The Wnt/β-catenin signaling pathway plays fundamental roles during development, stem cell differentiation, and homeostasis, and its abnormal activation can lead to diseases. In recent years, it has become clear that this pathway integrates signals not only from Wnt ligands but also from other proteins and signaling routes. For instance, Wnt/β-catenin signaling involves YAP and TAZ, which are transcription factors with crucial roles in mechanotransduction. On the other hand, Wnt/β-catenin signaling is also modulated by integrins. Therefore, mechanical signals might similarly modulate the Wnt/β-catenin pathway. However, and despite the relevance that mechanosensitive Wnt/β-catenin signaling might have during physiology and diseases such as cancer, the role of mechanical cues on Wnt/β-catenin signaling has received less attention. This review aims to summarize recent evidence regarding the modulation of the Wnt/β-catenin signaling by a specific type of mechanical signal, the stiffness of the extracellular matrix. The review shows that mechanical stiffness can indeed modulate this pathway in several cell types, through differential expression of Wnt ligands, receptors and inhibitors, as well as by modulating β-catenin levels. However, the specific mechanisms are yet to be fully elucidated.

Introduction

The Wnt signaling pathway plays crucial roles during stem cell differentiation, embryonic development, and homeostasis [1]. The pathway is composed of secreted Wnt ligands and modulators, membrane receptors and co-receptors, and intracellular effectors, ultimately leading to changes in gene expression and cell behavior by activating a collection of intracellular pathways.

Some Wnt ligands, such as Wnt1 and Wnt3a, activate intracellular signaling that depends on the stabilization of β-catenin. β-Catenin responds to the activation of the Wnt pathway by translocating to the nucleus, modulating gene expression together with members of the TCF/LEF family of transcription factors [2]. Concomitantly, this branch is usually referred to as the ‘Wnt/β-catenin pathway’ (or ‘canonical Wnt pathway’). Moreover, β-catenin binds to cadherins and α-catenin at adherens junctions (AJs) [3].

In contrast, other Wnt ligands, such as Wnt5a or Wnt11, signal through other intracellular effectors, such as calcium, JNK, and small GTPases Rho and Rac [4], leading to several ‘β-catenin independent’ signaling pathways [5]. However, the ultimate response to a specific Wnt ligand depends on the cellular context, and non-canonical Wnt ligands, particularly Wnt5a, can also activate β-catenin-dependent signaling [6].

The Wnt/β-catenin pathway relies on the binding of Wnt ligands to Frizzled receptors and LRP5/6 co-receptors at the cell surface. In the absence of Wnt ligands, ZNRF3/RNF43 ubiquitin ligases promote the ubiquitination and subsequent degradation of Frizzled receptors. In this context, β-catenin is mainly located at AJs, while the remaining pool of β-catenin is bound to a destruction complex, where becomes phosphorylated, ubiquitinated, and targeted for proteasomal degradation.

Upon binding of Wnt ligands, the cytoplasmic domain of LRP5/6 becomes phosphorylated, which leads to the translocation of the β-catenin destruction complex to the cytoplasmic side of the plasma membrane. In turn, this leads to the formation of a so-called signalosome that is internalized and targeted to multi-vesicular bodies [7–10]. Consequently, the β-catenin destruction complex is unable to target newly synthesized β-catenin for degradation. This stabilized pool of β-catenin can then translocate to the nucleus, where it binds to TCF/LEF transcription factors and activates the transcription of genes through binding to specific regulatory sequences [11]. In addition, other secreted proteins can potentiate or inhibit the pathway. For instance, R-spondin proteins bind to LGR4/5/6 receptors [12,13] and induce inactivation of the ZNRF3/RNF43 ubiquitin ligases [14,15], thus promoting activation of the pathway. In contrast, secreted inhibitors, such as WIF1 (Wnt inhibitory factor 1), DKK (Dickkopf), and sFRP (secreted Frizzled-related protein) proteins, inhibit the pathway through several mechanisms [16]. Finally, intracellular proteins, such as Dishevelled (Dvl), Axin, APC, and GSK-3β, play different roles along the Wnt/β-catenin pathway.

Given the crucial role of the Wnt/β-catenin pathway during development and homeostasis, alterations in the levels or activity of Wnt/β-catenin pathway components can lead to diseases, such as cancer. Mutations in genes encoding Wnt components, such as APC or CTNNB1, can lead to persistent activation of the pathway [17]. On the other hand, alterations at the level of AJs (such as mutations in CDH1, the gene encoding E-cadherin 1) can lead to AJ destabilization and release of the membrane pool of β-catenin, which in turn can translocate to the nucleus. The relationship between cadherin function and Wnt/β-catenin signaling is well known and has been reviewed elsewhere [18,19]. In addition, the Wnt/β-catenin pathway also influences stem cell differentiation [20], and alterations can also lead to diseases. For instance, mutations in Wnt/β-catenin components lead to bone defects, partly due to abnormal osteogenic differentiation of mesenchymal stem cells (reviewed in [21]).

