胰腺导管腺癌（PDAC）是一种致命的恶性肿瘤，主要是由于化学耐药性的内在发展。与化疗耐药相关的最明显的组织病理学特征是细胞外基质（ECM）蛋白的改变。小檗碱 (BBR) 和大黄素 (EMO) 等天然膳食植物已被证明通过调节各种癌症的 ECM 具有化学预防潜力。在此，我们进一步研究了 BBR 和 EMO 通过靶向胰腺癌中的 ECM 蛋白来增强抗癌功​​效的潜在协同作用。全基因组转录组分析发现，LAMB3 在 PDAC 组织中显着上调，并且与较差的总生存率（OS，风险比 [HR]，2.99，95% 置信区间 [CI]，1.46-6.15；p=0.003）和无进展高度相关。 PDAC 中的生存率（PFS、HR，2.59；95% CI，1.30-5.18；p=0.007）。在 BxPC-3 和 MIA-PaCa-2 细胞中进行的一系列系统功能实验表明，BBR 和 EMO 的组合表现出协同抗肿瘤潜力，如细胞增殖、克隆形成、迁移和侵袭测定所证明的那样 (p<0.05- 0.001）。该组合还改变了参与细胞凋亡、EMT 和 EGFR/ERK1,2/AKT 信号传导的关键蛋白的表达。这些发现得到了患者源性类器官 (PDO) 的进一步支持，与单独使用每种化合物相比，联合治疗产生的类器官更少且更小 (p<0.05-0.001)。我们的结果表明，BBR 与 EMO 联合通过干扰 PDAC 中的 LAMB3 来调节 EGFR 信号通路，从而发挥协同抗癌作用。版权所有 © 2024。由 Elsevier Inc. 出版。

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy, primarily due to the intrinsic development of chemoresistance. The most apparent histopathological feature associated with chemoresistance is the alterations in extracellular matrix (ECM) proteins. Natural dietary botanicals such as berberine (BBR) and emodin (EMO) have been shown to possess chemo-preventive potential by regulating ECM in various cancers. Herein, we further investigated the potential synergistic effects of BBR and EMO in enhancing anticancer efficacy by targeting ECM proteins in pancreatic cancer. Genomewide transcriptomic profiling identified that LAMB3 was significantly upregulated in PDAC tissue and highly associated with poor overall survival (OS, hazard ratio [HR], 2.99, 95 % confidence interval [CI], 1.46-6.15; p = 0.003) and progress-free survival (PFS, HR, 2.59; 95 % CI, 1.30-5.18; p = 0.007) in PDAC. A systematic series of functional experiments in BxPC-3 and MIA-PaCa-2 cells revealed that the combination of BBR and EMO exhibited synergistic anti-tumor potential, as demonstrated by cell proliferation, clonogenicity, migration, and invasion assays (p < 0.05-0.001). The combination also altered the expression of key proteins involved in apoptosis, EMT, and EGFR/ERK1,2/AKT signaling. These findings were further supported by patient-derived organoids (PDOs), where the combined treatment resulted in fewer and smaller organoids compared to each compound individually (p < 0.05-0.001). Our results suggest that BBR combined with EMO exerts synergistic anti-cancer effects by modulating the EGFR-signaling pathway through interference with LAMB3 in PDAC.Copyright © 2024. Published by Elsevier Inc.