Gregori Alessandro, Bergonzini Cecilia, Capula Mjriam, Mantini Giulia, Khojasteh-Leylakoohi Fatemeh, Comandatore Annalisa, Khalili-Tanha Ghazaleh, Khooei Alireza, Morelli Luca, Avan Amir, Danen Erik H, Schmidt Thomas, Giovannetti Elisa
Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit, 1081 HV Amsterdam, The Netherlands.
Department of Cancer Biology and Immunology, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands.
Cancers (Basel). 2023 Jan 19;15(3):628. doi: 10.3390/cancers15030628.
PDAC is an extremely aggressive tumor with a poor prognosis and remarkable therapeutic resistance. The dense extracellular matrix (ECM) which characterizes PDAC progression is considered a fundamental determinant of chemoresistance, with major contributions from mechanical factors. This study combined biomechanical and pharmacological approaches to evaluate the role of the cell-adhesion molecule ITGA2, a key regulator of ECM, in PDAC resistance to gemcitabine.
The prognostic value of ITGA2 was analysed in publicly available databases and tissue-microarrays of two cohorts of radically resected and metastatic patients treated with gemcitabine. PANC-1 and its gemcitabine-resistant clone (PANC-1R) were analysed by RNA-sequencing and label-free proteomics. The role of ITGA2 in migration, proliferation, and apoptosis was investigated using hydrogel-coated wells, siRNA-mediated knockdown and overexpression, while collagen-embedded spheroids assessed invasion and ECM remodeling.
High ITGA2 expression correlated with shorter progression-free and overall survival, supporting its impact on prognosis and the lack of efficacy of gemcitabine treatment. These findings were corroborated by transcriptomic and proteomic analyses showing that ITGA2 was upregulated in the PANC-1R clone. The aggressive behavior of these cells was significantly reduced by ITGA2 silencing both in vitro and in vivo, while PANC-1 cells growing under conditions resembling PDAC stiffness acquired resistance to gemcitabine, associated to increased ITGA2 expression. Collagen-embedded spheroids of PANC-1R showed a significant matrix remodeling and spreading potential via increased expression of CXCR4 and MMP2. Additionally, overexpression of ITGA2 in MiaPaCa-2 cells triggered gemcitabine resistance and increased proliferation, both in vitro and in vivo, associated to upregulation of phospho-AKT.
ITGA2 emerged as a new prognostic factor, highlighting the relevance of stroma mechanical properties as potential therapeutic targets to counteract gemcitabine resistance in PDAC.
胰腺导管腺癌（PDAC）是一种极具侵袭性的肿瘤，预后较差且具有显著的治疗抗性。构成PDAC进展特征的致密细胞外基质（ECM）被认为是化疗抗性的一个基本决定因素，其中机械因素起主要作用。本研究结合生物力学和药理学方法，评估细胞粘附分子整合素α2（ITGA2，ECM的关键调节因子）在PDAC对吉西他滨抗性中的作用。
在公开可用的数据库以及两组接受吉西他滨治疗的根治性切除和转移性患者的组织微阵列中分析ITGA2的预后价值。通过RNA测序和无标记蛋白质组学分析PANC-1及其吉西他滨抗性克隆（PANC-1R）。使用水凝胶包被的孔、小干扰RNA（siRNA）介导的敲低和过表达来研究ITGA2在迁移、增殖和凋亡中的作用，而胶原包埋的球体用于评估侵袭和ECM重塑。
ITGA2高表达与无进展生存期和总生存期缩短相关，支持其对预后的影响以及吉西他滨治疗缺乏疗效。转录组学和蛋白质组学分析证实了这些发现，表明ITGA2在PANC-1R克隆中上调。ITGA2沉默在体外和体内均显著降低了这些细胞的侵袭性行为，而在类似于PDAC硬度的条件下生长的PANC-1细胞获得了对吉西他滨的抗性，这与ITGA2表达增加有关。PANC-1R的胶原包埋球体通过增加CXCR4和基质金属蛋白酶2（MMP2）的表达显示出显著的基质重塑和扩散潜力。此外，MiaPaCa-2细胞中ITGA2的过表达在体外和体内均引发了吉西他滨抗性并增加了增殖，这与磷酸化蛋白激酶B（AKT）的上调有关。
ITGA2成为一种新的预后因素，突出了基质机械特性作为抵消PDAC中吉西他滨抗性的潜在治疗靶点的相关性。
Zotero 插件