Wnt/β-catenin signaling in the context of mechanosensing

Given the consequences of alterations in Wnt/β-catenin signaling, it is of paramount relevance to understanding the possible connections with other signaling routes that might affect Wnt/β-catenin outcomes. Cells are exposed in vivo to a variety of intrinsic and extrinsic mechanical signals, such as tensile and compressive forces, pressure, and shear stress [22–24], and these influence the behavior of cells during embryonic development and tissue homeostasis [25,26], mainly through cell–cell and cell–ECM adhesions [27,28]. In this regard, the role of the elastic (Young's) modulus, or stiffness, of the extracellular matrix (ECM) is of great interest. In cancer, matrix stiffening in the tumor microenvironment (TME) due to increased collagen cross-linking and deposition is commonly observed [29]. On the other hand, stem cells also need to respond to the local stiffness, which varies across tissues and organs. In consequence, the stiffness of the substrate influences cancer cell and stem cell behavior [30,31]. In addition to increased ECM stiffness, cell confinement, axial stretching, and pressure are also observed during developmental and pathological processes, including morphogenetic movements and tumor development. These mechanical cues can modulate specific aspects of the Wnt/β-catenin pathway. The effect of some of these forces, particularly strain, shear stress, and mechanical loading on the Wnt/β-catenin pathway has been reviewed recently [32], as well as the specific effect of these forces on β-catenin [33]. Therefore, discussing the effect of these types of mechanical forces on Wnt/β-catenin signaling is beyond the scope of this review. On the other hand, the role of the stiffness of the ECM on the Wnt/β-catenin pathway has received less attention. The purpose of this review, therefore, is to summarize recent findings regarding the influence of ECM stiffness on specific aspects of the Wnt/β-catenin pathway, from Wnt ligands and receptors to β-catenin.

Cells sense mechanical cues from the ECM through integrins [28,34], which bind to the ECM and form integrin-adhesion complexes (IACs) that comprise proteins involved in structural and signaling roles, thereby coupling the mechanical environment to intracellular signaling pathways [35]. Integrins rely on several linker proteins, including Vinculin, Talin, Kindlin, and the IPP (ILK; PINCH and Parvin) complex, leading to activation of SRC family kinases (SFK) and FAK, further activating downstream pathways [36,37]. Collective evidence suggests a relationship between the ECM, integrin signaling, and the Wnt pathway, as it has been discussed elsewhere [38].

In addition to integrins and their downstream effectors, the transcription factors YAP and TAZ have been identified as major mechanotransducers [39]. Unsurprisingly, YAP and TAZ are also implicated in cancer establishment [40,41] and stem cell differentiation [42]. YAP and TAZ have been extensively associated with the Wnt pathway in recent years. Both YAP and TAZ physically interact with Dvl. Dvl binds to phosphorylated YAP, modulating its localization [43]; on the other hand, TAZ binds to Dvl and inhibits Wnt/β-catenin signaling [44]. Moreover, TAZ is kept at low levels through the action of the β-catenin destruction complex. In contrast, β-catenin and TAZ become stabilized upon activation of the Wnt/β-catenin pathway [45]. Furthermore, the β-catenin degradation complex binds both YAP and TAZ, thus acting as a ‘sink’ [46]. Of note, TAZ also transduces the Wnt signal [45]. Finally, YAP and TAZ can retain β-catenin in the cytoplasm, thus preventing Wnt/β-catenin signaling [47].

Despite the growing body of evidence linking the ECM stiffness, integrins, and YAP/TAZ, the relationship between Wnt/β-catenin signaling and ECM stiffness has remained poorly understood. However, there is a growing body of evidence demonstrating that the stiffness of the ECM can indeed modulate the Wnt/β-catenin pathway, although the specific effect varies depending on the cell type.

Modulation of β-catenin signaling in response to substrate stiffness

Secretion of Wnt ligands in response to ECM stiffness

A first mechanism by which mechanical signals might influence Wnt/β-catenin signaling is by modulating the secretion of Wnt ligands (Figure 1). In this regard, two articles have reported differential expression of Wnt ligands in response to substrate stiffness. One study in human embryonic stem cells (hESCs) shows that cells cultured on soft substrates (0.4 kPa), which mimic the elasticity of embryonic gastrula tissue, induce higher expression of Wnt3a, which activates Wnt/β-catenin signaling [48].

Modulation of Wnt/β-catenin signaling by secreted ligands and inhibitors.

Figure 1.
Modulation of Wnt/β-catenin signaling by secreted ligands and inhibitors.

