID: 33479502; PMCID: PMC7820496.

[26] Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014 Mar;15(3):178-96. doi: 10.1038/nrm3758. PMID: 24556840; PMCID: PMC4240281.

[27] Kim DH, Xing T, Yang Z, Dudek R, Lu Q, Chen YH. Epithelial Mesenchymal Transition in Embryonic Development, Tissue Repair and Cancer: A Comprehensive Overview. J Clin Med. 2017 Dec 22;7(1):1. doi: 10.3390/jcm7010001. PMID: 29271928; PMCID: PMC5791009.

[28] Gheldof A, Berx G. Cadherins and epithelial-to-mesenchymal transition. Prog Mol Biol Transl Sci. 2013;116:317-36. doi: 10.1016/B978-0-12-394311-8.00014-5. PMID: 23481201.

[29] Schäfer G, Narasimha M, Vogelsang E, Leptin M. Cadherin switching during the formation and differentiation of the Drosophila mesoderm - implications for epithelial-to-mesenchymal transitions.
J Cell Sci. 2014 Apr 1;127(Pt 7):1511-22. doi: 10.1242/jcs.139485. Epub 2014 Feb 4. PMID: 24496448.

[30] Jen-Jung Pan, Muh-Hwa Yang The role of epithelial-mesenchymal transition in pancreatic cancer
J Gastrointest Oncol 2011; 2: 151-156. DOI: 10.3978/j.issn.2078-6891.2011.022

[31] Herranz N, Pasini D, Díaz VM, Francí C, Gutierrez A, Dave N, Escrivà M, Hernandez-Muñoz I, Di Croce L, Helin K, García de Herreros A, Peiró S. Polycomb complex 2 is required for E-cadherin repression by the Snail1 transcription factor. Mol Cell Biol. 2008 Aug;28(15):4772-81. doi: 10.1128/MCB.00323-08. Epub 2008 Jun 2. PMID: 18519590; PMCID: PMC2493371.

[32] Fischer, S., Weber, L.M. & Liefke, R. Evolutionary adaptation of the Polycomb repressive complex 2. Epigenetics & Chromatin 15, 7 (2022). https://doi.org/10.1186/s13072-022-00439-6

[33] Gloushankova NA, Rubtsova SN, Zhitnyak IY. Cadherin-mediated cell-cell interactions in normal and cancer cells. Tissue Barriers. 2017 Jul 3;5(3):e1356900. doi: 10.1080/21688370.2017.1356900. Epub 2017 Jul 20. PMID: 28783415; PMCID: PMC5571778.

[34] Serrano-Gomez SJ, Maziveyi M, Alahari SK. Regulation of epithelial-mesenchymal transition through epigenetic and post-translational modifications. Mol Cancer. 2016 Feb 24;15:18. doi: 10.1186/s12943-016-0502-x. PMID: 26905733; PMCID: PMC4765192.

[35] Kaufhold S, Bonavida B. Central role of Snail1 in the regulation of EMT and resistance in cancer: a target for therapeutic intervention. J Exp Clin Cancer Res. 2014 Aug 2;33(1):62. doi: 10.1186/s13046-014-0062-0. PMID: 25084828; PMCID: PMC4237825.

[36] Valenta T, Hausmann G, Basler K. The many faces and functions of β-catenin. EMBO J. 2012 Jun 13;31(12):2714-36. doi: 10.1038/emboj.2012.150. Epub 2012 May 22. PMID: 22617422; PMCID: PMC3380220.

[37] Wu D, Pan W. GSK3: a multifaceted kinase in Wnt signaling. Trends Biochem Sci. 2010 Mar;35(3):161-8. doi: 10.1016/j.tibs.2009.10.002. Epub 2009 Oct 31. PMID: 19884009; PMCID: PMC2834833.

[38] Miyazono K. Transforming growth factor-beta signaling in epithelial-mesenchymal transition and progression of cancer. Proc Jpn Acad Ser B Phys Biol Sci. 2009;85(8):314-23. doi: 10.2183/pjab.85.314. PMID: 19838011; PMCID: PMC3621568.

