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AMIGO2 is a pivotal therapeutic target related to M2 polarization of macrophages in pancreatic ductal adenocarcinoma.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a common kind of lethal cancer, with low early diagnostic rate and poor prognosis. In this study, we identified and verified the AMIGO2 with significant diagnostic and prognostic value in PDAC through LASSO regression combined with multiple machines learning methods, including RVM-RFE and Random Forest in TCGA and GEO datasets. The relevance between the expression of AMIGO2 and M2 polarization of macrophages was identified through pancancer, normal tissue, and cell lines data in TCGA, GTEx and CCLE datasets. The relevance between AMIGO2 and M2 polarization was then further identified in our local PDAC cohort. Finally, the role of AMIGO2 as cancer promoter and pivotal factor enrolled in M2 polarization was verified through siRNA transfection and M2 macrophages induction. These findings could facilitate diagnosis and treatment of PDAC. In addition, further research was deemed necessary on the deep mechanism between AMIGO2 and M2 polarization of macrophages in PDAC.

SUBMITTER: Chen S

PROVIDER: S-EPMC10866418 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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AMIGO2 is a pivotal therapeutic target related to M2 polarization of macrophages in pancreatic ductal adenocarcinoma.

Chen Shensi S Du Wujun W Feng Ke K Liu Ke K Li Cunji C Li Shengming S Yin Hua H

Aging 20240105 2

Pancreatic ductal adenocarcinoma (PDAC) is a common kind of lethal cancer, with low early diagnostic rate and poor prognosis. In this study, we identified and verified the AMIGO2 with significant diagnostic and prognostic value in PDAC through LASSO regression combined with multiple machines learning methods, including RVM-RFE and Random Forest in TCGA and GEO datasets. The relevance between the expression of AMIGO2 and M2 polarization of macrophages was identified through pancancer, normal tiss ...[more]

PMID: 38189855

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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 frequently diagnosed and treated in advanced tumor stages with poor prognosis. More effective screening programs and novel therapeutic means are urgently needed. Recent studies have regarded tight junction protein claudin 18.2 (CLDN18.2) as a candidate target for cancer treatment, and zolbetuximab (formerly known as IMAB362) has been developed against CLDN18.2. However, there are few data reported thus far related to the clinicopathological characteristics of CLDN18.2 expression for PDAC.AimTo investigate the expression of CLDN18.2 in PDAC patients and subsequently propose a new target for the treatment of PDAC.MethodsThe Cancer Genome Atlas, Genotype-Tissue Expression, Gene Expression Omnibus, and European Genome-phenome Archive databases were first employed to analyze the CLDN18 gene expression in normal pancreatic tissue compared to that in pancreatic cancer tissue. Second, we analyzed the expression of CLDN18.2 in 93 primary PDACs, 86 para-cancer tissues, and 13 normal pancreatic tissues by immunohistochemistry. Immunostained tissues were assessed applying the histoscore. subsequently, they fell into two groups according to the expression state of CLDN18.2. Furthermore, the correlations between CLDN18.2 expression and diverse clinicopathological characteristics, including survival, were investigated.ResultsThe gene expression of CLDN18 was statistically higher (P < 0.01) in pancreatic tumors than in normal tissues. However, there was no significant correlation between CLDN18 expression and survival in pancreatic cancer patients. CLDN18.2 was expressed in 88 (94.6%) of the reported PDACs. Among these tumors, 50 (56.8%) cases showed strong immunostaining. The para-cancer tissues were positive in 81 (94.2%) cases, among which 32 (39.5%) of cases were characterized for strong staining intensities. Normal pancreatic tissue was identified solely via weak immunostaining. Finally, CLDN18.2 expression significantly correlated with lymph node metastasis, distant metastasis, nerve invasion, stage, and survival of PDAC patients, while there was no correlation between CLDN18.2 expression and localization, tumor size, patient age and sex, nor any other clinicopathological characteristic.ConclusionCLDN18.2 expression is frequently increased in PDAC patients. Thus, it may act as a potential therapeutic target for zolbetuximab in PDAC.

Dataset Information

AMIGO2 is a pivotal therapeutic target related to M2 polarization of macrophages in pancreatic ductal adenocarcinoma.

Publications

AMIGO2 is a pivotal therapeutic target related to M2 polarization of macrophages in pancreatic ductal adenocarcinoma.

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