In some cells, such as hESCs [48], compliant environments might induce secretion of Wnt3a (left side of the figure). In this scenario, Frizzled receptors and LRP5/6 co-receptors can bind Wnt3a, resulting in the inhibition of the β-catenin destruction complex. Newly synthesized β-catenin, or β-catenin released from the membrane-bound pool located at AJs, can then translocate to the nucleus to induce the transcription of TCF/LEF target genes (‘WNT-ON’). On stiff environments (right side of the figure), integrins will activate intracellular signaling, possibly through IACs components, such as Src and FAK. This might result in the inhibition of Wnt ligands, either at the mRNA or protein (secretion) level. In addition, Wnt/β-catenin inhibitors, such as DKK1 or sFRP1, can also be expressed; these will inhibit Wnt/β-catenin signaling at the receptor level, thus resulting in the activation of the β-catenin destruction complex and β-catenin degradation (‘WNT-OFF’). For simplicity, some proteins are omitted in the figure. See the main text for details.

Figure 1.
Modulation of Wnt/β-catenin signaling by secreted ligands and inhibitors.

In some cells, such as hESCs [48], compliant environments might induce secretion of Wnt3a (left side of the figure). In this scenario, Frizzled receptors and LRP5/6 co-receptors can bind Wnt3a, resulting in the inhibition of the β-catenin destruction complex. Newly synthesized β-catenin, or β-catenin released from the membrane-bound pool located at AJs, can then translocate to the nucleus to induce the transcription of TCF/LEF target genes (‘WNT-ON’). On stiff environments (right side of the figure), integrins will activate intracellular signaling, possibly through IACs components, such as Src and FAK. This might result in the inhibition of Wnt ligands, either at the mRNA or protein (secretion) level. In addition, Wnt/β-catenin inhibitors, such as DKK1 or sFRP1, can also be expressed; these will inhibit Wnt/β-catenin signaling at the receptor level, thus resulting in the activation of the β-catenin destruction complex and β-catenin degradation (‘WNT-OFF’). For simplicity, some proteins are omitted in the figure. See the main text for details.

The modulation of Wnt/β-catenin signaling through ligand availability might depend on the cell type. For instance, increased substrate stiffness plays opposite effects on embryonic (ESCs) and mesenchymal (MSCs) stem cells. On hESCs, the expression of several Wnt ligands decreases at higher substrate elastic modulus [48]. Of note, culturing hESCs on stiff substrates (60 kPa) with a neutralizing antibody targeting β1-integrin abrogates the stiffness-induced reduction of WNT3A expression, which suggests that the potential role of substrate elasticity in modulating Wnt signaling depends on IACs.

On the contrary, in bone marrow MSCs (BMMSCs) and chondrocytes, the stiffness of the substrate induces activation of Wnt/β-catenin signaling [49]. In this case, increased stiffness (100 kPa) induced higher levels of Wnt proteins Wnt1 and Wnt3a, resulting in increased Wnt/β-catenin signaling, as revealed by activation and nuclear translocation of β-catenin and abundance of Wnt/β-catenin targets CD44 and Axin-2. Of note, both studies (from [48,49]) employed poly-acrylamide hydrogels coated with collagen, but they differed in stiffness (60 versus 100 kPa, respectively), although this difference might be insignificant. Instead, the main difference is provided by the cell type. Therefore, the same mechanical cue might induce different, even opposite effects, across cell types and tissues, providing further complexity to our assessment of mechanical signals at the physiological level.

The effect of stiffness on the expression of Wnt ligands seems to be independent of Wnt/β-catenin signaling at the extracellular level [49], thus suggesting that substrate stiffness modulates the Wnt/β-catenin pathway through a mechanism independent from the central axis composed by LRP6/Frizzled/Dishevelled, at least in this specific case. Mechanistically, Du et al. [49] also showed that the wnt1 gene contains a TCF-responsive element in its promoter region. The culture of chondrocytes on stiff substrates promoted binding of β-catenin to the wnt1 promoter; hence, mechanical cues can directly induce transcriptional modulation of the Wnt/β-catenin pathway. The authors assess the role of PKC, ILK, and YAP/TAZ in the differential response of chondrocytes to substrate stiffness; however, this failed to identify a specific modulator. Therefore, and based on experiments where GSK-3β activity is modulated, the authors proposed that the substrate stiffness ultimately regulates Wnt1 expression through an integrin- and FAK-dependent pathway mediated by GSK-3β [49].

