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. 2026 May 20;18:143. doi: 10.1186/s13148-026-02163-4

Fluid shear stress enhances pancreatic cancer motility through YAP activation

Juan Deng 1,2, Giulia Lencioni 3,4, Aldo Pastore 3,4, Adam E Frampton 5,6, Dongmei Deng 7, Elisa Giovannetti 1,2,8,✉
PMCID: PMC13371513  PMID: 42163409

Abstract

Background

Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate due to late-stage diagnosis. Although SUIT2 sublines differ in metastatic and drug-resistant behavior, the mechanisms behind these differences are unclear. Fluid shear stress can regulate tumor cell migration, and the mechanosensitive factor yes-associated protein (YAP) promotes PDAC progression. However, the impact of shear stress on YAP signaling in PDAC cells remains unknown. This study aims to better understand how fluid shear stress influences the behavior of PDAC cells and to elucidate the mechanisms by which shear stress regulates their metastatic potential, in order to support the development of more effective therapeutic strategies.

Results

Using the BioFlux-Shear-Flow-System, we observed that under static conditions, the more metastatic SUIT2-007 cells displayed greater migratory capacity than the less metastatic SUIT2-028 cells. However, exposure to fluid shear stress significantly enhanced the migration capacity of SUIT2-028 cells. Consequently, the migratory capacities of the two cell lines became comparable under shear stress conditions. RNA-sequencing revealed differences in yes-associated protein (YAP) activation between SUIT2-028 and SUIT2-007. Functional assays using a YAP activation inhibitor and scratch assay demonstrated that inhibition of YAP activity reduced migration in both tumor cell lines and abolished the differences in their migratory capacities.

Conclusions

Our findings highlight YAP as a mechanosensitive regulator of pancreatic cancer cell migration under shear stress, offering insights into how biomechanical forces can drive metastatic capacity.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13148-026-02163-4.

Keywords: Fluid shear stress, Pancreatic cancer, Yes-associated protein, Directional migration, Metastatic behavior

Introduction

Pancreatic cancer is often diagnosed at an advanced stage, frequently accompanied by metastases [1]. The SUIT2, pancreatic ductal adenocarcinoma (PDAC) cell line, comprises four sublines: SUIT2-007, SUIT2-013, SUIT2-020, and SUIT2-028. A previous study assessed the metastatic potential of these sublines by injecting them subcutaneously into nude mice. After 16 weeks, the SUIT2-007 subline demonstrated the highest metastatic potential, while the SUIT2-028 subline showed no evidence of distant metastasis [2]. Additionally, SUIT2-007 displayed greater resistance to Taxotere (docetaxel) compared to SUIT2-028 [3]. Collectively, these findings suggest that SUIT2-007 possesses a higher degree of malignancy than SUIT2-028. However, the molecular mechanisms underlying the increased aggressiveness of SUIT2-007 compared to SUIT2-028 remain poorly understood. Understanding these mechanisms could provide valuable insights for the development of more effective therapies targeting the most aggressive forms of PDAC.

Matrix hardness, traditionally considered a hallmark mechanical feature, plays a crucial role in affecting tumor metastasis and patient prognosis [4, 5]. In parallel, fluid dynamics within the tumor microenvironment has gained increasing attention as a key biomechanical factor. Fluid shear stress is the tangential force per unit area exerted by a fluid as it flows parallel to a surface or between adjacent fluid layers, measured in Newtons per square meter (N/m2) or dynes per square centimeter (dyn/cm2) [6]. Under physiological conditions, fluid shear stress serves as a central mechanical cue for regulating the expression of genes, thus maintaining endothelial structural integrity, anti-inflammatory, and antithrombotic states [7]. With the significant advancements in microfluidic technologies in recent years, fluid shear stress within tumors has increasingly been recognized as a contributor to cancer metastasis [8–10].

