Emerging S100A11 roles: Regulation of focal adhesion dynamics and mechanosensing

Abstract

S100A11 is a small calcium-binding protein that has been studied in the context of growth regulation and membrane repair. However, it has recently been linked to the disassembly of focal adhesions. This new role of S100A11 has been linked to calcium influx through the stretch-activated channel Piezo1. In this review, we look at what’s currently known about S100A11’s structural features, interactome, and functional roles. We focus on how it responds to mechanical stress and becomes recruited to focal adhesions. We also look into its role in the disassembly of these adhesions and consider potential mechanisms. To place its activity in context, we compare S100A11 with other members of the S100 family members and discuss its contribution to calcium-dependent cytoskeletal regulation and extracellular signaling. We examine the effects of S100A11 activity in cancer metastasis, wound healing, and fibrosis. Finally, we evaluate potential ways to modulate S100A11 function for prospective therapeutic intervention. Collectively, this review projects S100A11 as a mechanosensitive calcium effector at the intersection of adhesion biology and mechanotransduction.

Key words: S100A11, focal adhesions, mechanosensing, Piezo1, cytoskeleton, cell migration, cancer

Graphical Abstract

Introduction

S100A11, focal adhesions, and mechanotransduction

The human S100 protein family is a group of up to 25 small EF-hand Ca²⁺-binding proteins, including S100A1–A18, S100B, S100G, S100P, S100Z, trichohyalin, filaggrin, and repetin. They usually operate as homodimers, regulating the activity of other proteins in a calcium-dependent manner (Dempsey et al., 2016; Donato, 2001; Santamaria-Kisiel et al., 2006). They regulate diverse processes such as cytoskeletal remodeling, cell motility, inflammation, and tumor progression, highlighting their broad biological and pathological relevance (Donato et al., 2013).

S100A11, a member of this family, has lately garnered attention for its role in focal adhesion turnover and mechanosensitive calcium signaling, underscoring a functional niche that differentiates it from other S100 proteins (Mohammed et al., 2024). S100A11, like other S100 proteins, changes shape when it binds to Ca²⁺, which makes hydrophobic surfaces available for target interactions (Todoroki et al., 1991). S100A11 is known for its roles in intracellular Ca²⁺ signaling (Sakaguchi et al., 2003) and cytoskeletal dynamics (Shankar et al., 2010) and participates in several cellular processes, including cell membrane repair, growth control, and cancer progression (Jaiswal et al., 2014; Sakaguchi et al., 2008).

Focal adhesions (FAs) are integrin-dense macromolecular complexes that connect the extracellular matrix (ECM) to the actin cytoskeleton. Besides providing physical linkage, FAs function as mechanotransduction hubs, enabling cells to sense and adapt to mechanical force (Yamada and Geiger, 1997; Kanchanawong et al., 2010). Precise spatiotemporal turnover of FAs (formation at the leading edge and disassembly at the rear of moving cells) is essential for directed cell migration and invasion (Bijian et al., 2013; Hu et al., 2014).

Mechanotransduction, broadly defined, is the process by which cells convert mechanical stimuli into biochemical signals to regulate downstream biological functions (Tschumperlin, 2011). Structural proteins, including integrins, talin, and vinculin; mechanosensitive signaling proteins, such as focal adhesion kinase (FAK); and mechanosensitive ion channels, exemplified by Piezo1, are all involved in mechanotransduction at FAs (Yao et al., 2022).

In this review, we discuss the roles of S100A11 in FA regulation and mechanotransduction, place them in the broader context of the S100 protein family, and consider the therapeutic potential as well as the challenges of targeting this pathway in disease.

S100A11 structure, interactome, and classical functions

Endogenous S100A11 is a 105-amino-acid protein (~11–13 kDa) composed of two EF-hand motifs: a canonical C-terminal EF-hand and a slightly modified N-terminal EF-hand (pseudo-EF hand) common to S100 family members (Ohta et al., 1991; Réty et al., 2000). Ca²⁺ binding induces an open S100A11 conformation that exposes the surface for binding to Annexin A1 (Fig. 1a, b), whereas apo-S100A11 (Ca²⁺-free) is in a more compact form and lacks the surface required for binding to partners (Fig. 1c, d). This Ca²⁺-dependent structural rearrangement allows S100A11 to cross-link or stabilize connections among partner proteins. S100A11’s primary binding partners are Annexin A1 (ANXA1) and Annexin A2 (ANXA2), which are Ca²⁺/phospholipid-binding proteins with roles in cell membrane organization and repair (Gerke and Moss, 2002; Jaiswal et al., 2014). S100A11 binds the N-terminal domains of annexins in a Ca²⁺-dependent manner and helps tether cytoskeletal or signaling proteins to membrane sites (Réty et al., 2000; Zhang et al., 2021).

