COLLOIDS AND SURFACES B-BIOINTERFACES
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2025
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IF 5.6
Jiashuai Yan,Di Wu,Biwen Zhu,Xiaoqi Guan,Xue Zhang,Yibing Guo,Yuhua Lu
As a highly aggressive solid tumor, pancreatic ductal adenocarcinoma (PDAC) is featured by a conspicuous tumor microenvironment (TME) with abundant extracellular matrix (ECM) deposition, such as collagen and hyaluronic acid (HA). Accompanying with the pathological process, the dense matrix caused stiffen microenvironment, which leads to poor chemotherapy. Therefore, understanding the potential mechanism of mechanical microenvironment on PDAC chemoresistance is of great significance. To this end, 3D printed methacrylated gelatin (GelMA) and hyaluronic acid methacryloyly (HAMA) hydrogel model was fabricated to resemble the mechanical microenvironment of PDAC. The results presented that the PDAC cell lines (MIA-PaCa2 and PANC-1) embedded in the hydrogel were distinctively less sensitive to gemcitabine compared to tissue culture plate (TCP) group. Interestingly, immunofluorescence staining and qRT-PCR assay demonstrated that the NRF2 level was elevated, which further upregulated the downstream effectors, such as SLC7A11 and GPX4. Meanwhile, the GSH concentration and GPX4 activity of hydrogel group were increased, while the lipid peroxidation level was reduced, which indicated that the matrix stiffness microenvironment mediated ferroptosis phenotype. Furthermore, RNA interference experiment elaborated that shNRF2 group showcased significantly enhanced sensitivity to gemcitabine, which demonstrated that the biomimetic microenvironment modulated chemoresistance through ferroptosis. All in all, the 3D printed model may serve as a new platform for illustrating the underlying mechanism of the TME induced chemoresistance, and also proposed a novel therapeutic strategy for PDAC through NRF2 inhibition, which effectively promotes ferroptosis to overcome chemoresistance.
研究领域:
肿瘤学
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细胞生物学
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生物医学工程
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PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2024
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IF 7.7
Di Wu,Tiancheng Gong,Zhongxiang Sun,Xihao Yao,Dongzhi Wang,Qiyang Chen,Qingsong Guo,Xiaohong Li,Yibing Guo,Yuhua Lu
The tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is characterized by deposition of desmoplastic matrix (including collagen and hyaluronic acid). And the interactions between tumor-associated macrophages (TAMs) and tumor cells play a crucial role in progression of PDAC. Hence, the appropriate model of tumor cell-macrophage interaction within the unique PDAC TME is of significantly important. To this end, a 3D tumor niche based on dual-crosslinking gelatin methacrylate and hyaluronic acid methacrylate hydrogels was constructed to simulate the desmoplastic tumor matrix with matching compressive modulus and composition. The bionic 3D tumor niche creates an immunosuppressive microenvironment characterized by the downregulation of M1 markers and upregulation of M2 markers in TAMs. Mechanistically, RNA-seq analysis revealed that the PI3K-AKT signaling pathway might modulate the phenotypic balance and recruitment of macrophages through regulating SELE and VCAM-1. Furthermore, GO and GSEA revealed the biological process of leukocyte migration and the activation of cytokine-associated signaling were involved. Finally, the 3D tumor-macrophage niches with three different ratios were fabricated which displayed increased M2-like polarization and stemness. The utilization of the 3D tumor niche has the potential to provide a more accurate investigation of the interplay between PDAC tumor cells and macrophages within an in vivo setting.
