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  4. Vol 4, Issue 1, 2026

Inflammatory Cancer-associated Fibroblast-derived Fibronectin Promotes Oxaliplatin Resistance in Pancreatic Ductal Adenocarcinoma through Integrin-mediated Signaling

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DOI: 10.23977/medbm.2026.040109 | Downloads: 0 | Views: 14

Author(s)

Zhaohui Chen 1, Junfeng Li 2, Jiexiao Long 2

Affiliation(s)

1 Guangdong Provincial Key Laboratory of Malignant Tumor Pathogenesis and Precision Diagnosis and Treatment, Shenshan Medical Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Shanwei, Guangdong, China
2 Department of Neurosurgery, Shenshan Medical Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Shanwei, Guangdong, China

Corresponding Author

Zhaohui Chen

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense fibrotic stroma. Inflammatory cancer-associated fibroblasts (iCAFs) within this stroma have been implicated in tumor progression, but their role in oxaliplatin resistance remains poorly defined. Here, we isolated iCAFs from oxaliplatin-resistant tumors and identified fibronectin (FN1) as a highly upregulated secretory factor through RNA sequencing. Recombinant FN1 and iCAF-conditioned medium significantly attenuated oxaliplatin-induced cytotoxicity in Panc-1 and MIAPaCa-2 cells, while an anti-FN1 neutralizing antibody reversed the protective effect. Bioinformatic analysis of the GSE79669 dataset revealed elevated FN1 and ITGA3 expression in oxaliplatin-resistant pancreatic cancer cells, and high ITGA3 expression was associated with worse overall and disease-free survival in the TCGA cohort. Pathway enrichment analysis of FN1/ITGA3-coexpressed genes identified focal adhesion, ECM-receptor interaction, PI3K-Akt signaling, regulation of actin cytoskeleton, Rap1 signaling, and Hippo signaling as potentially involved downstream pathways. A protein-protein interaction network further highlighted key nodes within these pathways. These findings demonstrate that iCAF-derived FN1 promotes oxaliplatin resistance in vitro and suggest that ITGA3 integrin signaling may mediate this effect, providing a foundation for future therapeutic targeting of stromal-tumor interactions in pancreatic cancer.

KEYWORDS

Pancreatic ductal adenocarcinoma, iCAFs, fibronectin, oxaliplatin resistance, ITGA3, bioinformatic analysis

CITE THIS PAPER

Zhaohui Chen, Junfeng Li, Jiexiao Long. Inflammatory Cancer-associated Fibroblast-derived Fibronectin Promotes Oxaliplatin Resistance in Pancreatic Ductal Adenocarcinoma through Integrin-mediated Signaling. MEDS Basic Medicine (2026). Vol. 4, No. 1, 66-75. DOI: http://dx.doi.org/10.23977/medbm.2026.040109.