[39] Vincent T, Neve EP, Johnson JR, Kukalev A, Rojo F, Albanell J, Pietras K, Virtanen I, Philipson L, Leopold PL, Crystal RG, de Herreros AG, Moustakas A, Pettersson RF, Fuxe J. A SNAIL1-SMAD3/4 transcriptional repressor complex promotes TGF-beta mediated epithelial-mesenchymal transition. Nat Cell Biol. 2009 Aug;11(8):943-50. doi: 10.1038/ncb1905. Epub 2009 Jul 13. PMID: 19597490; PMCID: PMC3769970.

[40] Valcourt U, Kowanetz M, Niimi H, Heldin CH, Moustakas A. TGF-beta and the Smad signaling pathway support transcriptomic reprogramming during epithelial-mesenchymal cell transition. Mol Biol Cell. 2005 Apr;16(4):1987-2002. doi: 10.1091/mbc.e04-08-0658. Epub 2005 Feb 2. PMID: 15689496; PMCID: PMC1073677.

[41] Zheng H, Li W, Wang Y, Liu Z, Cai Y, Xie T, Shi M, Wang Z, Jiang B. Glycogen synthase kinase-3 beta regulates Snail and β-catenin expression during Fas-induced epithelial-mesenchymal transition in gastrointestinal cancer. Eur J Cancer. 2013 Aug;49(12):2734-46. doi: 10.1016/j.ejca.2013.03.014. Epub 2013 Apr 9. PMID: 23582741.

[42] Guo Y, Gupte M, Umbarkar P, Singh AP, Sui JY, Force T, Lal H. Entanglement of GSK-3β, β-catenin and TGF-β1 signaling network to regulate myocardial fibrosis. J Mol Cell Cardiol. 2017 Sep;110:109-120. doi: 10.1016/j.yjmcc.2017.07.011. Epub 2017 Jul 27. PMID: 28756206; PMCID: PMC5581678.

[43] Pećina-Šlaus N, Kafka A, Lechpammer M. Molecular Genetics of Intracranial Meningiomas with Emphasis on Canonical Wnt Signalling. Cancers (Basel). 2016 Jul 15;8(7):67. doi: 10.3390/cancers8070067. PMID: 27429002; PMCID: PMC4963809.

[44] Wang JZ, Nassiri F, Landry AP, Patil V, Liu J, Aldape K, Gao A, Zadeh G. The multiomic landscape of meningiomas: a review and update. J Neurooncol. 2023 Jan;161(2):405-414. doi: 10.1007/s11060-023-04253-2. Epub 2023 Feb 25. PMID: 36840836; PMCID: PMC9988797.

[45] Wellenreuther R, Kraus JA, Lenartz D, Menon AG, Schramm J, Louis DN, Ramesh V, Gusella JF, Wiestler OD, von Deimling A. Analysis of the neurofibromatosis 2 gene reveals molecular variants of meningioma. Am J Pathol. 1995 Apr;146(4):827-32. PMID: 7717450; PMCID: PMC1869258.

[46] Kirches E, Sahm F, Korshunov A, Bluecher C, Waldt N, Kropf S, Schrimpf D, Sievers P, Stichel D, Schüller U, Schittenhelm J, Riemenschneider MJ, Karajannis MA, Perry A, Pietsch T, Boekhoff S, Capper D, Beck K, Paramasivam N, Schlesner M, Brastianos PK, Müller HL, Pfister SM, Mawrin C. Molecular profiling of pediatric meningiomas shows tumor characteristics distinct from adult meningiomas. Acta Neuropathol. 2021 Nov;142(5):873-886. doi: 10.1007/s00401-021-02351-x. Epub 2021 Sep 8. PMID: 34495383; PMCID: PMC8500891.

[47] Brunner EC, Romeike BF, Jung M, Comtesse N, Meese E. Altered expression of beta-catenin/E-cadherin in meningiomas. Histopathology. 2006 Aug;49(2):178-87. doi: 10.1111/j.1365-2559.2006.02440.x. PMID: 16879395.

[48] Manfreda L, Rampazzo E, Persano L. Wnt Signaling in Brain Tumors: A Challenging Therapeutic Target. Biology (Basel). 2023 May 16;12(5):729. doi: 10.3390/biology12050729. PMID: 37237541; PMCID: PMC10215617.