研究领域:
癌症生物学
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组织工程
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生物材料
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免疫学
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细胞信号传导
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PubMed
高影响因子
Translational Oncology
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2026
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IF 4.9
Zhouyu Ning,Ying Zhu,Hui Li,Zhiqiang Meng
Serum metabolomics identifies novel biomarkers for PDAC diagnosis and prognosis. • A specific 4-metabolite panel distinguishes PDAC from chronic pancreatitis. • Combining these four metabolites with CA19-9 achieves a diagnostic AUC of 0.999. • The metabolic signature offers prognostic value independent of clinical stage. Background Pancreatic ductal adenocarcinoma (PDAC) lacks biomarkers for accurate diagnosis and prognostic stratification. The standard, CA19-9, has suboptimal specificity in differentiating PDAC from mimics like chronic pancreatitis (CP). We investigated serum metabolomic signatures to address these challenges. Methods We conducted a prospective, multi-cohort (n = 221) untargeted metabolomics study, analyzing PDAC (n = 66), healthy control (n = 92), other cancer (n = 40), and CP (n = 23) groups. Machine learning and survival analysis were employed to build diagnostic and prognostic models from serum samples collected at diagnosis. Results A two-metabolite panel distinguished PDAC from other cancers (AUC=0.894), and a five-metabolite signature showed high discrimination between PDAC and CP (AUC=0.998; 95% CI, 0.993–1.000). A leakage-resistant nested cross-validation sensitivity analysis yielded a mean AUC of 0.955 (SD, 0.020). The exploratory 18-metabolite risk score separated high- and low-risk groups and remained associated with overall survival after adjustment for stage, age, sex, and CA19-9 (adjusted HR, 3.94; 95% CI, 2.05–7.58; P < 0.001), with a C-index of 0.601. Conclusions Serum metabolomic profiles identified compact candidate panels that provided information complementary to CA19-9 for PDAC differential diagnosis, while the 18-metabolite risk score was associated with overall survival. These findings support targeted assay development and prospective multicenter evaluation of serum metabolomics for the clinical characterization of PDAC. Schematic: overview of the study design and analytical workflow. The study was conducted in three sequential phases. Phase 1 (Establishing a Baseline Metabolic Profile): the PC-a cohort (n = 33) was compared with healthy controls (HC, n = 92), identifying 17 annotated differential metabolites. Phase 2 (Exploratory Diagnostic Specificity): a separately enrolled single-center PC-b cohort (n = 33) was compared with other cancers (OC, n = 40) and chronic pancreatitis (CP, n = 23), yielding a two-metabolite candidate panel for PDAC versus OC and a five-metabolite candidate panel for PDAC versus CP. Phase 3 (Exploratory Prognostic Association): PC-a and PC-b were combined (n = 66; 59 deaths) to examine metabolic heterogeneity and an exploratory 18-metabolite risk score. Collectively, these sequential single-center cohorts supported discovery and internal evaluation. Download: Download high-res image (389KB) Download: Download full-size image
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ACTA PHARMACOLOGICA SINICA
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2024
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IF 6.9
Xing Fa-liang,Li Bo-rui,Fang Ying-jin,Liang Chen,Liu Jiang,Wang Wei,Xu Jin,Yu Xian-jun,Qin Yi,Zhang Bo
Pancreatic ductal adenocarcinoma (PDAC) is distinguished by its aggressive malignancy, limited treatment avenues and a tendency towards chemotherapy resistance, underscoring the critical need for advanced research to uncover new therapeutic approaches. Stress granules (SGs) that is implicated in cellular self-protection mechanism, along with its associated family molecules have shown pro-cancer effects and are closely related to tumor chemotherapy resistance. In this study we investigated the relationship between Ras GTPase-activating protein-binding proteins 2 (G3BP2), a core component of SGs, and the malignancy of PDAC as well as its resistance to the chemotherapy drug gemcitabine. Analyzing TCGA dataset revealed that the expression of G3BP1 and G3BP2 was significantly upregulated in PDAC compared with adjacent normal pancreatic tissues, and the high expression of G3BP2 rather than G3BP1 was significantly associated with poorer overall survival (OS) in PDAC patients. We demonstrated that knockdown of G3BP2 inhibited the proliferation and invasion of PANC‐1 and