REFERENCES

[1] Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7-33. doi:10.3322/caac.21708.
[2] Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74(11):2913-2921. doi:10.1158/0008-5472.CAN-14-0155.
[3] Park W, Chawla A, O’Reilly EM. Pancreatic cancer: a review. JAMA. 2021;326(9):851-862. doi:10.1001/jama.2021.13027.
[4] Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817-1825. doi:10.1056/NEJMoa1011923.
[5] Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691-1703. doi:10.1056/NEJMoa1304369.
[6] Raymond E, Faivre S, Chaney S, Woynarowski J, Cvitkovic E. Cellular and molecular pharmacology of oxaliplatin. Mol Cancer Ther. 2002;1(3):227-235.
[7] Yu S, Zhang C, Xie KP. Therapeutic resistance of pancreatic cancer: roadmap to its reversal. Biochim Biophys Acta Rev Cancer. 2021;1875(1):188461. doi:10.1016/j.bbcan.2020.188461.
[8] Nevala-Plagemann C, Hidalgo M, Garrido-Laguna I. From state-of-the-art treatments to novel therapies for advanced-stage pancreatic cancer. Nat Rev Clin Oncol. 2020;17(2):108-123. doi:10.1038/s41571-019-0281-6.
[9] Whatcott CJ, Diep CH, Jiang P, et al. Desmoplasia in primary tumors and metastatic lesions of pancreatic cancer. Clin Cancer Res. 2015;21(15):3561-3568. doi:10.1158/1078-0432.CCR-14-1051.
[10] Sahai E, Astsaturov I, Cukierman E, et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat Rev Cancer. 2020;20(3):174-186. doi:10.1038/s41568-019-0238-1.
[11] Biffi G, Tuveson DA. Diversity and biology of cancer-associated fibroblasts. Physiol Rev. 2021;101(1):147-176. doi:10.1152/physrev.00048.2019.
[12] Öhlund D, Handly-Santana A, Biffi G, et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J Exp Med. 2017;214(3):579-596. doi:10.1084/jem.20162024.
[13] Elyada E, Bolisetty M, Laise P, et al. Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. Cancer Discov. 2019;9(8):1102-1123. doi:10.1158/2159-8290.CD-19-0094.
[14] Boyd LNC, Andini KD, Peters GJ, Kazemier G, Giovannetti E. Heterogeneity and plasticity of cancer-associated fibroblasts in the pancreatic tumor microenvironment. Semin Cancer Biol. 2022;82:184-196. doi:10.1016/j.semcancer.2021.03.006.
[15] Pankov R, Yamada KM. Fibronectin at a glance. J Cell Sci. 2002;115(Pt 20):3861-3863. doi:10.1242/jcs.00059.
[16] Hiroshima Y, Kasajima R, Kimura Y, Komura D, Miyagi Y. Novel targets identified by integrated cancer-stromal interactome analysis of pancreatic adenocarcinoma. Cancer Lett. 2020;469:217-227. doi:10.1016/j.canlet.2019.10.031.
[17] Ye Y, Zhang R, Feng H. Fibronectin promotes tumor cells growth and drugs resistance through a CDC42-YAP dependent signaling pathway in colorectal cancer. Cell Biol Int. 2020;44(9):1840-1849. doi:10.1002/cbin.11390.
[18] Gao W, Liu Y, Qin R, Liu D, Feng Q. Silence of fibronectin 1 increases cisplatin sensitivity of non-small cell lung cancer cell line. Biochem Biophys Res Commun. 2016;476(1):35-41. doi:10.1016/j.bbrc.2016.05.081.
[19] Zhang X, Zheng S, Hu C, et al. Cancer-associated fibroblast-induced lncRNA UPK1A-AS1 confers platinum resistance in pancreatic cancer via efficient double-strand break repair. Oncogene. 2022;41(16):2372-2389. doi:10.1038/s41388-022-02265-4.
[20] Xavier CPR, Castro I, Caires HR, et al. Chitinase 3-like-1 and fibronectin in the cargo of extracellular vesicles shed by human macrophages influence pancreatic cancer cellular response to gemcitabine. Cancer Lett. 2021;501:210-223. doi:10.1016/j.canlet.2020.11.013.
[21] Lei X, Li Y, Chen Z, et al. Comprehensive analysis of abnormal expression, prognostic value and oncogenic role of the hub gene FN1 in pancreatic ductal adenocarcinoma via bioinformatic analysis and in vitro experiments. PeerJ. 2021;9:e12141. doi:10.7717/peerj.12141.
[22] Hu JK, Du W, Shelton SJ, Oldham MC, DiPersio CM, Klein OD. An FAK-YAP-mTOR signaling axis regulates stem cell-based tissue renewal in mice. Cell Stem Cell. 2017;21(1):91-106. doi:10.1016/j.stem.2017.03.023.
[23] Lv PC, Jiang AQ, Zhang WM, Zhu HL. FAK inhibitors in cancer, a patent review. Expert Opin Ther Pat. 2018;28(2):139-145. doi:10.1080/13543776.2018.1414183.
[24] Liu-Chittenden Y, Huang B, Shim JS, et al. Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP. Genes Dev. 2012;26(12):1300-1305. doi:10.1101/gad.192856.112.

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