Fig. 1

S100A11 structure

A. Ribbon representation of the human S100A11 homodimer (hS100A11) in the Ca²⁺-bound state (PDB: 1QLS). Helices are shown in cornflower blue and light gray, with an Annexin A1 peptide in purple and bound Ca²⁺ ions as orange spheres. B. Semi-transparent molecular surface (50% transparency) of Ca²⁺-bound hS100A11 homodimer with Ca²⁺ ions (orange spheres) at EF-hand binding sites; the Annexin A1 peptide is shown in purple. C. Ribbon representation of the rabbit S100A11 homodimer (PDB: 1NSH) in the Ca²⁺-free state (apo form). Helices are shown in cornflower blue and light gray. S100 proteins are highly conserved, and rabbit S100A11 shares 89% sequence identity with human S100A11. D. Semi-transparent molecular surface (50% transparency) of apo RbS100A11 homodimer, highlighting the Ca²⁺-free conformation.

The wide subcellular localizations of S100A11 enable it to have a broad interactome (Fig. 2). Transforming growth factor-beta (TGF-β) or calcium signaling causes S100A11 to translocate to the nucleus, where it competitively binds nucleolin. This S100A11-nucleolin interaction then affects Smad2/3/4 activity and activates cyclin-dependent kinase inhibitor p21 (WAF1), finally leading to cell growth arrest (Ji et al., 2019; Sakaguchi et al., 2003). Conversely, in numerous cancer cells, S100A11 is overexpressed in the cytoplasm or secreted, functioning as a pro-proliferative factor (Koh and Lee, 2018; Tu et al., 2019; Zheng et al., 2023). S100A11’s dual function has led to its designation as a “dual growth regulator,” capable of both inhibiting and facilitating growth based on its localization and context (Sakaguchi et al., 2008). S100A11 has been reported to associate with cytoskeletal proteins such as microtubules (Davey et al., 2000), F-actin (Sakaguchi et al., 2000), and intermediate filaments (Bianchi et al., 2003) within the cytoplasm, as well as with annexins A1 and A2 in a Ca²⁺-dependent manner (Ashraf and Gerke, 2022), thus connecting S100A11 to cell membrane dynamics. S100A11-annexin complexes, for example, assist in the repair of an injured plasma membrane by moving to the wound site and facilitating actin polymerization as depicted in Fig. 2 (injury site) (Jaiswal et al., 2014). In this regard, S100A11 has been found to influence actin rearrangement and protrusion formation in migrating cells, suggesting a role in cell motility (Shankar et al., 2010). Meanwhile, S100A11 can also be secreted through a non-canonical pathway via exosomes and then act as an extracellular factor (Broome and Eckert, 2004). Secreted S100A11 is then covalently linked by transglutaminase 2 to form a homodimer that engages RAGE (Receptor for Advanced Glycation End-products) on adjacent cells. This, in turn, turns on pathways including AKT/CREB, which trigger an increase of EGF (epidermal growth factor) family growth factors (Cecil and Terkeltaub, 2008; Sakaguchi et al., 2008), NF-κB, and p38 MAPK (Katsumi et al., 2019). All of these interactions help S100A11 to play a role in regulating the cytoskeleton, cell survival, and inflammation signaling.

Fig. 2

S100A11 interactome: key interaction partners and cellular localizations

In the nucleus, S100A11 can bind nucleolin and Smad proteins (SMAD2/3/4) upon TGF-β or calcium signals to induce p21(WAF1) and growth arrest. In the cytoplasm, S100A11 associates with cytoskeletal elements such as tubulin, actin, and intermediate filaments, and with annexins A1 and A2 in a Ca²⁺-dependent manner, linking S100A11 to membrane dynamics. At the inner plasma membrane, S100A11-annexin complexes contribute to plasma membrane repair by accumulating at wound sites. S100A11 can also be secreted via an unconventional, exosome-mediated pathway and function extracellularly. Secreted S100A11 tends to form dimers (facilitated by transglutaminase 2 cross-linking) that engage the receptor RAGE on neighboring cells, activating pathways such as AKT/CREB (to induce EGF family growth factors), NF-κB, and p38 MAPK.