Yes-associated protein (YAP) is a key transcriptional co-activator in the Hippo signaling pathway, playing an essential role in regulating cell proliferation, apoptosis, stemness, and organ size. Its oncogenic activation has been observed across almost every tissue type [11]. In PDAC, YAP can promote epithelial-mesenchymal transition (EMT) and also disrupts tumor-stromal interactions, thereby facilitating cell migration and metastasis [12, 13]. YAP is also an important mechanoregulated transcriptional effector that transduces physical cues into changes in gene expression and cellular responses [14, 15]. While previous studies have shown that fluid shear stress can activate YAP and enhance tumor cell migration [9], its specific impact on YAP signaling in PDAC cells has yet to be investigated.

In the current study, we report for the first time the distinct effects of fluid shear stress on the directional migration of SUIT2 pancreatic cancer cell sublines and investigate the role of YAP in mediating these differences.

Materials and methods

Cell culture

The human PDAC cell lines SUIT2-028 and SUIT2-007 were kindly provided by Prof. Adam E. Frampton (University of Surrey and Imperial College London, UK). All cell lines were maintained in culture at 37 °C with 5% CO2. SUIT2-028 and SUIT2-007 cells were cultured in RPMI-1640 medium (Gibco), supplemented with 10% heat-inactivated newborn calf serum (Biowest) and 1% penicillin/streptomycin (Lonza). Mycoplasma contamination was routinely tested using polymerase chain reaction (PCR) through Eurofins Genomics.

RNA-sequencing (RNA-seq)

Total RNA was isolated using the miRVana kit (Ambion, Thermo Fisher Scientific). RNA libraries were prepared with the Illumina TruSeq Stranded Total RNA Library Prep Gold Kit (20020598, Illumina) and purified with Agencourt AMPure XP beads (Beckman Coulter). Library concentrations were measured using the Qubit dsDNA BR kit (Thermo Scientific), and size distribution was assessed with an Agilent Bioanalyzer. Libraries were sequenced using paired-end 75 bp reads on a NextSeq500 platform (Illumina). Raw data were processed with BclToFastq for trimming and filtering, and further cleaned with Trimmomatic to remove adapters and low-quality reads. Clean reads were aligned to the human reference genome (GRCh38) using STAR (version 2.5.3a), and gene counts were generated with HTSeq. The raw RNA-seq data are available in the GEO database under accession number GSE228106. Differential expression analysis was performed using DESeq2. Differences with P value < 0.05 and | log2 (fold change) | > 1 were considered statistically significant.

Wound healing assay and YAP inhibition

SUIT2-028 and SUIT2-007 cells were seeded in 96-well flat-bottom plates at a density of 5 × 104 cells/well in a volume of 100 µL. After 24 h of pre-incubation, scratches of consistent width were introduced to the cell monolayers using a specialized multi-needle tool. Following the removal of detached cells by washing with phosphate-buffered saline (PBS), the control wells received only medium, whereas the experimental wells were supplemented with the compounds of interest. The wound confluence was monitored at specific time points (T = 0, 6, 20, and 24 h after treatment) using a Nikon ECLIPSE TS2-LS phase-contrast microscope. Images were captured at each time point, and the wound closure was analyzed using Fiji, an open-source image processing software based on ImageJ [16]. To inhibit YAP activation, SUIT2-028 and SUIT2-007 cells were exposed to verteporfin (S7306, Selleck) at a concentration of 1 µM.

Application of fluid shear stress using the BioFlux system

We utilized the BioFlux Shear Flow System (Fig. 1A) to apply controlled fluid shear stress to PDAC cells. The microfluidic channels of the BioFlux plate were pre-coated with a 50 µg/mL solution of type I bovine collagen (PureCol®). A total of 250 µL of this solution were added to each inlet well and flushed through the channels at 0.5 dyn/cm² until fully filled. Plates were then incubated at 37 °C for 2 h to facilitate coating, rinsed with cell culture medium to prevent osmotic shock, and stored at 4 °C for up to several days.

Fig. 1.

