Journal Article

Integrin αvβ3-dependent pathogenic effect and therapeutic effects of DL-N2 combined with EGFR inhibitors in pancreatic adenocarcinoma

Shih, Ya-Jung, Huang, Lin-Yi, Crawford, Dana R., Kumar, Sachin, Chang, Tung-Cheng, Xuan, Do Thi Minh, Lin, Hung-Yun, Gionfra, Fabio, Solomon, Dahlak Daniel, Wang, Kuan, Li, Zi-Lin, Yang, Yung-Ning, Whang-Peng, Jaqueline, Lee, Yung-Kuo, Aher, Amruta, Wang, Chih-Yang, Yao, Chih-Jung, Abhista, Nandana Bayu, Lee, Sheng-Yang, Huang, Haw-Ming, Yang, San-Nan, Ko, Ching-Chung, Lin, Hui-Ru

2026

Overview

Background Pancreatic adenocarcinoma (PDAC) remains one of the most lethal malignancies, characterized by aggressive progression, pronounced stromal desmoplasia, and a limited response to targeted therapies. Although epidermal growth factor receptor (EGFR) inhibitors have shown promise in preclinical studies, their clinical efficacy has been modest, suggesting the existence of compensatory signaling networks. Methods An integrated analytical framework was employed, combining bulk transcriptomic analyses of TCGA-PDAC and GTEx datasets, DNA methylation profiling, protein–protein interaction (PPI) network analysis, immune infiltration estimation, and single-cell RNA sequencing. Expression patterns and clinical associations of integrin αvβ3 were evaluated using TCGA, GEPIA, UALCAN, and the Human Protein Atlas. Functional validation was performed using in vitro assays in pancreatic cancer cell lines to assess the effects of DL-N2, a tetrac-conjugated nanoparticle targeting integrin αvβ3, alone or in combination with gefitinib. Results Integrin αvβ3 (ITGAV/ITGB3) was upregulated in PDAC tissues compared with normal pancreatic tissue and was associated with poor prognosis. Single-cell transcriptomic profiling localized αvβ3 expression to malignant ductal cells and stromal fibroblasts. Computational analyses predicted strong associations of αvβ3 with EGFR, MMP2, and MMP9, implicating it in epithelial–mesenchymal transition (EMT), extracellular matrix (ECM) remodeling, and immune regulation. In vitro, experiments showed that DL-N2 suppressed basal and EGF-induced proliferation, decreased the expression of EGFR , PCNA , and CCND1 , and reduced angiogenic and invasive mediators, including VEGF-α , bFGF2 , and MMP9 . Notably, DL-N2 inhibited PD-L1 expression, linking αvβ3 signaling to immune evasion. In addition, both DL-N2 and gefitinib inhibited cell migration, and their combined treatment exerted an additive effect on the suppression of pancreatic cancer cell migration. Conclusion Our findings establish integrin αvβ3 as a multifunctional regulator of pancreatic cancer progression, integrating growth-associated signaling, extracellular matrix regulation, and immune-associated pathways. Targeting αvβ3 with DL-N2 remodels both tumor-intrinsic and microenvironmental pathways, potentially enhancing EGFR inhibition and restoring chemosensitivity. Dual blockade of αvβ3 and EGFR represents a rational therapeutic strategy to overcome drug resistance and improve outcomes in PDAC. Highlights Mechanistic Crosstalk Clarity : Ensure the introduction (which you've drafted well) leads directly to results that prove how integrin αvβ3 and EGFR interact. Mentioning FAK (Focal Adhesion Kinase) as the bridge is a common 2026 reviewer expectation for this pathway. Clinical Relevance : JTM editors look for \"human-centric\" data. If your paper relies on cell lines, ensure you have validated the expression of αvβ3 and EGFR in human PDAC tissue samples or publicly available databases (like TCGA or GTEx) to prove clinical significance. Address “Thyroid Hormone” Implications : Since you mentioned thyroid hormones (T3/T4) binding to αvβ3, reviewers may ask if patients on thyroid medication show different PDAC outcomes. Briefly addressing this \"translational\" clinical potential in your discussion can significantly strengthen your case

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Adenocarcinoma / Angiogenesis / Antineoplastic Combined Chemotherapy Protocols - pharmacology / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / B7-H1 Antigen - genetics / B7-H1 Antigen - metabolism / Biomedical and Life Sciences / Biomedicine / Carcinoma, Pancreatic Ductal - drug therapy / Carcinoma, Pancreatic Ductal - genetics / Carcinoma, Pancreatic Ductal - immunology / Carcinoma, Pancreatic Ductal - pathology / Cell Line, Tumor / Cell migration / Cell Movement - drug effects / Cell Movement - genetics / Chemotherapy / Colorectal cancer / Datasets / DNA fingerprinting / DNA methylation / Drug resistance / Drug Resistance, Neoplasm - drug effects / Drug Resistance, Neoplasm - genetics / Drug Resistance, Neoplasm - immunology / Drug Synergism / Epidermal growth factor / Epidermal growth factor receptors / ErbB Receptors - antagonists & inhibitors / ErbB Receptors - metabolism / Extracellular matrix / Focal adhesion kinase / Gefitinib / Gelatinase A / Gelatinase B / Gene expression / Gene Expression Regulation, Neoplastic - drug effects / Gene Expression Regulation, Neoplastic - immunology / Hormones / Humans / Immunoregulation / Integrin alphaVbeta3 - antagonists & inhibitors / Integrin alphaVbeta3 - genetics / Integrin alphaVbeta3 - metabolism / Kinases / Localization / Malignancy / Medical prognosis / Medicine/Public Health / Metastases / Metastasis / Nanoparticles / Nanoparticles - chemistry / Nanoparticles - therapeutic use / Pancreatic cancer / Pancreatic Neoplasms - drug therapy / Pancreatic Neoplasms - genetics / Pancreatic Neoplasms - immunology / Pancreatic Neoplasms - pathology / Proteins / Signal transduction / Signal Transduction - drug effects / Signal Transduction - genetics / Signal Transduction - immunology / Single-Cell Gene Expression Analysis / Survival analysis / Thyroid gland / Thyroid hormones / Thyroxine / Thyroxine - analogs & derivatives / Thyroxine - chemistry / Thyroxine - pharmacology / Thyroxine - therapeutic use / Transcriptomics / Translational Signaling and System Biology / Triiodothyronine / Tumor cell lines / Tumor Microenvironment - drug effects / Tumor Microenvironment - genetics / Tumor Microenvironment - immunology / Tyrosine Kinase Inhibitors - pharmacology / Tyrosine Kinase Inhibitors - therapeutic use / Vascular endothelial growth factor