Tumor Cell Derived Lnc‐FSD2‐31:1 Contributes to Cancer‐Associated Fibroblasts Activation in Pancreatic Ductal Adenocarcinoma Progression through Extracellular Vesicles Cargo MiR‐4736

• Published in: Advanced science Vol. 10; no. 10; pp. e2203324 - n/a
• Main Authors: Geng, Xinglong, Li, Le, Luo, Yan, Yang, Wenbo, Hu, Jisheng, Zhao, Zhongjie, Cheng, Chundong, Zhang, Tao, Zhang, Yangyang, Liu, Liwei, Xie, Yu, Li, Guanqun, Liu, Danxi, Bai, Rui, Bai, Xuewei, Wang, Gang, Chen, Hua, Wang, Yongwei, Chen, Hongze, Sun, Bei
• Format: Journal Article
• Language: English
• Published: Germany John Wiley & Sons, Inc 01.04.2023; John Wiley and Sons Inc; Wiley
• Subjects: Animals; autophagy; Cancer-Associated Fibroblasts - pathology; cancer‐associated fibroblasts; Carcinoma, Pancreatic Ductal - genetics; Cell adhesion & migration; Correlation analysis; Extracellular vesicles; Fibroblasts; Metastasis; Mice; MicroRNAs - genetics; noncoding RNA; Pancreatic cancer; pancreatic ductal adenocarcinoma; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Patients; Polymerase chain reaction; RNA, Long Noncoding - genetics; Statistical significance; Survival analysis; Tumor Microenvironment; Tumorigenesis; Tumors; cancer-associated fibroblasts; autophagy; extracellular vesicles; noncoding RNA; pancreatic ductal adenocarcinoma
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202203324

Pancreatic ductal adenocarcinoma (PDAC) presents with high mortality and short overall survival. Cancer‐associated fibroblasts (CAFs) act as refuge for cancer cells in PDAC. Mechanisms of intracelluar communication between CAFs and cancer cells need to be explored. Long noncoding RNAs (lncRNAs) are involved in the modulation of oncogenesis and tumor progression of PDAC; however, specific lncRNAs and their mechanism of action have not been clarified clearly in tumoral microenvironment. This work aims to identify novel lncRNAs involved in cellular interaction between cancer cells and CAFs in PDAC. To this end, differentially expressed lncRNAs between long‐term and short‐term survival PDAC patients are screened. Lnc‐FSD2‐31:1 is found to be significantly increased in long‐term survival patients. This work then discovers that tumor‐derived lnc‐FSD2‐31:1 restrains CAFs activation via miR‐4736 transported by extracellular vesicles (EVs) in vitro and in vivo. Mechanistically, EVs‐derived miR‐4736 suppresses autophagy and contributes to CAFs activation by targeting ATG7. Furthermore, blocking miR‐4736 suppresses tumor growth in genetically engineered KPC (LSL‐KrasG12D/+, LSL‐Trp53R172H/+, and Pdx‐1‐Cre) mouse model of PDAC. This study demonstrates that intratumoral lnc‐FSD2‐31:1 modulates autophagy in CAFs resulting in their activation through EVs‐derived miR‐4736. Targeting miR‐4736 may be a potential biomarker and therapeutic target for PDAC. This work reports a downregulated lncRNA, lnc‐FSD2‐31:1, which is featured as tumor suppressor and sentry duty of screening pancreatic ductal adenocarcinoma (PDAC) patient's outcome. Cancer cell‐derived lnc‐FSD2‐31:1 releases miR‐4736 through extracellular vesicles (EVs) cargo that regulates autophagy and fibrotic phenotypes in cancer‐associated fibroblasts (CAFs). This study discovers a framework of understanding EVs‐dependent communications between cancer cells and CAFs in PDAC.