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Review Open Access

Pancreatic cancer EMT‑targeted therapy: Molecular mechanisms and clinical translation (Review)

  • Authors:
    • Guirui Zhang
    • Yongmo Wu
    • Mingzhen Wei
    • Shupeng Huang
    • Qinghao Wang
    • Zhengyi Xie
    • Sisi Liu
    • Jin Wang
  • View Affiliations / Copyright

    Affiliations: Guangxi University of Science and Technology, Liuzhou, Guangxi Zhuang Autonomous Region 545005, P.R. China
    Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 54
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    Published online on: March 6, 2026
       https://doi.org/10.3892/ijo.2026.5867
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Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a dismal 5‑year survival rate of ~9%, primarily due to late diagnosis, aggressive metastasis and profound resistance to conventional therapies. Epithelial‑mesenchymal transition (EMT) has been identified as a pivotal driver of these malignant phenotypes, facilitating early invasion, dissemination and treatment failure. The present review systematically elaborated on the multidimensional mechanisms underlying EMT in PDAC, emphasizing its operation as a spectrum of hybrid epithelial/mesenchymal states rather than a binary switch. Key molecular mechanisms include the activation of core transcription factors (such as Snail, ZEB, Twist), intricate crosstalk within the tumor microenvironment (such as transforming growth factor-β and hepatocyte growth factor signaling from stromal cells) and dynamic epigenetic reprogramming. Furthermore, EMT critically contributes to the acquisition of cancer stem cell properties and enhances the survival and colonization of circulating tumor cells. The present review also outlined emerging translational strategies targeting EMT‑related pathways, highlighting agents such as STNM01 that have entered early-phase clinical trials. By synthesizing unprecedented insights into EMT's plastic spectrum states and subtype‑specific regulatory networks, this work establishes a paradigm‑shifting framework for advancing EMT‑targeted therapies; offering transformative potential to overcome PDAC's historical therapeutic barriers and substantially improve patient survival outcomes. By synthesizing current insights from molecular pathways to therapeutic applications, the present review confirmed EMT as a promising therapeutic target and provides a strategic framework for advancing PDAC treatment, with the ultimate goal of improving clinical outcomes.
View Figures

Figure 1

Mechanism of TME-induced EMT and the
CAF-cancer cell feedback loop in PDAC progression. During the PanIN
stage, signals derived from the TME, such as TGF-β and HGF,
activate the EMT program via their cognate receptors. As a core
component of epithelial adherens junctions, E-cadherin maintains
junctional stability by binding to p120 catenin. The core executors
of EMT-TFs bind to the promoter region of the CDH1 gene and recruit
epigenetic modification complexes (such as HDACs, DNMTs) to
suppress the expression of the epithelial marker E-cadherin, while
simultaneously upregulating the mesenchymal marker N-cadherin. This
'cadherin switching' liberates cancer cells from their original
cell-cell connections, allowing them to anchor to the stroma via
heterotypic adhesion with CAFs and enhances directed migration by
activating the α-catenin/vinculin-FAK/Src signaling pathway.
Concurrently, TGF-β signaling modulates the activity of Rho GTPases
(such as activating Rac1, inhibiting RhoA) by mediating the
alternative splicing of genes such as ARHGEF11and CTTN. This drives
cytoskeletal remodeling and stress fiber formation. The
intracellular tension gradient generated by myosin contraction,
coordinated with traction forces transmitted via integrin-mediated
focal adhesions, helps cells overcome stromal resistance, thereby
powering cell migration. To pave the way for invasion,
EMT-transformed cancer cells secrete factors such as TGF-β and
PDGF, which induce the transformation of PSCs into CAFs via the
SMAD pathway and MAPK/ERK signaling, respectively. Activated CAFs
not only highly express matrix metalloproteinases, becoming a major
source of matrix-degrading enzymes, but also secrete excess TGF-β.
This excess TGF-β further reinforces the EMT phenotype in cancer
cells through both SMAD and non-SMAD pathways (such as MAPK/ERK).
Simultaneously, mechanical tension generated by ECM remodeling
amplifies invasion signals via integrin/FAK signaling, ultimately
forming a malignant positive-feedback loop that drives progressive
invasion. TME, tumor microenvironment; EMT, epithelial-mesenchymal
transition; CAF, cancer-associated fibroblast; PDAC, pancreatic
ductal adenocarcinoma; PanIN, precancerous pancreatic
intraepithelial neoplasia; TGF-β, transforming growth factor-β;
HGF, hepatocyte growth factor; EMT-TFs, EMT-EMT transcription
factors; HDACs, histone deacetylases; DNMTs, DNA
methyltransferases; FAK, focal adhesion kinase; PDGF,
platelet-derived growth factor; PSCs, pancreatic stellate
cells.