Secretion of Wnt inhibitors in response to ECM stiffness

ECM mechanical cues can also stimulate the secretion of extracellular Wnt inhibitors. The study from [48], for instance, reported that the culture of hESCs on stiff substrates (60 kPa) correlated with increased Sfrp expression. Concomitantly, conditioned medium from these cultures abrogated mesoderm differentiation of hESCs on soft substrates. In agreement with this finding, a study using epithelial ovarian cancer cells (EOCs) cultured in three-dimensional collagen I gels observed decreased expression of Dickkopf-1 (DKK1), an established Wnt/β-catenin signaling inhibitor [50]. This effect was also observed in cells cultured on PA and PEG gels with varying stiffness, and it was corroborated in a panel of ovarian cancer cell lines. In agreement with the decreased expression of DKK1, β-catenin showed increased nuclear translocation in 3D collagen matrices, an effect that was abolished by restoring DKK1, thus suggesting that Wnt/β-catenin signaling occurs at the receptor level in these cells in a compliant environment. Therefore, Wnt/β-catenin signaling might also be modulated extracellularly in response to substrate stiffness through the secretion of Wnt inhibitors (Figure 1).

Stiffness-induced Wnt/β-catenin modulation at the receptor level

Another possible way to modulate Wnt/β-catenin signaling is by regulating either the abundance or activity of Wnt/β-catenin receptors and co-receptors. Han et al. [51] showed that Wnt3a induces proliferation of NMuMG mammary epithelial cells cultured on stiff substrates (4 kPa), through a pathway relying on integrin-linked kinase (ILK). The authors showed that substrate stiffness increased the expression of Frizzled-1, but not Frizzled-4 or -6. Moreover, reducing Frizzled-1 expression blocked the proliferative effect of Wnt3a on stiff substrates. Given that YAP and TAZ were shown to be dispensable for this effect induced by Wnt3a, it is possible that mechanical cues, possibly through integrin signaling, induce ILK-mediated Frizzled-1 expression (Figure 2A). Together with the results reported by Du et al. [49], it is possible to delineate a β1-integrin-dependent pathway, which can modulate the expression of Wnt-related genes and GSK3β/β-catenin levels or activity.

Other mechanisms for stiffness-dependent Wnt/β-catenin signaling modulation.

Figure 2.
Other mechanisms for stiffness-dependent Wnt/β-catenin signaling modulation.

(A) In some cells, integrin signaling through ILK (dashed arrow) might result in the expression of Frizzled receptors, such as Frizzled-1 [51]. If Wnt ligands are available, increased availability of Frizzled receptors can result in the inhibition of the β-catenin destruction complex, thus leading to β-catenin stabilization and transcription of TCF/LEF target genes. (B) In addition, stiffness-dependent β-catenin modulation might also result through ligand- and receptor-independent mechanisms. In some cases, inhibition of GSK-3β might be required for β-catenin stabilization. However, in other cell types, GSK-3β activation can lead to β-catenin degradation [48]. β-Catenin might be also sequestered at, or released from, AJs in response to mechanical tension, thus reducing (AJs acting as a ‘sink’) or increasing (AJs acting as a ‘pool’) available β-catenin for signaling. In some cell types, for instance, increasing NM-II activity might promote titration of β-catenin towards AJs, as described [72]. Finally, increased secretion of collagen or lysyl oxidase (LOX) can result in higher stiffness, providing a feedback loop. Components from IACs are likely involved in stiffness-dependent β-catenin modulation. For simplicity, some proteins are omitted in the figure, and only the ‘WNT-ON’ outcome is depicted. See the main text for details.

Figure 2.
Other mechanisms for stiffness-dependent Wnt/β-catenin signaling modulation.

(A) In some cells, integrin signaling through ILK (dashed arrow) might result in the expression of Frizzled receptors, such as Frizzled-1 [51]. If Wnt ligands are available, increased availability of Frizzled receptors can result in the inhibition of the β-catenin destruction complex, thus leading to β-catenin stabilization and transcription of TCF/LEF target genes. (B) In addition, stiffness-dependent β-catenin modulation might also result through ligand- and receptor-independent mechanisms. In some cases, inhibition of GSK-3β might be required for β-catenin stabilization. However, in other cell types, GSK-3β activation can lead to β-catenin degradation [48]. β-Catenin might be also sequestered at, or released from, AJs in response to mechanical tension, thus reducing (AJs acting as a ‘sink’) or increasing (AJs acting as a ‘pool’) available β-catenin for signaling. In some cell types, for instance, increasing NM-II activity might promote titration of β-catenin towards AJs, as described [72]. Finally, increased secretion of collagen or lysyl oxidase (LOX) can result in higher stiffness, providing a feedback loop. Components from IACs are likely involved in stiffness-dependent β-catenin modulation. For simplicity, some proteins are omitted in the figure, and only the ‘WNT-ON’ outcome is depicted. See the main text for details.

