Dataset Information

Signaling in the microenvironment of pancreatic cancer: Transmitting along the nerve.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is a dismal malignant disease with the lowest stage-combined overall survival rate compared to any other cancer type. PDA has a unique tumor microenvironment (TME) comprised of a dense desmoplastic reaction comprising over two-thirds of the total tumor volume. The TME is comprised of cellular and acellular components that all orchestrate different signaling mechanisms together to promote tumorigenesis and disease progression. Particularly, the neural portion of the TME has recently been appreciated in PDA progression. Neural remodeling and perineural invasion (PNI), the neoplastic invasion of tumor cells into nerves, are common adverse histological characteristics of PDA associated with a worsened prognosis and increased cancer aggressiveness. The TME undergoes dramatic neural hypertrophy and increased neural density that is associated with many signaling pathways to promote cell invasion. PNI is also considered one of the main routes for cancer recurrence and metastasis after surgical resection, which remains the only current cure for PDA. Recent studies have shown multiple cell types in the TME signal through autocrine and paracrine mechanisms to enhance perineural invasion, pancreatic neural remodeling and disease progression in PDA. This review summarizes the current findings of the signaling mechanisms and cellular and molecular players involved in neural signaling in the TME of PDA.

SUBMITTER: Jurcak N

PROVIDER: S-EPMC6626552 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Signaling in the microenvironment of pancreatic cancer: Transmitting along the nerve.

Jurcak Noelle N Zheng Lei L

Pharmacology & therapeutics 20190429

Pancreatic ductal adenocarcinoma (PDA) is a dismal malignant disease with the lowest stage-combined overall survival rate compared to any other cancer type. PDA has a unique tumor microenvironment (TME) comprised of a dense desmoplastic reaction comprising over two-thirds of the total tumor volume. The TME is comprised of cellular and acellular components that all orchestrate different signaling mechanisms together to promote tumorigenesis and disease progression. Particularly, the neural portio ...[more]

PMID: 31047906

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Project description:Essentials Elimination of PDAC tumor cell PAR1 increased cytotoxic T cells and reduced tumor macrophages. PAR1KO PDAC cells are preferentially eliminated from growing tumors. Thrombin-PAR1 signaling in PDAC tumor cells drives an immunosuppressive gene signature. Csf2 and Ptgs2 are thrombin-PAR1 downstream immune suppressor genes in PDAC tumor cells. ABSTRACT: Background Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prothrombotic state and a lack of host antitumor immune responsiveness. Linking these two key features, we previously demonstrated that tumor-derived coagulation activity promotes immune evasion. Specifically, thrombin-protease-activated receptor-1 (PAR1) signaling in mouse PDAC cells drives tumor growth by evading cytotoxic CD8a+ cells. Methods Syngeneic mixed cell tumor growth, transcriptional analyses, and functional tests of immunosuppressive response genes were used to identify cellular and molecular immune evasion mechanisms mediated by thrombin-PAR-1 signaling in mouse PDAC tumor cells. Results Elimination of tumor cell PAR1 in syngeneic graft studies increased cytotoxic T lymphocyte (CTL) infiltration and decreased tumor-associated macrophages in the tumor microenvironment. Co-injection of PAR1-expressing and PAR1-knockout (PAR-1KO ) tumor cells into immunocompetent mice resulted in preferential elimination of PAR-1KO cells from developing tumors, suggesting that PAR1-dependent immune evasion is not reliant on CTL exclusion. Transcriptomics analyses revealed no PAR1-dependent changes in the expression of immune checkpoint proteins and no difference in major histocompatibility complex-I cell surface expression. Importantly, thrombin-PAR1 signaling in PDAC cells upregulated genes linked to immunosuppression, including Csf2 and Ptgs2. Functional analyses confirmed that both Csf2 and Ptgs2 are critical for PDAC syngeneic graft tumor growth and overexpression of each factor partially restored tumor growth of PAR1KO cells in immunocompetent mice. Conclusions Our results provide novel insight into the mechanisms of a previously unrecognized pathway coupling coagulation to PDAC immune evasion by identifying PAR1-dependent changes in the tumor microenvironment, a PAR1-driven immunosuppressive gene signature, and Csf2 and Ptgs2 as critical PAR1 downstream targets.

Dataset Information

Signaling in the microenvironment of pancreatic cancer: Transmitting along the nerve.

Publications

Signaling in the microenvironment of pancreatic cancer: Transmitting along the nerve.

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