Dataset Information

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.

SUBMITTER: Geng X

PROVIDER: S-EPMC10074102 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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

Geng Xinglong X Li Le L Luo Yan Y Yang Wenbo W Hu Jisheng J Zhao Zhongjie Z Cheng Chundong C Zhang Tao T Zhang Yangyang Y Liu Liwei L Xie Yu Y Li Guanqun G Liu Danxi D Bai Rui R Bai Xuewei X Wang Gang G Chen Hua H Wang Yongwei Y Chen Hongze H Sun Bei B

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20230202 10

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 ...[more]

PMID: 36727832

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Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the deadliest gastrointestinal cancers with a 5-year survival rate of less than 10%. Biomarkers for early PDAC detection are useful in treating patients with PDAC. Extracellular vesicles (EVs) are lipid-bound vesicles that are potential biomarkers of various diseases such as PDAC. In this study, we quantitatively measured the serum levels of EVs (CD63+-EVs) or platelet-derived EVs (CD41+- and CD61+-EVs) and evaluated their potential use as biomarkers of PDAC.MethodsWe measured the serum levels of CD63+-, CD41+-, CD61+-EVs using sandwich enzyme-linked immunosorbent assay based on Tim4 with specificity for phosphatidylserine on EVs in age- and sex-matched healthy controls (HCs, n = 39) and patients with PDAC (n = 39). We also examined the effect of tumor burden on the serum EV levels after surgical resection (n = 28). CA19-9, a clinical PDAC biomarker, was also measured for comparison.ResultsSerum levels of CD63+-EVs, CD41+-EVs, and CD61+-EVs were significantly increased in patients with PDAC compared to HCs. Receiver operating characteristic analysis revealed that CD63+-EVs exhibited the highest diagnostic performance to discriminate patients with PDAC from HCs (area under the curve (AUC): 0.846), which was comparable to CA19-9 (AUC: 0.842). CA19-9 showed lower AUC values in early stages (I-II, AUC: 0.814) than in late stages (III-IV, AUC: 0.883) PDAC. Conversely, CD63+-EVs, CD41+-EVs, and CD61+-EVs showed comparable AUCs between early- and late-stage PDAC. The combined use of CA19-9 and CD63+-EVs showed a higher diagnostic performance for early-stage PDAC (AUC: 0.903) than CA19-9. The serum levels of CD63+-EVs, CD41+-EVs, CD61+-EVs, and CA19-9 decreased significantly after surgical resection, demonstrating that EVs are increased in sera of patients depending on the tumor burden.ConclusionsThe serum levels of CD63+-EVs and platelet-derived EVs (CD41+-EVs, CD61+-EVs) are increased in patients with PDAC than HCs. Since CD63+-EVs showed a high AUC to discriminate patients with PDAC from HCs; they might be useful as potential biomarkers for PDAC.

Project description:BackgroundThe differential diagnosis of pancreatic ductal adenocarcinoma (PDAC) from chronic pancreatitis (CP) is clinically challenging due to a lack of minimally invasive diagnosis methods. MicroRNAs (miRNAs) derived from small extracellular vesicles (EVs) in the blood have been reported as a promising diagnosis biomarker for various types of cancer. However, blood small EV miRNA signatures and their diagnostic value to differentiate between PDAC and CP remain to be determined.MethodsIn this study, 107 patients with PDAC or CP were recruited, and 90 patients were finally enrolled for a training cohort (n = 48) and test cohort (n = 42). Small RNA sequencing was used to assess the expression of blood small EV miRNAs in these patients.ResultsThe linear model from the differentially expressed blood small EV miR-95-3p divided by miR-26b-5p showed an average sensitivity of 84.1% and an average specificity of 96.6% to identify PDAC from CP in the training cohort and the test cohort, respectively. When the model was combined with serum carbohydrate antigen 19-9 (CA19-9), the average sensitivity increased to 96.5%, and the average specificity remained at 96.4% of both cohorts, which demonstrated the best performance of all the published biomarkers for distinguishing between PDAC and CP. The causal analysis performed using the Bayesian network demonstrated that miR-95-3p was associated with a "consequence" of "cancer" and miR-26b-5p as a "cause" of "pancreatitis." A subgroup analysis revealed that blood small EV miR-335-5p/miR-340-5p could predict metastases in both cohorts and was associated with an overall survival (p = 0.020).ConclusionsThis study indicated that blood small EV miR-95-3p/miR-26b-5p and its combination with serum levels of CA19-9 could separate PDAC from CP, and miR-335-5p/miR-340-5p was identified to associate with PDAC metastasis and poor prognosis. These results suggested the potentiality of blood small EV miRNAs as differential diagnosis and metastases biomarkers of PDAC.

Dataset Information

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

Publications

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

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