Figure 2

Mechanisms of circulating tumor cell
survival and metastasis in PDAC. After detaching from the primary
tumor and entering the bloodstream as CTCs, PDAC cells exhibit
distinct metastatic behaviors: cells undergoing complete EMT,
despite gaining enhanced motility via the RhoA/ROCK pathway, are
vulnerable as single cells to shear stress and NK cell-mediated
attacks. In contrast, the 'partial'mixed EMT/ phenotype
demonstrates the highest metastatic efficiency, acquiring
anti-apoptotic capabilities through the Twist1/MAPK pathway. CTCs
retaining E-cadherin can form clusters, which markedly enhance
circulatory survival and metastatic potential via multidimensional
cooperative mechanisms. These aggregates, shielded by platelet-rich
microthrombi, reduce direct shear stress damage and facilitate
immune evasion through PD-L1 expression (suppressing T cells) and
CD47 expression (blocking macrophage phagocytosis). Interactions
with platelets, such as TGF-β release activating SMAD signaling and
ADP-P2Y12 receptor engagement promoting further TGF-β secretion,
augment survival, while adhesion via integrins to platelets or
soluble matrix proteins (such as PDGF and VEGF) creates a
protective microenvironment that minimizes apoptosis. The final
critical step in the metastatic cascade, successful colonization at
distant organs, hinges on MET, which reestablishes epithelial
polarity and intercellular adhesion capabilities. PDAC, pancreatic
ductal adenocarcinoma; CTCs, circulating tumor cells; EMT,
epithelial-mesenchymal transition; MAPK, mitogen-activated protein
kinase; PD-L1, programmed cell death ligand 1; PDGF,
platelet-derived growth factor; VEGF, vascular endothelial growth
factor; MET, mesenchymal-epithelial transition.

Figure 3

Therapeutic resistance mechanisms in
PDAC. The extreme resistance of PDAC to chemotherapy and
radiotherapy stems from its unique EMT-stemness-therapy resistance
axis. The initiation of this vicious cycle critically depends on
EVs secreted by CAFs. These EVs deliver molecules such as miR-146a
(activating Snail) and circFARP1 (activating the LIF/STAT3 axis),
which collaboratively induce the EMT program and the acquisition of
CSC traits. TGF-β signaling further reinforces EMT via the Smad
pathway and activates EMT-TFs such as ZEB1 and Snail, enabling
differentiated non-stem-like cancer cells to gain CSC properties.
Among these, ZEB1 directly interacts with YAP1 in response to TGF-β
signaling, coregulating stem cell pluripotency, while ZEB1/2
maintains the EMT phenotype and reduces drug sensitivity by
transcriptionally inhibiting the miR-200 family (microRNAs that
themselves form a mutual inhibitory feedback by targeting the
3'UTRs of ZEB1'2). The EMT program also enhances cell survival
signals by activating pathways such as PI3K/AKT and increases the
apoptotic threshold through upregulation of the anti-apoptotic
molecule Bcl-xL and suppression of the pro-apoptotic factor BOK,
allowing cells to improved survive DNA damage induced by drugs or
radiation. Simultaneously, EMT promotes CSC-like characteristics,
including a transient entry into a dormant, cell cycle-arrested
state, helping cells evade proliferation-targeting drugs.
Metabolically, EMT-activated cells sustain energy supply by
upregulating glucose transporter GLUT3 and enhancing the Warburg
effect, thereby tolerating metabolic stress induced by
chemotherapy. Additionally, ZEB1 directly binds to the ATM promoter
to increase ATM expression and stabilizes CHK1, accelerating DNA
damage repair and reducing radiation-induced cell death.
Radiotherapy itself can further upregulate EMT-TFs such as ZEB1 and
Snail by activating pathways such as TGF-β and NF-κB, forming a
positive feedback loop that exacerbates therapy resistance. In
summary, this multidimensional mechanism, encompassing EV-mediated
signaling initiation, EMT-stemness coupling, survival signal
enhancement, metabolic reprogramming and DNA repair activation,
collectively underlies PDAC treatment failure. PDAC, pancreatic
ductal adenocarcinoma; EMT, epithelial-mesenchymal transition; EVs
CAFs, cancer-associated fibroblasts; CSC, cancer stem cell; TGF-β,
transforming growth factor-β; EMT-TFs, EMT-transcription factors;
LIF, leukemia inhibitory factor; STAT3, signal transducer and
activator of transcription 3; ZEB1, Zinc Finger E-Box Binding
Homeobox 1; YAP1, Yes-Associated Protein 1; GLUT3, glucose
transporter 3; ATM, ataxia-telangiectasia mutated.