Fig. 1

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SUIT2-007 cells display higher baseline migration than SUIT2-028, A Schematic representation of the BioFlux system used to apply controlled fluid shear stress to cultured cells. B Diagram illustrating the parameters used to quantify cell migration, including displacement and path length. C Representative example of single-cell trajectory (solid white line) under static conditions. Red and cyan cell images indicate positions at the start (t = 0 min) and end (t = 300 min) of the time-lapse, respectively. D Quantification of migration persistence for SUIT2-028 and SUIT2-007 cells under static and shear stress conditions. All experiments were independently repeated at least three times

For cell seeding, SUIT2-028 and SUIT2-007 cells were trypsinized and resuspended at a concentration of 1 × 10⁶ cells/mL. Then, 50 µL of the cell suspension was added to the outlet well and introduced into the channels at 0.5 dyn/cm². Cells were incubated at 37 °C for 30 min to allow for adhesion, after which the channels were filled with approximately 1.2 mL of cell culture medium. Following a 24-hour incubation at 37 °C, cell migration assays were performed under either shear stress conditions (2 dyn/cm²) or static conditions. Of note, this shear stress condition does not fully recapitulate the complex interstitial mechanical forces present in PDAC, but represents a simplified yet effective in vitro model of mechanical stimulation, as reported in previous studies [17, 18]. Brightfield images were acquired using a 10× objective (1.3 μm/pixel) at a frame rate of 1/300 Hz for up to 5–8 h (see Additional file 2).

Quantification of cell migration parameters

Cell migration parameters, including displacement (D) and path length (L), were quantified as illustrated in Fig. 1B. Raw migration tracks were generated by connecting the centroid positions of individual cells over time (Fig. 1C), using custom-written MATLAB scripts. Displacement was defined as the linear distance between the starting and final centroid positions of each cell. To evaluate the directionality of migration, persistence was calculated as the ratio of displacement to total path length, with higher values indicating straighter migration trajectories.

Quantitative real-time polymerase chain reaction (qPCR)

Total RNA was isolated from tissues or cells using TRIzol reagent (Thermo Fisher Scientific) according to the manufacturer’s instructions. cDNA was synthesized from 500 ng RNA using the M-MuLV Reverse Transcriptase kit (Thermo Fisher Scientific) with oligo(dT)₁₈ primers. qPCR was performed in triplicates using 3 µL of 1:3 diluted cDNA, 500 nM primers, and SsoAdvanced Universal SYBR Green Supermix (Bio-Rad, #1725271) in a 10 µL reaction volume on a CFX96 Real-Time System (Bio-Rad). Cycling conditions were: 95 °C for 30 s, followed by 39 cycles of 95 °C for 10 s and 58 °C for 30 s. Melting curve analysis confirmed amplification specificity. GUSB was used as the reference gene. Primer sequences for the connective tissue growth factor (CTGF) were as follows: Forward 5′- TGGTGCAGCCAGAAAGCTC-3′ and Reverse 5′- CCAATGACAACGCCTCCTG-3′; GUSB (human), Forward 5′- CACCAGGATCCACCTCTGAT-3′ and Reverse 5′- TCCAAATGAGCTCTCCAACC-3′; TET1 (human), Forward 5′-CATCAGTCAAGACTTTAAGCCCT-3′; and Reverse 5′- CGGGTGGTTTAGGTTCTGTTT-3′.

Immunofluorescence

Cells were subjected to static or flow conditions for 5 h prior to fixation. Channels were fixed with 4% paraformaldehyde under flow (0.5 dyn/cm2) for 15 min. Cells were permeabilized with 0.1% Triton X-100 for 10 min and blocked with 3% BSA for 1 h. Samples were incubated with a primary antibody against YAP (Santa Cruz Biotechnology, sc-101199) overnight at 4 °C, followed by incubation with a secondary antibody. The YAP nuclear-to-cytoplasmic ratio was quantified using MATLAB.