Overall, the ability of S100A11 to act as a calcium-modulated molecular sensor underlies its pleiotropic functions in the cell. These foundational interactions possibly drive the newly recognized role of S100A11 in the mechanics of cell adhesion, wherein it links Ca²⁺ influx and cytoskeletal contractile forces to adhesion turnover.

Focal adhesion dynamics and mechanosensing

Focal adhesions are dynamic, micron-sized complexes that physically couple the extracellular matrix (ECM) to the actin cytoskeleton through transmembrane integrin receptors and dozens of adaptor and signaling proteins (Kanchanawong et al., 2010). They not only hold the cell in place, but they also act as centers of mechanotransduction, converting mechanical cues (such as matrix stiffness or cytoskeletal tension) into biochemical signals (Kuo, 2013). Their formation and disassembly are tightly controlled events that are essential for cell migration. New adhesions develop at the leading edge, where protrusive forces are generated, and older adhesions at the back disintegrate to facilitate forward movement (Webb et al., 2004). The equilibrium of forces and signals at FAs directs their maturation status and turnover rate. When mechanical stress is applied, proteins like talin unfold to reveal binding sites, which allows vinculin to be recruited while α-actinin and paxillin help to stabilize the connection between integrins and actin filaments (del Rio et al., 2009; Grashoff et al., 2010). Similarly, mechanical force and integrin clustering activate mechanosensitive signaling proteins like FAK (a kinase) and the adaptor protein p130Cas. The resulting effect activates downstream pathways, such as Src, Rho GTPases, and MAPK, which affect adhesion dynamics and gene expression (Martino et al., 2018; Sawada et al., 2006). For more comprehensive discussions of these established mechanotransduction processes at adhesions, readers are directed to further pertinent reviews (Geiger and Yamada, 2011; Jansen et al., 2015).

An important aspect of FA mechanosensing is the integration of external forces such as substrate stiffness and shear stress with internal forces generated by the actomyosin cytoskeleton (Zhou et al., 2017). Non-muscle myosin II pulling on actin stress fibers exerts traction force on FAs, which can promote adhesion growth or induce their disintegration depending on context (Kuo, 2013). Sufficiently strong forces can also raise membrane tension at adhesion sites, which has recently been demonstrated to activate mechanosensitive ion channels, adding another layer of control (Lewis and Grandl, 2015). One such channel is Piezo1, a large trimeric Ca²⁺-permeable channel in the plasma membrane that opens in response to membrane stretch. Piezo1, initially characterized for sensing shear stress and hydrostatic pressure, has now been reported to exhibit a diffuse membrane localization while producing localized Ca² flickers near regions of traction force (Ellefsen et al., 2019). More recent research demonstrated that Piezo1 can also appear at focal adhesions under strong cytoskeletal tension (Yao et al., 2022). Consistently, live-cell studies have demonstrated that localized Ca²⁺ rises at adhesion sites are tightly coupled to FA disassembly (Giannone et al., 2004) and that rhythmic Ca²⁺ pulses at the leading edge coordinate cycles of lamellipodial retraction and adhesion remodeling (Tsai and Meyer, 2012). These findings support the idea that localized, spatiotemporally confined Ca²⁺ signals, rather than global cytosolic changes, are important regulators of FA turnover. In this setting, microdomain Ca²⁺ signals activate calpains. The activated calpains subsequently cleave talin and FAK at the adhesion site (Franco et al., 2004), thereby linking mechanotransduction to focal adhesion disassembly. Focal adhesion disassembly is therefore a closely regulated response to both biochemical and mechanical signals (Chan et al., 2010; D’Souza et al., 2020). Collectively, these findings establish calcium as a central regulator of adhesion dynamics, with local Piezo1-mediated Ca²⁺ entry providing spatiotemporal precision and global Ca²⁺ rises acting as broader modulators of turnover.

