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

Abstract

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.

Stromal and tumor immune microenvironment reprogramming through multifunctional cisplatin-based liposomes boosts the efficacy of anti-PD-1 immunotherapy in pancreatic cancer

“…To establish the stromal-rich xenograft models, 34 Panc02 and NIH/3T3 (3 : 1) 1 × 10 6 cells were injected in the right flank of C57/BL mice and the tumors were expected to grow to 50 mm 3 . Mice bearing Panc02 tumor were treated with saline, Pt, Pt@Lps, ATF@Pt Lps, anti PD-1 mb and ATF@Pt Lps + anti PD-1 mb ( n = 6 per group).…”

Crosstalk between cancer-associated fibroblasts and regulated cell death in tumors: insights into apoptosis, autophagy, ferroptosis, and pyroptosis

“…Recent studies have addressed not only the intrinsic functions of autophagy in tumor cells but also the involvement of autophagy in the TME, including immune cells and stromal cells [ 100 – 102 ]. Although several publications have documented that autophagy occurs in CAFs [ 103 – 105 ], herein, we aimed to summarize the impacts exerted by CAFs on the regulation of autophagy signaling in tumor cells (Fig. 2 ).…”

Pancreatic cancer and fibrosis: Targeting metabolic reprogramming and crosstalk of cancer-associated fibroblasts in the tumor microenvironment

“…Collagen secretion can be facilitated by the mitophagy-regulated synthesis of proline in CAFs ( 99 ). In addition, a recent study found that PDAC cells generate lnc-FSD2-31:1 to promote the autophagy of CAFs via miR-4736, thereby inhibiting the activation of CAFs ( 100 ).…”