Cell transfection with YAP-targeting siRNA

Cells were transfected with YAP-targeting siRNA (Santa Cruz Biotechnology, sc-38637) or control siRNA (Thermo Fisher Scientific) using a lipid-based transfection reagent according to the manufacturer’s instructions. Cells were either subjected to scratch wound healing assays or harvested for RNA extraction and subsequent qPCR analysis 48 h post-transfection.

Statistics

All statistical analyses were conducted using GraphPad Prism software (version 9; GraphPad Software, San Diego, CA, USA). Data are expressed as the mean ± SEM. Comparisons among four groups across different time points were performed using a two-way ANOVA, while comparisons between two groups were evaluated using an unpaired two-tailed Student’s t-test. All experiments were performed with at least three independent biological replicates. Statistical significance was set at p < 0.05.

Results

Fluid shear stress selectively enhances directional migration of pancreatic cancer cells with low migratory capacity

Persistence was used as a metric to assess the straightness of the migration path [19]. When a cell migrates in a highly directed manner, D and L are almost equal, resulting in a persistence value (D/L) approaching 1. This indicates strong directional migration. Quantitative analysis of cell migration under static conditions revealed that SUIT2-007 cells exhibited significantly higher persistence than SUIT2-028 cells. However, upon application of fluid shear stress, the persistence of SUIT2-028 increased significantly compared to its static state, whereas SUIT2-007 cells showed no appreciable change in persistence. Additionally, when both cell lines were subjected to fluid shear stress, no significant difference in persistence was observed between SUIT2-028 and SUIT2-007 (Fig. 1D). These findings indicate that shear stress increased directional migration in SUIT2-028 cells, with minimal effect on SUIT2-007. Under fluid shear stress conditions, the persistence of SUIT2-028 and SUIT2-007 became comparable, suggesting that fluid shear stress differentially affects the two cell types and may reduce their migratory differences observed under static conditions.

Previous studies have shown that, within a given tumor cell type, cells with greater migration ability often exhibit smaller spreading areas under static conditions [20, 21]. Consistent with these findings, we observed that SUIT2-007 cells, known to have greater migratory ability than SUIT2-028, display a smaller spreading area under static conditions. However, upon application of fluid shear stress, no significant changes were observed in the spreading areas of either SUIT2-028 or SUIT2-007 cells, indicating that shear stress does not influence cell spreading area (Additional file 1. Figure S1A). To complement the analysis of migratory behavior, we also measured the average migration speed of the cells. We found that flow increased the migration speed of SUIT2-028 cells, whereas it had no significant effect on the migration speed of SUIT2-007 cells (Additional file 1. Figure S1B). The difference in migratory capacity between SUIT2-028 and SUIT2-007 cells disappeared under fluid shear stress. We propose that this convergence is driven by differential activation of specific signaling pathways in the two cell types, with fluid shear stress normalizing these differences.

Cells with higher migratory capacity exhibit enhanced YAP activation

To further investigate the differences between SUIT2-028 and SUIT2-007, we performed RNA-seq analysis on both cell types. RNA-seq analysis identified 4474 differentially expressed genes, with 1075 genes significantly upregulated and 3399 genes significantly downregulated in SUIT2-007 relative to SUIT2-028 (Fig. 2A). KEGG pathway analysis identified enrichment in several pathways associated with cell migration, including the PI3K-Akt pathway, MAPK pathway, cytokine-cytokine interaction pathway, Hippo pathway, ECM-receptor interaction pathway, and ABC transporter pathway (Fig. 2B). Notably, fluid shear stress has been shown to suppress the Hippo signaling pathway, leading to activation of its key regulator, YAP [9]. Heatmap analysis revealed significant differences in the expression levels of YAP target genes, as defined by Wang et al. [22], between SUIT2-028 and SUIT2-007, with the majority of these genes being predominantly upregulated in SUIT2-007 (Fig. 2C). These findings suggest higher YAP pathway activity in SUIT2-007 cells. Furthermore, qPCR analysis showed that the expression of the YAP downstream target CTGF was significantly increased in SUIT2-028 cells exposed to fluid shear stress compared to those under static conditions (Fig. 2D). These results suggest that fluid shear stress promotes YAP activation in SUIT2-028 cells, inducing the expression of downstream targets (Fig. 2E). Immunofluorescence analysis further confirmed that YAP nuclear localization was increased in SUIT2-028 cells under flow conditions, supporting enhanced YAP activation (Fig. 2F). We conclude that SUIT2-007 cells exhibit inherently high YAP activation, while fluid shear stress enhances YAP activity in SUIT2-028 to levels comparable to SUIT2-007, thereby eliminating differences in their migratory abilities.