Despite these insights, the whole spectrum of molecules connecting mechanical forces to calcium signaling at FAs is incomplete. The discovery of S100A11 as a Ca²⁺-responsive factor at FAs now fills an important gap by providing a direct Ca²⁺-sensing effector that promotes adhesion turnover. Considering the ability of S100A11 to bind F-actin and other cytoskeletal regulators, its presence at FAs positions it as a potential mediator between Ca²⁺ influx and the disassembly of the adhesion complex.

Mechanosensitive recruitment of S100A11 to focal adhesions

In our previous study, initial clues to S100A11’s role in adhesion dynamics came from imaging studies in cultured cells. In HeLa and U2OS cells, S100A11 was observed to localize along actin stress fibers and concentrate at FAs, especially at the cell periphery. Remarkably, live-cell fluorescence showed that S100A11 levels at individual focal adhesions spike transiently just before those adhesions disassemble (Fig. 3). Quantitative analysis of timelapse movies revealed that >85% of adhesions exhibiting an S100A11 flash underwent disassembly within the following 8 minutes, whereas adhesions without accumulation remained stable. Consequently, S100A11 flashes function as a dependable indicator of turnover events, acting as a probabilistic signal that an adhesion is ready for disassembly (Mohammed et al., 2024).

Fig. 3

S100A11 transiently accumulates at focal adhesions shortly before disassembly

A. Live-cell imaging of HeLa cells expressing GFP–S100A11 and vinculin–mCherry are shown at 0 s (top panel) and 156 s (bottom panel). B. Crop of the area indicated by the white rectangle in the images in A. S100A11 levels spike transiently at disassembling FAs just prior to their disassembly while stable FAs show no such S100A11 spike. Images adapted and simplified from Mohammed TO, et al., 2024 under CC BY 4.0 license via Journal of Cell Science. Dis: Disassembling FA; Stab: Stable FA. Scale bars: 10 μm (A); 4 μm (B).

Mechanistically, to recruit S100A11, both actomyosin contractility and mechanosensitive Ca²⁺ influx are needed. Artificial elevation of intracellular Ca²⁺ accelerated recruitment and FA disassembly, while inhibition of non-muscle myosin II or blockade of Piezo1 abolished recruitment. These results position S100A11 downstream of cytoskeletal tension and Piezo1-mediated Ca²⁺ entry. In this model, myosin II–driven contractility increases tension at adhesion sites, activating Piezo1 channels and creating localized Ca²⁺ microdomains. The resulting Ca²⁺ rise causes the recruitment of S100A11, which marks adhesions destined for disassembly.

Linking S100A11 to focal adhesion disassembly: Possible mechanisms

The precise mechanisms by which S100A11 facilitates focal adhesion disassembly remain to be elucidated. A few possibilities include facilitating calpain-mediated cleavage of adhesion proteins, interacting with actin regulators to impact stress fibers, or influencing structural linkers like talin–vinculin and paxillin–actinin complexes, thereby weakening adhesion stability. Calpains mediate FA disassembly by cleaving structural components like talin and FAK, thereby weakening the adhesion (Franco et al., 2004; Kerstein et al., 2017). For adhesions to remain stable, actin cytoskeleton regulators play crucial roles (Ridley, 2011; Shankar et al., 2010). Structural linkers like talin and vinculin are mechanosensors, and the conformational changes they undergo in response to tension affect the adhesion turnover (del Rio et al., 2009). Moreover, S100A11 may transiently engage with kinases or phosphatases to enhance disassembly signals or collaborate with annexin complexes and endocytic machinery to facilitate membrane turnover at adhesion sites, a mechanism analogous to annexin–S100 complexes promoting membrane remodeling (Gerke and Moss, 2002). The S100A11–annexin A2 complexes aggregate in regions of membrane stress and participate in cortical actin remodeling and membrane repair (Jaiswal et al., 2014), processes intimately associated with adhesion turnover. Together, these prospective interactions suggest that once recruited, S100A11 links a mechanosensitive Ca²⁺ influx to the molecular processes that dismantle focal adhesions, as proposed in Fig. 4. Research on other S100 proteins establishes a precedent for this regulatory mechanism: S100A4 directly interacts with NMIIA and dissociates its filaments (Li and Bresnick, 2006; Ramagopal et al., 2013), which decreases cytoskeletal tension and promotes adhesion turnover. S100P has similarly been demonstrated to bind to NMIIA and disperse its fibers (Du et al., 2012). Moreover, it has been suggested that S100A4 may participate in mechanotransduction through interaction with talin (Indo et al., 2015; Jurewicz et al., 2025), indicating that S100 proteins might influence the integrin–talin linkage.