Modulation of β-catenin levels and/or activity in response to ECM stiffness

The activation of the Wnt/β-catenin pathway ultimately relies on the stabilization of β-catenin and its nuclear translocation, where it promotes the transcription of TCF/LEF target genes. Mechanical cues might promote the stabilization of β-catenin, thus bypassing the need to modulate the expression of Wnt ligands or receptors. In fact, it has long been known that some mechanical cues, such as axial strain in epithelial monolayers [52] or tumor pressure [53], can activate β-catenin. For instance, mechanical strain induced during morphogenetic movements in Drosophila embryonic development promotes nuclear translocation of β-catenin [54,55], as well as in zebrafish [56]. The AJs act as a mechanosensor [57,58], and mechanical tension acting at AJs triggers the exposure of a phosphorylation site in β-catenin, thus promoting its release from the E-cadherin membrane pool [59]. Therefore, mechanical forces acting at cell–cell interactions promote the release of β-catenin from AJs, rendering available for signaling.

However, it must be noted that Wnt signaling can cooperate rather than compete, with mechanically induced β-catenin activation, as seen in MDCK cells [60]. In this article, stretching-induced β-catenin activation proved insufficient to promote cell progression through mitosis, and β-catenin stabilization through inactivation of the β-catenin degradation complex by Wnt3a stimulation or inhibition of CKI was required for this progression to occur. In this same line, β-catenin responds to Wnt signals in cells devoid of E-cadherin.

It is usually thought that β-catenin is shared between a cytoplasmic and the membrane pool. However, it remains possible that the membrane pool represents only a fraction of the available β-catenin for signaling (for a discussion, see [61]), while β-catenin itself might segregate into specific pools depending on its binding preference and phosphorylation status [62,63]. Therefore, mechanical induction of β-catenin through E-cadherin likely represents only one modality of mechanosensitive β-catenin signaling, posing an interesting question about whether other modalities of mechanically induced β-catenin activation, potentially independent of E-cadherin, might exist.

Of note, the role of stretching and axial strain on β-catenin is beyond the scope of this review, but a recent review analyzes this phenomenon in detail [33]. More importantly, unlike mechanical strain and axial stretching, the role of ECM stiffness on β-catenin modulation has received somewhat less attention. However, several articles have reported an altered abundance of β-catenin in response to changes in substrate stiffness. For instance, adipose-derived stem cells (ASCs) show increased levels of β-catenin and Lef-1 in stiffer substrates made of polydopamine-coated PDMS, and this increase correlates with higher levels of Cyclin-D1, an established TCF/LEF target gene [64].

In agreement with this report, a second study that used ASCs and PDMS substrates also observed increased β-catenin levels in response to stiffness [65]. Moreover, this study assessed the activation of β-catenin by immunofluorescence, reporting that increased substrate stiffness induces nuclear localization of β-catenin. Additionally, the authors correlated β-catenin activation with osteogenic differentiation of ASCs, measured by Runx2 transcript abundance, and they identified Lef-1 binding sites in the Runx2 promoter. Therefore, β-catenin is activated by stiffness in ASCs, correlating with osteogenic differentiation.

Other studies have also reported stiffness-induced increased β-catenin levels in human mesenchymal stem cells (hMSCs) cultured on PA gels [66] and in apical papilla dental stem cells (SCAPs) cultured on PDMS gels [67]. In SCAPs, stiffness also modulated β-catenin activation, as revealed by protein phosphorylation and nuclear localization. β-Catenin activation correlated again with osteogenic differentiation, and binding sites for TCF-1 and Lef-1 were also identified through bioinformatic analysis in the Runx2 gene promoter [67]. Increased levels of β-catenin in response to stiffness were also observed in human dental pulp stem cells (DPSCs) cultured on PDMS gels [68], and another study showed that primary uterine leiomyoma cells isolated from patients also displayed increased levels of β-catenin when cultured on stiff PA gels [69].

Although this evidence suggests that higher substrate stiffness induces the stabilization of β-catenin, some cell types might respond differently. In contrast to the observations reviewed above, hESCs display increased β-catenin activity on soft substrates, which correlates with increased mesodermal marker expression [48]. The article employed an experimental system devised to study the involvement of β-catenin along with the mesodermal differentiation of hESCs. In a first stage, hESCs are characterized by robust cell–cell adhesions, and abrogation of either β-catenin, E-cadherin, or P120-cadherin impaired mesodermal differentiation. The authors propose that cell–cell adhesions in this context serve to accumulate a pool of β-catenin before Wnt/β-catenin activation, thus ‘priming’ hESCs. On stiff substrates, the authors found that β-catenin levels are reduced, presumably due to the destabilization of cell–cell adhesions and release of this β-catenin pool, rendering β-catenin unavailable for mesodermal differentiation. The authors also show that this destabilization mechanism depends on the activation of β1-integrin and requires SRC family kinase signaling [48].