Fig. 2.

Fig. 2

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Enhanced migratory capacity correlates with increased YAP activation in SUIT2 cell sublines.A Volcano plot depicting differentially expressed genes between the highly migratory SUIT2-007 and the less migratory SUIT2-028 cells. B KEGG pathway enrichment analysis highlighting key signaling pathways altered between SUIT2-028 and SUIT2-007 cells. C Heatmap illustrating the expression profiles of canonical YAP target genes in SUIT2-028 versus SUIT2-007 cells. D Quantitative analysis of CTGF gene expression in SUIT2-028 cells cultured under static conditions compared to those exposed to flow-induced shear stress. E Schematic model demonstrating how flow shear stress triggers YAP activation, leading to modulation of downstream target genes involved in migratory behavior. F Representative images and quantitative analysis of YAP staining (green) and nuclear DAPI staining (blue) in SUIT2-028 cells under static and flow conditions. All experiments were independently repeated at least three times

In addition, heatmap analysis of RNA-seq data revealed reduced expression of DNA methylation-associated genes and increased expression of DNA demethylation-associated genes in SUIT2-007 cells compared with SUIT2-028 cells, suggesting a potential increase in epigenetic plasticity in SUIT2-007 cells (Additional file 1. Figure S2A). As summarized in previous reviews, alterations in gene methylation status can contribute to the promotion of tumor cell migration [23, 24]. Therefore, we hypothesize that the high migratory capacity observed in SUIT2-007 cells may be associated with their relatively lower levels of gene methylation. Further functional experiments are required to validate this hypothesis.

The enhanced metastatic ability of SUIT2-007 compared to SUIT2-028 is attributed to its elevated levels of YAP activation

To further confirm that the higher metastatic ability of SUIT2-007 compared to SUIT2-028 is driven by its elevated YAP activation, we treated both SUIT2-028 and SUIT2-007 cells with the YAP inhibitor verteporfin. The scratch assay results revealed that after 20 and 24 h, SUIT2-007 exhibited a greater migration ability than SUIT2-028. However, verteporfin treatment significantly reduced the migration abilities of both SUIT2-007 and SUIT2-028 lines and eliminated the difference in their migratory capacities (Fig. 3A and B). We further used siRNA targeting YAP to successfully suppress the expression of the downstream YAP target gene (Additional file 1. Figure S3A). In addition, scratch wound healing assays showed that YAP knockdown inhibited the migratory capacity of SUIT2-028 cells (Additional file 1. Figure S3B). Taken together, these findings suggest that the superior migratory ability of SUIT2-007 compared to SUIT2-028 may be associated with increased YAP activity (Fig. 3C).

Fig. 3.

Fig. 3

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YAP inhibition by verteporfin reduces migration in SUIT2-007 and SUIT2-028 pancreatic cancer cells, equalizing their motility.A, B Representative images and quantitative analysis of wound healing assays performed on SUIT2-028 and SUIT2-007 cells treated with or without the YAP inhibitor verteporfin. C Schematic model illustrating the relationship between YAP activation and migratory behavior in SUIT2-028 and SUIT2-007 cells under static and flow conditions. Abbreviations: VP, verteporfin; YAP, yes-associated protein. All experiments were independently repeated at least three times

Discussion

The present study is the first to investigate the effects of fluid shear stress on pancreatic cancer cells, demonstrating that fluid shear significantly enhances the directional migratory capacity of SUIT2-028 cells. Pancreatic cancer is typically diagnosed at advanced stages, often with metastasis. Previous studies have shown that increased mechanical forces promote PDAC cell migration [25–27]. Fluid shear stress enhances the migratory capabilities of multiple cancer cells through various pathways, including the Hippo pathway, the PI3K/AKT pathway, and autophagy [28–30].

