Nagaraju Ganji Purnachandra, Saddala Madhu Sudhana, Foote Jeremy B, Khaliq Ateeq M, Masood Ashiq, Golivi Yuvasri, Bandi Dhana Sekhar Reddy, Sarvesh Sujith, Reddy Sudhir Putty, Switchenko Jeffrey, Carstens Julienne L, Akce Mehmet, Herting Cameron, Alese Olatunji B, Yoon Karina J, Manne Upender, Bhasin Manoj K, Lesinski Gregory B, Sukhatme Vikas P, El-Rayes Bassel F
Department of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
Bioinformatics, Genomics and Proteomics, University of California, Irvine, Irvine, CA 92697, USA.
Cell Rep Med. 2025 Jan 21;6(1):101881. doi: 10.1016/j.xcrm.2024.101881. Epub 2024 Dec 26.
Pancreatic ductal adenocarcinoma (PDAC) has a minimal (<15%) 5-year existence, in part due to resistance to chemoradiotherapy. Previous research reveals the impact of paricalcitol (P) and hydroxychloroquine (H) on altering the lysosomal fusion, decreasing stromal burden, and triggering PDAC to chemotherapies. This investigation aims to elucidate the molecular properties of the H and P combination and their potential in sensitizing PDAC to gemcitabine (G). PH potentiates the effects of G in in vitro, orthotopic mouse models, and a patient-derived xenograft model of PDAC. Proteomic and single-cell RNA sequencing (RNA-seq) analyses reveal that GPH treatment upregulates autophagy and endoplasmic reticulum (ER) stress-related transcripts. GPH treatment decreases the number of Ki67, fibroblast-associated protein (FAP), and alpha-smooth muscle actin (SMA)-expressing fibroblasts with a decrease in autophagy-related transcripts. The GPH treatment increases M1 polarization and CD4 and CD8 T cells and reduces CD4 and CD8 regulatory T cells (Tregs). These effects of GPH were confirmed in paired biopsies obtained from patients treated in a clinical trial (NCT04524702).
胰腺导管腺癌（PDAC）的5年生存率极低（<15%），部分原因是对放化疗耐药。先前的研究揭示了帕立骨化醇（P）和羟氯喹（H）在改变溶酶体融合、减轻基质负担以及使PDAC对化疗敏感方面的作用。本研究旨在阐明H和P联合使用的分子特性及其使PDAC对吉西他滨（G）敏感的潜力。PH在体外、原位小鼠模型以及PDAC患者来源的异种移植模型中增强了G的作用。蛋白质组学和单细胞RNA测序（RNA-seq）分析表明，GPH处理上调了自噬和内质网（ER）应激相关转录本。GPH处理减少了表达Ki67、成纤维细胞相关蛋白（FAP）和α平滑肌肌动蛋白（SMA）的成纤维细胞数量，同时自噬相关转录本减少。GPH处理增加了M1极化以及CD4和CD8 T细胞，并减少了CD4和CD8调节性T细胞（Tregs）。GPH的这些作用在一项临床试验（NCT04524702）治疗的患者获得的配对活检中得到了证实。