Finally, β-catenin activity might be modulated independently of its relative abundance in the cell. For instance, β-catenin activation in response to substrate stiffness is observed in aortic valve interstitial cells (VICs). In these cells, treatment with TGF-β induces nuclear translocation of β-catenin without altering its total levels, and the amount of nuclear β-catenin in response to TGF-β increases in response to substrate stiffness, particularly above 20 kPa, in collagen I-coated PA-gels. In consequence, TGF-β-dependent VICs differentiation is enhanced in response to increased stiffness [70]. In contrast, aortic valve endothelial cells (VECs) cultured on soft (5 kPa) and stiff (50 kPa) collagen I-coated PDMS substrates also exhibited different responses to TGF-β, with VECs cultured on stiff substrates displaying increased differentiation. In this case, TGF-β treatment both increased β-catenin levels and induced its nuclear translocation, and VECs cultured on stiffer substrates showed increased levels of nuclear β-catenin [71].

Therefore, the specific effect of matrix stiffness on β-catenin might differ across cell types. But how are β-catenin levels modulated in these contexts? Different, or even redundant mechanisms, might explain the effects of substrate stiffness on β-catenin levels (Figure 2B). One possible mechanism might be provided by a study that employed Drosophila and mammalian cells to assess the effect of mechanical tension on β-catenin-dependent Wnt signaling [72]. In this study, the authors show that, under high tension, non-muscle myosin II (NM-II) promotes AJs enforcement, leading to increased membrane β-catenin binding at the expense of the cytoplasmic β-catenin pool, thus leading to attenuated Wnt signaling. Experiments in cells without E-cadherin, as well as knockdown assays targeting PP1β and MYPT3 myosin phosphatases, allowed to confirm that NM-II and F-actin stabilization were required by actomyosin contractility to modulate β-catenin compartmentalization and thus Wnt signaling. Whether this mechanism is conserved in response to substrate stiffness is a question that merits further investigation.

On the other hand, a study in transgenic mice shows that ROCK hyperactivation promotes β-catenin stabilization and nuclear localization, leading to hyperproliferation and epidermal hyperplasia, and ultimately to progression from papilloma to carcinoma [73]. Transgenic mice with increased ROCK activity exhibited higher collagen deposition and matrix stiffness, which correlated with enhanced β-catenin activity, as revealed by TCF/LEF target gene transcription. Mechanistically, actomyosin contractility and FAK activation were required for β-catenin activation. Moreover, the inhibition of collagen cross-linking with the lysyl oxidase inhibitor β-aminopropionitrile (BAPN) abrogated β-catenin nuclear accumulation. Collectively, this leads to a model whereby collagen deposition and cross-linking promote increased stiffness, integrin clustering, and FAK activation, which in turn activates PI3K/AKT signaling and inhibits GSK-3β, thus allowing β-catenin stabilization.

Concluding remarks

Collectively, this evidence indicates that Wnt/β-catenin-dependent signaling might be modulated, or initiated, in response to changes in substrate stiffness. The specific mechanisms by which β-catenin signaling might be modulated likely differ depending on the cell type, as summarized in Table 1. However, these mechanisms can be broadly grouped into two main categories: a mechanism that relies on the modulation of traditional (or ‘canonical’) Wnt components, such as Wnt ligands, receptors or inhibitors (Figures 1 and 2A); and a collection of mechanisms that activates β-catenin downstream of the ligand/receptor complexes (Figure 2B). In both cases, however, the functional result is similar: triggering of TCF/LEF-dependent transcriptional responses. Whether the non-canonical branch of the Wnt pathway can be similarly modulated is a question that warrants more in-depth examination, especially considering the possible role of non-canonical ligands, particularly Wnt5a, in cancer cell migration and invasion [74–77].

Table 1.
Summary of findings relating to stiffness-modulated Wnt/β-catenin signaling
Cell typeModulation levelSubstrate; stiffness range (kPa)Outcome (on stiff substrates)References
hESCs Ligand; Inhibitor PA; 0.4–60 Low expression of Wnt3a; higher expression of sFRPs [48
Chondrocytes, BMMSCs Ligand PA; 0.5–100 Higher expression of Wnt1 and Wnt3a (chondrocytes only) [49
EOCs Inhibitor PA; PEG; collagen gels Increased expression of DKK1 [50
NMuMG cells Receptor PA; 0.13–4 Increased expression of Frizzled-1 [51
ASCs β-catenin PDMS; 1.4–134 [64]; 46–1014 [65Increased levels of β-catenin [64,65]; nuclear β-catenin [65[64,65
hMSCs β-catenin PA; 13/16–62/68 Increased levels of β-catenin [66
SCAPs β-catenin PDMS; below 250–1000 Increased levels of β-catenin [67
DPSCs β-catenin PDMS; 6–135 Increased levels of β-catenin [68
VICs β-catenin PA; 3–144 Increased nuclear β-catenin [70
VECs β-catenin PDMS; 5–50 Increased nuclear β-catenin [71
Cell typeModulation levelSubstrate; stiffness range (kPa)Outcome (on stiff substrates)References
hESCs Ligand; Inhibitor PA; 0.4–60 Low expression of Wnt3a; higher expression of sFRPs [48
Chondrocytes, BMMSCs Ligand PA; 0.5–100 Higher expression of Wnt1 and Wnt3a (chondrocytes only) [49
EOCs Inhibitor PA; PEG; collagen gels Increased expression of DKK1 [50
NMuMG cells Receptor PA; 0.13–4 Increased expression of Frizzled-1 [51
ASCs β-catenin PDMS; 1.4–134 [64]; 46–1014 [65Increased levels of β-catenin [64,65]; nuclear β-catenin [65[64,65
hMSCs β-catenin PA; 13/16–62/68 Increased levels of β-catenin [66
SCAPs β-catenin PDMS; below 250–1000 Increased levels of β-catenin [67
DPSCs β-catenin PDMS; 6–135 Increased levels of β-catenin [68
VICs β-catenin PA; 3–144 Increased nuclear β-catenin [70
VECs β-catenin PDMS; 5–50 Increased nuclear β-catenin [71

