Pancreatic ductal adenocarcinoma cells regulated the gemcitabine‐resistance function of CAFs by LINC00460

• Published in: Cancer science Vol. 113; no. 11; pp. 3735 - 3750
• Main Authors: Zhu, Xiao‐Xu, Li, Jian‐Hui, Ni, Xuhao, Wu, Xiao, Hou, Xun, Li, Ya‐Xiong, Li, Shi‐Jin, Zhao, Wei, Yin, Xiao‐Yu
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.11.2022; John Wiley and Sons Inc
• Subjects: Adenocarcinoma; Antimetabolites, Antineoplastic - pharmacology; Antimetabolites, Antineoplastic - therapeutic use; Cancer; cancer associated fibroblasts; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - genetics; Cell culture; Cell interactions; Cell Line, Tumor; Chemotherapy; Chromatography, Liquid; Cytoplasm; Drug Resistance, Neoplasm - genetics; Experiments; Extracellular matrix; Fibroblasts; Gemcitabine; gemcitabine‐resistance; Growth factors; Hospitals; Humans; Immunoblotting; Intercellular Signaling Peptides and Proteins; Laboratory animals; LINC00460; Malignancy; Medical prognosis; Original; Pancreas; pancreatic ductal adenocarcinoma; Pancreatic Neoplasms; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Patients; PDAP1; Precision medicine; RNA, Long Noncoding - genetics; Signal transduction; Tandem Mass Spectrometry; Tumor cells; Tumors; China; LINC00460; PDAP1; gemcitabine-resistance; cancer associated fibroblasts; pancreatic ductal adenocarcinoma
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.15547

Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal malignancy with extremely poor prognosis. Gemcitabine resistance is a major challenge in the treatment of PDAC. Here, we showed that LINC00460 was associated with the response to gemcitabine both in PDAC patients and PDAC‐PDX. After knocking down LINC00460 in PDAC tumor cells, results of RNA sequencing followed by gene ontology analysis indicated that LINC00460 influenced the activity of growth factors and modified the extracellular matrix. FISH showed that LINC00460 is mostly located in the cytoplasm. Results of RNA pull‐down, LC–MS/MS, RIP, and immunoblotting confirmed that LINC00460 could directly bind to PDAP1. Furthermore, we demonstrated that LINC00460 mediated the cellular communication of PDAC tumor cells and CAFs by PDAP1/PDGFA/PDGFR signaling pathway and regulated the gemcitabine‐resistance function of CAFs, which could be reversed by treatment with a PDGFR inhibitor (crenolanib). PDAC‐PDX tumors with lower expression of LINC00460 showed a better response to gemcitabine plus crenolanib treatment. Our finding supported the application of LINC00460 in precision medicine that uses gemcitabine plus crenolanib to treat PDAC with low expression of LINC00460. LINC00460 regulates the gemcitabine chemotherapy‐resistance function of CAFs via the PDAP1/PDGFA/PDGFR pathway, which could be attenuated by treatment with a PDGFR inhibitor (crenolanib).PDAC with low expressed LINC00460 is an indicator to apply treatment therapy of gemcitabine combine with crenolanib.