CFPAC-1 cells in vitro and in vivo. By analyzing the differentially expressed genes in G3BP2 knockdown and overexpressed PANC‐1 cells, we identified DKC1 that was associated with RNA stability and regulation as the target of G3BP2. We demonstrated that G3BP2 bound to PDIA3 mRNA and recruited them into SGs, increasing the stability of PDIA3 mRNA and attenuating its translation efficiency, thereby promoting DKC1 expression. Furthermore, DKC1 could bind to hENT mRNA and inhibited its expression, which enhanced gemcitabine resistance of PDAC. Therefore, we propose a novel mechanism wherein G3BP2 facilitates PDAC’s resistance to chemotherapy by modulating PDIA3-DKC1-hENT in a SGs-dependent way, suggesting G3BP2 SGs a protentional therapeutic target for the treatment in PDAC.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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癌症研究
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Cancer Treatment and Research Communications
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2026
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IF 3.5
Bo Ren,Han-mei Li,Ju-ying Zhang,Jiawei Wang,You Yang,Li-tao Ye,Jinhong Yu,Jian Xu,Gang Quan,Jingdong Li,Wong Charng Choon
Pancreatic ductal adenocarcinoma (PDAC) constitutes one of the most malignant tumours with limited treatment options and poor prognosis. This study designed a targeting nanoplatform, GCP@NBs, combining paclitaxel (PTX)-mediated chemotherapy and chlorin e6 (Ce6)-assisted sonodynamic therapy (SDT) for PDAC. In vitro targeting ability was validated via glypican-1 antibodies (GPC1-Abs) on the surface. Phase transition of perfluoropentane (PFP) facilitated the ultrasound (US) imaging and the controlled drug release. Live/Dead Cell Dual-fluorescence Staining and flow cytometry were performed to corroborate cell apoptosis. Meanwhile, the generation of reactive oxygen species (ROS) was confirmed by ROS Content Detection Kit. Mitochondrial Membrane Potential (MMP) Assay Kit was leveraged to verify the depolarization of MMP, and western blot was performed to reveal the expression of proteins involved in apoptosis. Additionally, biosafety of GCP@NBs in the absence of US irradiation was validated. Consequently, GCP@NBs exhibited optimal particle size of 378.4 ± 10.54 nm and surface charge of -22.63 ± 0.32 mV, showing excellent stability and drug loading capacity (47.35 ± 0.21% for Ce6 and 64.80 ± 0.19% for PTX). GCP@NBs showed good biosafety and US imaging capability, exhibited specific targeting ability and cellular uptake, demonstrated efficient drug release and US-responsive ROS generation, and achieved excellent anti-cancer effects at low concentration. JC-1 staining showed the obvious MMP depolarization, and Western blot illustrated the increased expression of caspase-3 and Bax/Bcl-2 ratio during the cell apoptosis process. This study highlights the potential of GCP@NBs as novel and highly effective nanoplatforms for treatment of PDAC.
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JOURNAL OF NANOBIOTECHNOLOGY
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2024
·Vol. 22
·期 1
·1-21
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IF 10.6
Zhou Hao,Wang Wei,Cai Zedong,Jia Zhou-Yan,Li Yu-Yao,He Wei,Li Chen,Zhang Bang-Le
Chemotherapy and immunotherapy have shown no significant outcome for unresectable pancreatic ductal adenocarcinoma (PDAC). Multi-drug combination therapy has become a consensus in clinical trials to explore how to arouse anti-tumor immunity and meanwhile overcome the poorly tumoricidal effect and the stroma barrier that greatly hinders drug penetration. To address this challenge, a comprehensive strategy is proposed to fully utilize both the ferroptotic vulnerability of PDAC to potently irritate anti-tumor immunity and the desmoplasia-associated focal adhesion kinase (FAK) to wholly improve the immunosuppressive microenvironment via sustained release of drugs in an injectable hydrogel for increasing drug penetration in tumor location and averting systematic toxicity. The injectable hydrogel ED-M@CS/MC is hybridized with micelles loaded with erastin that exclusively induces ferroptosis and a FAK inhibitor defactinib for inhibiting stroma formation, and achieves sustained release of the drugs for up to 12 days. With only a single intratumoral injection, the combination treatment with erastin and defactinib produces further anti-tumor performance both in xenograft and Kras G12D -engineered primary PDAC mice and synergistically promotes the infiltration of CD8 + cytotoxic T cells and the reduction of type II macrophages. The findings may provide a novel promising strategy for the clinical treatment of PDAC.