The table summarizes some findings described in the main text. Modulation level refers to the place at which the modulation takes place, according to the respective articles. Outcome refers to the biological mechanism that leads to Wnt/β-catenin signaling modulation, in cells cultured on stiffer substrates. For β-catenin, increased nuclear localization as an outcome is mentioned only when directly assessed by the respective study. The stiffness range employed in each study, when specified by the authors, is indicated. See the abbreviation list for details.

The findings discussed in this review posit interesting questions. First, are YAP and TAZ required for this form of β-catenin activation? In addition to their known role as mechanotransducers, YAP and TAZ are components of the Wnt/β-catenin pathway machinery, as reviewed above [43–47]. However, whether the modulation of the Wnt/β-catenin pathway by mechanical cues requires YAP/TAZ dissociation, and to what extent, are pending questions. On the other hand, should we refer to ‘Wnt’ signaling in the context of stiffness-induced β-catenin activation? The new findings discussed in this review expand the array of mechanical signals that can influence β-catenin activity (summarized in Figure 3). The evidence discussed above suggests that increased stiffness might indeed lead to the secretion of Wnt ligands, which in turn might cooperate with integrin-mediated signaling to promote β-catenin nuclear accumulation; however, increased stiffness or other mechanical signals might also lead to β-catenin transcriptional activity downstream of the ligand/receptor complexes. Therefore, perhaps it would be more precise to refer to ‘ligand-dependent β-catenin signaling’ and ‘mechanically-dependent β-catenin signaling’ to denote these two types of pathways that rely ultimately on β-catenin and TCF/LEF transcriptional responses.

Summary of biochemical and mechanical signals activating β-catenin.

Figure 3.
Summary of biochemical and mechanical signals activating β-catenin.

Cells respond to biochemical signals (dashed line), such as the availability of canonical Wnt ligands secreted from cells (i.e. macrophages), and β-catenin becomes stabilized and translocates to the nucleus. In addition, β-catenin becomes activated in response to a variety of mechanical signals, such as axial stretching in epithelial monolayers (blue arrows) or tumor pressure (red arrows), and to pulling forces in cell–cell contacts (green arrows). In addition to this rich diversity of stimulatory signals, recent evidence suggests that increased stiffness of the ECM also induces β-catenin stabilization and nuclear translocation (orange arrows). For simplicity, mechanisms and proteins other than β-catenin and Wnt ligands are not detailed. AJs, adherens junctions; β-cat, β-catenin; TME, tumor microenvironment; BM, basement membrane. See the main text for details.

Figure 3.
Summary of biochemical and mechanical signals activating β-catenin.

Cells respond to biochemical signals (dashed line), such as the availability of canonical Wnt ligands secreted from cells (i.e. macrophages), and β-catenin becomes stabilized and translocates to the nucleus. In addition, β-catenin becomes activated in response to a variety of mechanical signals, such as axial stretching in epithelial monolayers (blue arrows) or tumor pressure (red arrows), and to pulling forces in cell–cell contacts (green arrows). In addition to this rich diversity of stimulatory signals, recent evidence suggests that increased stiffness of the ECM also induces β-catenin stabilization and nuclear translocation (orange arrows). For simplicity, mechanisms and proteins other than β-catenin and Wnt ligands are not detailed. AJs, adherens junctions; β-cat, β-catenin; TME, tumor microenvironment; BM, basement membrane. See the main text for details.

On the other hand, the role of traditional Wnt components in stiffness-modulated β-catenin signaling also merit further investigation, and future studies should aim to address the role of proteins such as LRP5/6, Axin, or Dishevelled, in the context of mechanotransduction.