Figure 4

EMT regulatory network: Multi-layer
control of transcription factors. TGF-β1 upregulates Snail1 via the
Smad2/3-Numb-PRRL pathway and synergizes with Notch1 signaling to
enhance EMT. The WNT/β-catenin pathway forms a positive feedback
loop with Snail1: STMN2 activates the WNT pathway to upregulate
Snail1 and nuclear β-catenin/TCF complexes transactivate STMN2.
RHOF enhances glycolysis through the c-Myc-PKM2 axis and the
resulting lactate induces Snail1 lactylation and nuclear
translocation. Snail1 stability is controlled by ubiquitin-mediated
degradation, while its transcriptional activity is enhanced by
phosphorylation and acetylation. EZH2 suppresses miR-139-5p via
H3K27me3 modification, relieving its targeted inhibition of ZEB1/2.
In the inflammatory microenvironment, MIF downregulates miR-200b
and NF-κB directly binds to the ZEB1 promoter to enhance its
expression, while VASH2 upregulates ZEB1/2 by activating the Hh
pathway; moreover, TGF-β-induced EMT requires ZEB1 participation.
Upstream hypoxia stabilizes HIF-1α to activate Twist1
transcription; TGF-β upregulates Twist1 through the SMAD-SOX5
pathway and synergizes with STAT3/ETS1/2 and RAS signaling; AURKA
phosphorylates Twist1 to inhibit its ubiquitin-mediated
degradation, while miR-539 targets Twist1 mRNA to inhibit its
translation. EMT, epithelial-mesenchymal transition; TGF-β,
transforming growth factor-β; STMN2, stathmin 2; TCF, T Cell
Factor; RHOF, Ras Homolog Family Member F; c-Myc, cellular Myc;
PKM2, pyruvate kinase M2; EZH2, enhancer of Zeste Homolog 2; miR,
microRNA; ZEB1, Zinc Finger E-Box Binding Homeobox 1; MIF,
macrophage migration inhibitory factor; NF-κB, nuclear factor-kappa
B; HIF-1α, hypoxia-inducible factor 1 alpha; SMAD, Sma- and
Mad-related Protein; SOX5, SRY-Box transcription factor 5; RAS, rat
sarcoma viral oncogene homolog; AURKA, aurora kinase A.