Fig. 4

Proposed mechanism of S100A11 mechanosensitivity and S100A11-mediated focal adhesion disassembly

Mechanical tension generated by myosin II contractility (inside-out force) or external mechanical load (outside-in force) increases membrane tension and opens Piezo1 channels. The resulting Ca²⁺ influx produces two parallel Ca²⁺-dependent pathways at focal adhesions. (1) Ca²⁺ binding activates S100A11 which translocates to FAs where it potentially modulates adhesion stability or remodeling through interactions with yet-unidentified scaffolding proteins. (2) Ca²⁺ activates calpain, which cleaves talin, FAK, and other adhesion components to drive proteolytic remodeling. Together, these coordinated parallel pathways promote focal adhesion turnover.

In summary, these recent findings suggest S100A11 is a new element of the cellular mechanotransduction network at focal adhesions. Mechanical force activates Piezo1, which causes Ca²⁺ to flow into a localized area. This, in turn, recruits S100A11 to focal adhesions. This newly discovered role positions S100A11 as a key molecular link coupling biomechanical cues to FA turnover. S100A11 essentially acts as a Ca²⁺-dependent effector that senses when a FA is under mechanical stress and requires disassembly and subsequently facilitates that disassembly.

S100A11 in cancer cell migration and mechanotransduction

In this section, we examine mechanosensing as the central axis through which S100A11 influences cancer cell behavior. S100A11 functions as a Ca²⁺-responsive effector that promotes focal adhesion (FA) disassembly. Cancer is discussed as a disease context in which this mechanosensing pathway is frequently rewired to support invasive behavior.

Mechanosensitive adhesion turnover in invasive cancer cells

Cell migration and invasion are key processes in cancer metastasis, and in highly invasive cancer cells, focal adhesion dynamics are frequently modified (Chan et al., 2009; Wu et al., 2011). Tumor cells experience and generate elevated mechanical stresses within stiffened matrices (Northcott et al., 2018; Shu et al., 2024). Under normal physiological conditions, mechanical tension at focal adhesions causes localized calcium influx via mechanosensitive channels such as Piezo1, promoting adhesion maturation and turnover (Yao et al., 2022). In tumor cells, this mechanotransduction route is often impaired. It is either weakened at adhesion sites or spatially modified, altering the adhesion turnover balance and enabling persistent migration (De Felice and Alaimo, 2020; Liu et al., 2023). In this context, the mechanosensitive recruitment of S100A11 to focal adhesions offers a biochemical pathway by which mechanical signals (sent as localized Ca²⁺ microdomains) might expedite the disassembly of adhesion. Raised S100A11 levels in many malignancies correlate with increased migratory and invasive behavior, especially in stiff tumor microenvironments characterized by significant contractile loads (Anania et al., 2013; Zhou et al., 2024). Increased matrix stiffness, common in tumors (Mancini et al., 2024), may enhance S100A11 activation cycles and promote the mechanoresponsive recruitment of S100A11, thus enabling cancer cells to disengage from adhesions and traverse rigid extracellular matrices or confined spaces.