研究领域:
肿瘤学
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药学
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免疫学
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PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2023
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IF 10.8
Fu Zhang,Qida Hu,Bowen Li,Yong Huang,Meng Wang,Shiyi Shao,Honglin Tang,Zhuo Yao,Yuan Ping,Tingbo Liang
Pancreatic ductal adenocarcinoma (PDAC) remains to be one of the highest malignant tumors due to its poor chemotherapeutic efficacy and multidrug resistance . A major reason for the failure in chemotherapy is poor drug accumulation into PDAC tumor tissues due to the overexpressed extracellular matrix (ECM) stroma, which forms a major obstacle limiting the deep tissue penetration of chemotherapeutics. Herein, we report a tumor microenvironment (TME)-responsive nanodrug, based on PDAC cell membrane-coated gold nanocages (AuNCs), to co-deliver the chemotherapeutics (GEM) and nitrogen oxide (NO) donor (L-Arg) to enhance drug accumulation and reduce chemoresistance. The high glutathione (GSH) level can trigger the cleavage of the disulfide bond on nanodrug to release GEM . Moreover, the elevated ROS level could activate L-Arg to generate NO, which synergistically facilitate GEM to penetrate into deep tissues by means of vasodilation and normalization of blood vessels in the PDAC tumor tissue. In addition, AuNCs not only serve as a photothermal agent for chemotherapy, but also generate photoacoustic signals to monitor drug accumulation and distribution. As expected, the strategy demonstrates to be remarkable in treating different xenograft mice models, especially in orthotopic and patient-derived xenograft (PDX) models. The current study defines a useful therapeutic tool for treating PDAC tumors.
研究领域:
肿瘤学
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纳米医学
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化疗
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药理学
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癌症生物学
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BIOCHEMICAL PHARMACOLOGY
·
2023
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IF 5.8
Dongchao Xu,Ajuan Liu,Qiang Liu,Hongchen Zhang,Mengyao Tian,Ying Bian,Xiaofeng Zhang,Meidan Ying,Hongzhang Shen
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most devastating diseases; it has a considerably poor prognosis and may become the second most lethal malignancy in the next 10 years. Chemotherapeutic resistance is common in PDAC; thus, it is necessary to exploit effective alternative drugs. In recent years, traditional folk medicines and their extracts have shown great potential in cancer treatment. The seed of Lagenaria siceraria (Molina) Standl. is a traditional medicine in Asia. Because of its analgesic effects and ability to reduce swelling, it is often used as an adjuvant treatment for abdominal tumors. Cucurbitacin compounds are extracts abundant in Lagenaria siceraria (Molina) Standl. Here, we found that cucurbitacin C (CuC), a member of the cucurbitacin family, has apparent anti-PDAC therapeutic properties. CuC decreased the viability and suppressed the proliferation of PDAC cells in a time- and dose-dependent manner. Further studies revealed that CuC inhibited cell migration and invasion by inhibiting epithelial-mesenchymal transition (EMT). In addition, G2/M arrest was induced, and the apoptotic pathway was activated. Transcriptomic and bioinformatic analyses showed that CuC inhibited the cGMP-PKG-VASP axis, increasing the content of cGMP to restore tumor characteristics. The antitumor activity of CuC in vivo was verified through animal experiments, and no obvious side effects were observed. Overall, our study indicates a candidate therapeutic compound for PDAC that is worthy of further development.
研究领域:
肿瘤学
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药理学
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分子生物学
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传统医学
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高影响因子
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