Figure 5

The dual role of signaling and
pathway crosstalk in pancreatic cancer EMT. The role of the TGF-β
pathway in EMT of pancreatic cancer is context-dependent. In the
presence of SMAD4, TGF-β not only activates the SMAD2/3-SMAD4
complex to regulate key transcription factors such as Snail and
Twist but also, with the assistance of PHF13, maintains the
super-enhancer activity of SNAI1 and SOX9, ensuring sustained
expression of EMT genes. Conversely, SMAD4 loss switches SOX4 from
an oncogenic to a pro-apoptotic function. CircEIF3I enhances
pathway activation by strengthening the interaction between SMAD3
and TGFβRI. Under TGF-β1 stimulation, Numb-PRRL activates the
SMAD2/3-Snail pathway and forms a cross-activation loop with
Notch1, synergistically promoting EMT. TGF-β also exhibits
crosstalk with the EGF-EGFR-ERK/MAPK pathway to collectively
enhance cancer cell migration and invasion. Intracellularly, FAM83A
binds to β-catenin to disrupt the degradation complex, an effect
potentiated by BLK phosphorylation, jointly promoting β-catenin
nuclear translocation and Snail transcription; STYK1 maintains
pathway activity by sequestering GSK3β into multivesicular bodies.
Non-coding RNAs contribute to this regulation, such as circRREB1
binds to YAP1 to promote WNT7B transcription and glycolysis.
Furthermore, the Notch signaling pathway, activated by
membrane-bound ligands (such as DLL and Jagged) from neighboring
cells, and the Hh pathway, initiated by secreted ligands (such as
SHH) binding to the PTCH receptor, also participate in the
fine-tuned regulation of EMT. EMT, epithelial-mesenchymal
transition; TGF-β, transforming growth factor-β; SMAD4, Sma- and
Mad-related Protein 4; PHF13, PHD Finger Protein 13; SOX, SRY-Box
Transcription Factor; TGFβRI, Transforming Growth Factor-beta
Receptor I; EGF, Epidermal Growth Factor; EGFR, Epidermal Growth
Factor Receptor; ERK, Extracellular Signal-Regulated Kinase; MAPK,
Mitogen-Activated Protein Kinase; FAM83A, Family With Sequence
Similarity 83 Member A; BLK, B Lymphoid Tyrosine Kinase; STYK1,
Serine/Threonine/Tyrosine Kinase 1; GSK3β, Glycogen Synthase Kinase
3 Beta; YAP1, Yes-Associated Protein 1; DLL, Delta-like ProteinHh,
Hedgehog; SHH, Sonic Hedgehog; PTCH, Patched.
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Copy and paste a formatted citation
Spandidos Publications style
Zhang G, Wu Y, Wei M, Huang S, Wang Q, Xie Z, Liu S and Wang J: Pancreatic cancer EMT‑targeted therapy: Molecular mechanisms and clinical translation (Review). Int J Oncol 68: 54, 2026.
APA
Zhang, G., Wu, Y., Wei, M., Huang, S., Wang, Q., Xie, Z. ... Wang, J. (2026). Pancreatic cancer EMT‑targeted therapy: Molecular mechanisms and clinical translation (Review). International Journal of Oncology, 68, 54. https://doi.org/10.3892/ijo.2026.5867
MLA
Zhang, G., Wu, Y., Wei, M., Huang, S., Wang, Q., Xie, Z., Liu, S., Wang, J."Pancreatic cancer EMT‑targeted therapy: Molecular mechanisms and clinical translation (Review)". International Journal of Oncology 68.5 (2026): 54.
Chicago
Zhang, G., Wu, Y., Wei, M., Huang, S., Wang, Q., Xie, Z., Liu, S., Wang, J."Pancreatic cancer EMT‑targeted therapy: Molecular mechanisms and clinical translation (Review)". International Journal of Oncology 68, no. 5 (2026): 54. https://doi.org/10.3892/ijo.2026.5867
Copy and paste a formatted citation
x
Spandidos Publications style
Zhang G, Wu Y, Wei M, Huang S, Wang Q, Xie Z, Liu S and Wang J: Pancreatic cancer EMT‑targeted therapy: Molecular mechanisms and clinical translation (Review). Int J Oncol 68: 54, 2026.
APA
Zhang, G., Wu, Y., Wei, M., Huang, S., Wang, Q., Xie, Z. ... Wang, J. (2026). Pancreatic cancer EMT‑targeted therapy: Molecular mechanisms and clinical translation (Review). International Journal of Oncology, 68, 54. https://doi.org/10.3892/ijo.2026.5867
MLA
Zhang, G., Wu, Y., Wei, M., Huang, S., Wang, Q., Xie, Z., Liu, S., Wang, J."Pancreatic cancer EMT‑targeted therapy: Molecular mechanisms and clinical translation (Review)". International Journal of Oncology 68.5 (2026): 54.
Chicago
Zhang, G., Wu, Y., Wei, M., Huang, S., Wang, Q., Xie, Z., Liu, S., Wang, J."Pancreatic cancer EMT‑targeted therapy: Molecular mechanisms and clinical translation (Review)". International Journal of Oncology 68, no. 5 (2026): 54. https://doi.org/10.3892/ijo.2026.5867
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