Dataset Information

Macrophages and pancreatic ductal adenocarcinoma.

ABSTRACT: Monocytes and macrophages make up part of the innate immune system and provide one of the first defenses against variety of treats. Macrophages can also modulate the adaptive immune system. Efficient sensing and response to tissue environmental cues highlights the complexity and dynamic nature of macrophages and their plasticity. Macrophages may have divergent roles depending on their polarity and stimulus received. Accumulating evidence demonstrates the critical role played by macrophages in tumor initiation, development, and progression. In this review, we discuss the characteristics of tumor-associated macrophages (TAMs) and their role in pancreatic adenocarcinoma. In addition, we give an overview on recent advances related to the therapeutic implication associated with targeting TAMs in pancreas cancer.

SUBMITTER: Habtezion A

PROVIDER: S-EPMC4912945 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Macrophages and pancreatic ductal adenocarcinoma.

Habtezion Aida A Edderkaoui Mouad M Pandol Stephen J SJ

Cancer letters 20151218 1

Monocytes and macrophages make up part of the innate immune system and provide one of the first defenses against variety of treats. Macrophages can also modulate the adaptive immune system. Efficient sensing and response to tissue environmental cues highlights the complexity and dynamic nature of macrophages and their plasticity. Macrophages may have divergent roles depending on their polarity and stimulus received. Accumulating evidence demonstrates the critical role played by macrophages in tu ...[more]

PMID: 26708507

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Project description:BackgroundIncreasing evidence supports that infiltration M2 Macrophages act as pivotal player in tumor progression of pancreatic ductal adenocarcinoma (PDAC). Nonetheless, comprehensive analysis of M2 Macrophage infiltration and biological roles of hub genes (FAM53B) in clinical outcome and immunotherapy was lack.MethodThe multiomic data of PDAC samples were downloaded from distinct datasets. CIBERSORT algorithm was performed to uncover the landscape of TIME. Weighted gene co-expression network analysis (WGCNA) was performed to identify candidate module and significant genes associated with M2 Macrophages. Kaplan-Meier curve and receiver operating characteristic (ROC) curves were applied for prognosis value validation. Mutation data was analyzed by using "maftools" R package. Gene set variation analysis (GSVA) was employed to assign pathway activity estimates to individual sample. Immunophenoscore (IPS) was implemented to estimate immunotherapeutic significance of risk score. The half-maximal inhibitory concentration (IC50) of chemotherapeutic drugs was predicted by using the pRRophetic algorithm. Finally, quantitative real-time polymerase chain reaction was used to determine FAM53B mRNA expression and TIMER database was utilized to uncover its possible role in immune infiltration of PDAC.ResultsHerein, 17,932 genes in 234 samples (214 tumor and 20 normal) were extracted from three platforms. Taking advantage of WGCNA, significant module (royalblue) and 135 candidate genes were considered as M2 Macrophages-related genes. Subsequently, risk signature including 5 hub genes was developed by multiple analysis, which exhibited excellent prognostic performance. Besides, comprehensive prognostic nomogram was constructed to quantitatively estimate risk. Then, intrinsic link between risk score with tumor mutation burden (TMB) was explored. Additionally, risk score significantly correlated with diversity of tumor immune microenvironment (TIME). PDAC samples within different risk presented diverse signaling pathways activity and experienced significantly distinct sensitivity to administering chemotherapeutic or immunotherapeutic agents. Finally, the biological roles of FAM53B were revealed in PDAC.ConclusionsTaken together, comprehensive analyses of M2 Macrophages profiling will facilitate prognostic prediction, delineating complexity of TIME, and contribute insight into precision therapy for PDAC.

Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is highly malignant due to its late diagnosis and early metastasis. Lung metastasis of PDAC occurs in a significant number of diagnosed patients and represents high severity of disease and poor clinical outcome. However, the molecular regulation of lung metastasis of PDAC is still not fully understood. Tumor-associated macrophages (TAMs) have recently been found to play an important role in cancer initiation, proliferation, progression, and metastasis. The proliferation, differentiation, and polarization of macrophages has been shown to be regulated by interleukin 1β (IL-1β), which is generated by NLR family pyrin domain containing 3 (NLRP3)-induced formation of inflammasome. Herein we investigated whether NLRP3 plays a role in lung metastasis of PDAC through regulation of macrophage polarization.MethodsGene profiles for NLRP3 (+/+) and NLRP3 (-/-) macrophages obtained from the Gene Expression Omnibus (GEO) public database were compared and analyzed for altered genes related to macrophage polarization. The regulation of macrophage polarization by NLRP3 was examined in a coculture system with naïve NLRP3 (+/+) or NLRP3 (-/-) macrophages and PDAC cells. Cell growth was analyzed by a Cell Counting Kit-8 (CCK-8) assay. Cell invasiveness and migratory potential were analyzed by transwell cell invasion assay and cell migration assay, respectively. PDAC formation and lung metastasis were analyzed in a mouse model of PDAC with and without NLRP3 knockout.ResultsGEO database analysis revealed significant alteration in genes that regulate macrophage polarization in NLRP3-depleted macrophages. NLRP3-depletion in macrophages seemed to favor an M1/M2b polarization. In vitro, the presence of NLRP3 in macrophages led to M2a/c/d TAM-like polarization when they were cocultured with PDAC cells. Conversely, NLRP3 depletion in macrophages led to M1/M2b polarization when they were cocultured with PDAC cells. NLRP3-depletion significantly inhibited tumor growth and stage progression in a mouse model of PDAC and significantly reduced the occurrence of lung metastasis.ConclusionsOur results suggested that NLRP3 activation in TAM enhanced lung metastasis of PDAC through regulation of TAM polarization.

Dataset Information

Macrophages and pancreatic ductal adenocarcinoma.

Publications

Macrophages and pancreatic ductal adenocarcinoma.

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