Remarkably, we demonstrated that fluid shear stress enhances the directional migration of SUIT2-028 cells but does not further increase the migratory capacity of the highly motile SUIT2-007 cells. We propose that this difference stems from the intrinsically elevated YAP activation in SUIT2-007 cells, which may limit additional activation by fluid shear. In contrast, YAP in SUIT2-028 cells appears more responsive to fluid shear-induced activation.

Activated YAP promotes metastasis in pancreatic cancer cells [31], consistent with our findings that the migration ability of PDAC cells decreases following treatment with a YAP inhibitor. As the YAP inhibitor verteporfin may exert off-target effects beyond inhibiting YAP activity, including potential modulation of pathways such as autophagy [32], we additionally employed siRNA-mediated knockdown to more specifically target the YAP signaling pathway. While these complementary approaches improve the specificity of our findings, further rescue experiments will be required to more definitively establish the causal role of YAP. In addition, we found that SUIT2-007 exhibits greater epigenetic plasticity than SUIT2-028. Given that YAP has been reported to promote gene demethylation and further amplify YAP signaling through demethylation of key pathway components [33], our finding that YAP knockdown reduces TET1 mRNA expression (Additional file 1, Fig. S3C) is consistent with a functional link between YAP activity and epigenetic regulation. In this context, this epigenetic mechanism may help explain the enhanced migratory capacity observed in SUIT2-007 (Additional file 1. Figure S2B). Notably, our study is the first to attribute the differing metastatic potentials of SUIT2-028 and SUIT2-007 cells to their inherent differences in YAP activity.

Conclusion

In conclusion, we demonstrate that fluid shear stress differentially impacts the migratory capacities of SUIT2-028 and SUIT2-007 cells, driven by their distinct levels of YAP activation. A deeper understanding of the mechanisms underlying these differences in migratory behavior may offer valuable insights for the development of targeted clinical therapies in pancreatic cancer.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary Material 1 (7.5MB, mp4)
Supplementary Material 2 (355KB, docx)

Acknowledgements

The authors would like to acknowledge Paolo Aretini, Stefano Coppola, Btissame El Hassouni, Michel A. Hoogenkamp and Yehuda G. Assaraf for their support and contributions as well as the fruitful discussions within the EORTC-PAMM, I-PCC and COST Action TRANSPAN - CA21116 international networks. Our sincere appreciation also goes to the patient associations Fondazione Nadia Valsecchi and Oltre la Ricerca.

Author contributions

JD: Visualization, Investigation, Data curation, Methodology, Software, Writing- Original draft preparation. GL: Software, Validation, Visualization. AP: Software, Validation, Visualization. AEF: Methodology, Writing- Reviewing and Editing. DD: Methodology, Writing- Reviewing and Editing, Supervision. EG: Methodology, Conceptualization, Writing- Reviewing and Editing, Supervision.

Funding

JD is supported by China Scholarship Council (Number: 202306260050). The purchase of the BioFlux Z1000 system was (partially) funded by NWO Earth and Life Sciences (ALW; http://www.nwo.nl/en), Project Number 834.13.00. Additional funding was provided by the Cancer Center Amsterdam (CCA), AIRC, and the Dutch Cancer Society (KWF) grant #11957, 15305.

Data availability

All data generated or analysed during this study are included in this published article and its supplementary information files. The code used for statistical analyses is available upon request from the corresponding author.

Declarations

Ethical approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional file 1

Supplementary methods.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Material 1 (7.5MB, mp4)
Supplementary Material 2 (355KB, docx)

Data Availability Statement

All data generated or analysed during this study are included in this published article and its supplementary information files. The code used for statistical analyses is available upon request from the corresponding author.

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