Finally, it is of interest to integrate these findings into current studies addressing the role of mechanical properties of the ECM in development and disease. In cancer, the Wnt/β-catenin pathway has been commonly associated with cancer initiation due to mutations in genes encoding pathway components, while the non-canonical Wnt pathway plays an important role during migration and invasion [74]. In this regard, while cancer cells invade, they might face a stiffened matrix, due to collagen deposition and cross-linking. Therefore, cancer cells might also undergo abnormal β-catenin signaling due to the stiffening of the ECM, thus suggesting a previously unrecognized role of the Wnt/β-catenin pathway in this context.

In conclusion, the studies addressed in this review shed light on the variety and complexity of the mechanisms leading to β-catenin modulation in response to ECM stiffness, and suggest that the activation of the Wnt/β-catenin pathway can be achieved through parallel and complementary pathways, which might allow cellular adaptation in response to changing mechanical environments. Although much work is still needed to establish the full clinical relevance of the findings discussed here, the growing interest in the study of cellular mechanotransduction, particularly in the context of cancer, might provide additional connections between the mechanical properties of the ECM and the Wnt/β-catenin pathway.

Perspectives

  • Importance of the field. The Wnt/β-catenin pathway plays fundamental roles in development and homeostasis, and alterations in this pathway lead to diseases. Therefore, it is of paramount relevance to understanding how diverse physiological contexts modulate this pathway. In this regard, the field of mechanotransduction has gained attention in recent years, thus shedding light on the role of mechanical signals in cell behavior, providing an opportunity to assess how these might modulate different signaling pathways.

  • Current state of the field. There is a deep understanding of the mechanisms by which Wnt ligands activate the Wnt/β-catenin pathway, and findings in recent years have related this pathway with the YAP and TAZ transcription factors, as well as with integrin-mediated signaling. In addition, recent evidence shows that the stiffness of the ECM plays a vital role during stem cell and cancer biology. However, the relationship between the Wnt/β-catenin pathway and mechanotransduction is less understood, although evidence that points to a possible role of matrix stiffness on Wnt/β-catenin signaling is emerging.

  • Future directions. Recent evidence suggests that the stiffness of the ECM modulates the Wnt/β-catenin pathway; however, these effects vary depending on the cell type. In addition to providing a detailed mechanism for mechanosensitive Wnt/β-catenin signaling, future studies should address the role of classical Wnt components and produce an integrative view about mechanosensitive Wnt/β-catenin signaling, particularly in the context of development and disease.

Competing Interests

The author declares that there are no competing interests associated with this manuscript.

Funding

This work was supported by the following grant: ‘CONICYT PAI Convocatoria Nacional Subvención a la Instalación en la Academia, Convocatoria Año 2017, No. 77170063’.

Abbreviations

     
  • α-SMA

    α-smooth muscle actin

  •  
  • AJ

    adherens junctions

  •  
  • APC

    adenomatous polyposis coli

  •  
  • ASCs

    adipose-derived stem cells

  •  
  • BAPN

    β-aminopropionitrile

  •  
  • BMMSCs

    bone marrow mesenchymal stem cells

  •  
  • DKK

    Dickkopf

  •  
  • DPSCs

    human dental pulp stem cells

  •  
  • Dvl

    Dishevelled

  •  
  • ECM

    extracellular matrix

  •  
  • EOCs

    epithelial ovarian cancer cells

  •  
  • FAK

    focal adhesion kinase

  •  
  • GSK-3β

    glycogen synthase kinase-3 β

  •  
  • hESCs

    human embryonic stem cells

  •  
  • hMSCs

    human mesenchymal stem cells

  •  
  • IAC

    integrin-adhesion complex

  •  
  • ILK

    integrin-linked protein kinase

  •  
  • JNK

    c-Jun N-terminal kinase

  •  
  • LRP5/6

    low-density lipoprotein receptor-related protein 5/6

  •  
  • NM-II

    non-muscle myosin II

  •  
  • PA

    poly-acrylamide

  •  
  • PDMS

    Poly(dimethylsiloxane)

  •  
  • PEG

    Poly(ethylene glycol)

  •  
  • SCAPs

    apical papilla dental stem cells

  •  
  • SFK

    SRC family kinases

  •  
  • sFRP

    secreted Frizzled-related protein

  •  
  • SRC

    Proto-oncogene tyrosine-protein kinase Src

  •  
  • TCF/LEF

    T-cell-specific transcription factor/Lymphoid enhancer-binding factor

  •  
  • TGF-β

    transforming growth factor β-1 proprotein

  •  
  • TME

    tumor microenvironment

  •  
  • VECs

    aortic valve endothelial cells

  •  
  • VICs

    aortic valve interstitial cells

  •  
  • WIF

    Wnt inhibitory factor

  •  
  • ZNRF3/RNF43

    E3 ubiquitin-protein ligase ZNRF3/E3 ubiquitin-protein ligase RNF43.

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