Cooperative roles in tumor progression beyond adhesion dynamics

Apart from migration, S100A11 has been involved in various spheres of cancer biology, including the promotion of proliferation and escape from cell death. While the inhibition of S100A11 induces cell death in certain cancer cell lines, cytoplasmic S100A11 can avert apoptosis in tumor cells. The survival advantage, along with increased motility, makes cancer cells with heightened S100A11 expression more metastatic (Xiao et al., 2018). In addition to its internal roles, extracellular S100A11 released into the tumor microenvironment may interact with the receptor for advanced glycation end products (RAGE), thereby activating cancer-promoting signaling pathways, including NF-κB and MAPK (Sparvero et al., 2009). These effects, albeit separate from the primary mechanosensing-to-disassembly pathway, are anticipated to collaborate with adhesion turnover to facilitate sustained invasion through dense matrices. S100A11 is among the S100 proteins shown to be critical for pseudopod protrusion as well as for the migration and invasion of metastatic tumor cells (Shankar et al., 2010). It may cooperate with other metastasis-related S100 proteins to reorganize the cytoskeleton and adhesion landscape of cancer cells. For instance, S100A4/metastasin has been shown to colocalize with myosin IIA at leading edges and increase motility by disassembling actomyosin fibers (Kriajevska et al., 1994; Li and Bresnick, 2006; Ramagopal et al., 2013). TGF-β signaling during epithelial-mesenchymal transition (EMT) can induce S100A4 (Ning et al., 2018) and S100A11 (Niu et al., 2016; Zhang et al., 2018), therefore tying them to pathways that facilitate invasiveness. It is attractive to hypothesize that in metastatic cells, S100A11 and S100A4 might have complementary roles, with S100A4 boosting actin-based protrusions and matrix breakdown and S100A11’s mechanosensitivity promoting release of adhesions, collectively driving the migration cycle.

Mechanosensing roles in fibrosis and vascular remodeling

Another possible context for S100A11 and mechanotransduction is tissue fibrosis and wound healing, where myofibroblasts exert strong forces on FAs. Cells respond to mechanical stress by altering their function, motility, and signaling through mechanotransduction, affecting wound healing outcomes (Kuehlmann et al., 2020). The mechanosensitive activity of S100A11 may contribute to how fibrotic cells sense and move through rigid matrices. Furthermore, despite limited direct evidence linking S100A11 upregulation in vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) to disturbed flow or injury, S100A11 has been implicated in vascular remodeling processes. For example, it has been observed that S100A11-positive cells are increased in wounded arteries, and the S100A11/RAGE signaling pathway facilitates vascular remodeling via modulating the AMPK pathway through liver kinase B1 and STAT3 (Yu et al., 2012). This indicates S100A11 might partake in mechanosensing in endothelial cells under shear stress, perhaps analogously to its role at stressed FAs.

In summary, S100A11 likely acts as a mechanosensitive Ca²⁺-dependent disassembly factor that, when recruited to FAs, can interact with other proteins to loosen and break down the adhesion complex. This mechanism exemplifies an innovative mode of interaction between mechanosensors such as integrins and Piezo1 and Ca²⁺-dependent proteins like S100A11.

Therapeutic potential and challenges in targeting S100A11

Considering the role of S100A11 in focal adhesion disassembly and invasive migration (Sections 1–2), here we consider whether modulating this activity may offer therapeutic benefit. We anticipate therapeutic approaches such as direct inhibition of S100A11, neutralization of its extracellular functions, and genetic silencing approaches. Each avenue carries its opportunities and challenges.

Neutralizing extracellular S100A11 and use of small molecule inhibitors

Given that S100A11 is released in certain settings and communicates via the RAGE receptor (Cecil and Terkeltaub, 2008), one strategy is to employ antibodies or soluble receptors to neutralize S100A11 extracellularly. This strategy could reduce inflammation, e.g., in osteoarthritis (Cecil et al., 2005; He et al., 2009) or chronic kidney disease (Panda et al., 2018), where S100A11/RAGE drives inflammatory signaling and calcification and possibly reduces tumor-stroma interactions that favor metastasis. In fact, monoclonal antibodies against other S100 proteins like S100A8/A9 are being explored for anti-inflammatory effects (Cesaro et al., 2012). The challenge is that S100A11’s main pro-metastatic function is intracellular, so an antibody may not affect that directly. Small molecules that disrupt Ca²⁺ binding or S100A11–partner interactions represent a direct intracellular strategy. In this regard, drug discovery attempts on S100A4 (Giroud et al., 2024; Wilder et al., 2019) and S100B (Roy Choudhury et al., 2023) are promising.

Peptide inhibitors or decoys

Another possible approach is to use peptides from S100A11’s interaction partners as decoys. Decoys from S100A11’s binding partners (e.g., Annexin A1 motifs) may sequester S100A11 and inhibit its functional interactions (Makino et al., 2004). The downside is that peptide drugs face delivery challenges and susceptibility to degradation (Pereira et al., 2024). Cell-penetrating peptides (Aroui et al., 2020) or stapled peptides (Verdine and Hilinski, 2012) might overcome some issues.

