ArticleCancers2023
Prognostic Significance of Integrin Subunit Alpha 2 (ITGA2) and Role of Mechanical Cues in Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma (PDAC).
Article in Cancers, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed.
- Biofabrication and artificial intelligence strategies for investigating solid- and fluid-pressure mechanobiology in pancreatic ductal adenocarcinoma.Cancer metastasis reviews · 2026Review
- A ternary association of KRas, EphA2, and integrins controls PDAC cell behavior.The Journal of biological chemistry · 2026Article
- Computational design and molecular characterization of a multi-epitope peptide vaccine targeting pancreatic cancer.Journal, genetic engineering & biotechnology · 2026Article
- Fluid shear stress enhances pancreatic cancer motility through YAP activation.Clinical epigenetics · 2026Article
- Dynamic evaluation of the glycolytic determinants LDH-A and GLUT-1 enhances prognostic significance and their inhibition affects the growth of mesothelioma spheroids.Molecular metabolism · 2026Article
- Development of the relationship between tumor and mechanobiology over the past 30 years: a bibliometric analysis.Discover oncology · 2026Article
- Integrin α2: mode of regulation and functioning in the metastatic cancer cascade.Journal of translational medicine · 2026Review
- Membrane and soluble VTCN1 (B7H4) converge on Src signaling to mediate gemcitabine resistance in intrahepatic cholangiocarcinoma.Theranostics · 2026Article
- Bioengineering 3D Pancreatic Cancer Models with Fibrotic Stroma for In Vitro Cancer Modeling.Micromachines · 2025Review
- ITGA2 Mediates the Resistance of Hepatocellular Carcinoma to Lenvatinib by Activating the AKT/FOXO3A Signaling Pathway.Cancers · 2025Article
- Identifying and validating PLAU as a potential prognostic biomarker for PDAC.Scientific reports · 2025Article
- Integrins in Cancer Drug Resistance: Molecular Mechanisms and Clinical Implications.International journal of molecular sciences · 2025Review
- Quantitative characterization of the 3D self-organization of PDAC tumor spheroids reveals cell type and matrix dependence through advanced microscopy analysis.APL bioengineering · 2025Article
- Article
- Novel kinase regulators of extracellular matrix internalisation identified by high-content screening modulate invasive carcinoma cell migration.PLoS biology · 2024Article
- Altered Mechanobiology of PDAC Cells with Acquired Chemoresistance to Gemcitabine and Paclitaxel.Cancers · 2024Article
- Targeting the pancreatic tumor microenvironment by plant-derived products and their nanoformulations.Medical oncology (Northwood, London, England) · 2024Review
- A stumbling block in pancreatic cancer treatment: drug resistance signaling networks.Frontiers in cell and developmental biology · 2024Review
- Revolutionizing Cancer Treatment: Unveiling New Frontiers by Targeting the (Un)Usual Suspects.Cancers · 2023Article
- 1,3,4-Oxadiazole and 1,3,4-Thiadiazole Nortopsentin Derivatives against Pancreatic Ductal Adenocarcinoma: Synthesis, Cytotoxic Activity, and Inhibition of CDK1.Marine drugs · 2023Article
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Authors and funding
13 authors.
Funding
Abstract
introductionPDAC is an extremely aggressive tumor with a poor prognosis and remarkable therapeutic resistance. The dense extracellular matrix (ECM) which characterizes PDAC progression is considered a fundamental determinant of chemoresistance, with major contributions from mechanical factors. This study combined biomechanical and pharmacological approaches to evaluate the role of the cell-adhesion molecule ITGA2, a key regulator of ECM, in PDAC resistance to gemcitabine.
methodsThe prognostic value of ITGA2 was analysed in publicly available databases and tissue-microarrays of two cohorts of radically resected and metastatic patients treated with gemcitabine. PANC-1 and its gemcitabine-resistant clone (PANC-1R) were analysed by RNA-sequencing and label-free proteomics. The role of ITGA2 in migration, proliferation, and apoptosis was investigated using hydrogel-coated wells, siRNA-mediated knockdown and overexpression, while collagen-embedded spheroids assessed invasion and ECM remodeling.
resultsHigh ITGA2 expression correlated with shorter progression-free and overall survival, supporting its impact on prognosis and the lack of efficacy of gemcitabine treatment. These findings were corroborated by transcriptomic and proteomic analyses showing that ITGA2 was upregulated in the PANC-1R clone. The aggressive behavior of these cells was significantly reduced by ITGA2 silencing both in vitro and in vivo, while PANC-1 cells growing under conditions resembling PDAC stiffness acquired resistance to gemcitabine, associated to increased ITGA2 expression. Collagen-embedded spheroids of PANC-1R showed a significant matrix remodeling and spreading potential via increased expression of CXCR4 and MMP2. Additionally, overexpression of ITGA2 in MiaPaCa-2 cells triggered gemcitabine resistance and increased proliferation, both in vitro and in vivo, associated to upregulation of phospho-AKT.
conclusionsITGA2 emerged as a new prognostic factor, highlighting the relevance of stroma mechanical properties as potential therapeutic targets to counteract gemcitabine resistance in PDAC.
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