Gene silencing approaches

Silencing S100A11 with siRNA or shRNA reduces proliferation, migration, and invasion in multiple cancer cell types, including gastric, pancreatic, and lung cancers (Cui et al., 2021; Ji et al., 2019; Zhang et al., 2019). In vitro, the lack of S100A11 impairs plasma membrane repair in endothelial and invasive cancer cells subjected to mechanical stress (Ashraf and Gerke, 2022; Jaiswal et al., 2014). Although many mechanistic insights have come from in vitro studies, S100A11 downregulation in mouse models of hepatocellular carcinoma and steatohepatitis significantly restrained inflammation and fibrosis, implicating S100A11 in early tumorigenic and fibrotic processes (Sobolewski et al., 2020). Similarly, S100A11 knockdown led to reduced tumor growth and metastasis in vivo, underscoring its therapeutic relevance (Wang et al., 2025; Zhou et al., 2024). Delivery remains a hurdle, and long-term silencing could have drawbacks since S100A11 also has roles in normal tissue repair and homeostasis (Foertsch et al., 2016).

Despite the availability of potential approaches as outlined above, there are significant challenges. Like many S100 proteins, S100A11 lacks enzymatic activity and works by interacting with several partners (He et al., 2009), so its inhibition must be achieved by preventing those interactions. There is also potential functional redundancy among S100 members since cells often express multiple S100 proteins, some of which might compensate for S100A11 loss (Simon et al., 2020). This redundancy is not well understood, and individual S100 proteins demonstrate distinct roles: S100A4 promotes metastasis (Boye and Mælandsmo, 2010), S100B affects p53 activity (Brozzi et al., 2009), S100A8/A9 mediates inflammatory signaling (Vogl et al., 2007), and S100A1 is necessary for handling calcium in the heart (Rohde et al., 2010). Therefore, because of their distinct roles, other S100 proteins are unlikely to fully compensate for S100A11 inhibition.

In conclusion, while S100A11 offers an appealing target because of its involvement in essential cellular processes such as mechanotransduction and migration, targeting it for potential therapeutic purposes would need careful navigation of its diverse biology. We expect this endeavor to benefit from the ongoing expansion of our understanding of S100A11’s interactome, structure, and function.

Conclusions and Future Perspectives

We believe that the identification of S100A11 as a force- and calcium-regulated focal adhesion disassembly component will contribute to advancing our knowledge of cellular mechanosensing. It exemplifies how mechanical forces can be translated into biochemical actions via a calcium-binding protein that had not previously been linked to mechanotransduction. S100A11 emerges as a crucial linker between the cytoskeletal contractile machinery (i.e., actomyosin tension) and the machinery of adhesion turnover. Through a pathway involving myosin II contractility and Piezo1-mediated Ca²⁺ influx, S100A11 is activated locally at mechanically stressed adhesion sites to trigger their disassembly. This mechanism highlights that calcium-binding proteins such as S100A11 can be major participants in adhesion dynamics beyond kinases and small GTPases, therefore adding a new dimension to focal adhesion biology.

Finally, the newly discovered role for S100A11 demonstrates the versatility of the S100 family and that of calcium-binding proteins in general. The mechanosensitive nature of S100A11 may also be relevant to other high-force physiological contexts, such as wound healing, fibrosis, or vascular remodeling, where cells must readjust adhesions to mechanical stress.

Author Declaration Statements

Funding

This work was supported by the Japan Society for the Promotion of Science (JSPS) (23K19200 and 25K08445).

Conflict of Interest Statement

The authors declare no competing financial interests.

Data Availability Statement

Not applicable.

Author Contribution Statement

Conceptualization: TOM; Writing—Original Draft: TOM; Writing—Review & Editing: TOM, MIS, DEC; Funding Acquisition: DEC.

Ethics Approval and Consent to Participate

Not applicable.

Patient Consent for Publication

Not applicable.

Acknowledgments

This work was supported by the World Premier International Research Center Initiative (WPI), MEXT, Japan. The authors acknowledge Abdelmalek Djaaraoui from the National School of Nanoscience and Nanotechnology (Algeria) for support with graphical design.

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