Pan-cancer analysis identifies migrasome-related genes as a potential immunotherapeutic target: A bulk omics research and single cell sequencing validation

Introduction: The migrasome is a newly discovered organelle that resembles extracellular vesicles in structure. However, the function of the migrasome in tumors, particularly in relation to tumor immunity and tumor microenvironment, is unclear.

Methods: Gene expression data, copy number variation raw data, and methylation data of 33 Cancer types were downloaded from The Cancer Genome Atlas database. Immunohistochemistry (IHC) based on 114 case of colorectal Cancer was used to validate the expression of the migrasome hub-gene. We analyzed the expression, prognosis, genetic variation, and drug sensitivity profiles of migrasome-related genes (MRGs) in pan-cancer datasets. A migrasome score was constructed based on gene set enrichment analysis, and the correlation of migrasomes with the tumor microenvironment was assessed. The CancerSEA was used to perform a single-cell level functional analysis of the migrasome. Additionally, we also analyzed the correlation between migrasomes and tumor mutational burden (TMB), microsatellite instability (MSI), and tumor immune dysfunction and exclusion scores. Single-cell transcriptome sequencing (scRNA-seq) data was used to assess the activation state of migrasomes in the tumor microenvironment.

Results: PIGK expression was significantly up-regulated in 22 of 33 tumors, and high expression of migrasome was estimated to have contributed to poor prognosis. Missense mutations are the most common type of mutation in MRGs. We identified piperlongumine as a potential drug targeting migrasomes. The migrasome score was significantly and positively correlated with the tumor immunity score and the stroma score. In most tumors, the abundance of macrophages in the tumor microenvironment was significantly and positively correlated with the migrasome score. Additionally, the migrasome scores were significantly correlated with the immune checkpoint genes in pan-cancer as well as immune checkpoint therapy-related markers including TMB and MSI. According to scRNA-seq analysis, migrasome differed significantly among cells of the tumor microenvironment. IHC confirmed low expression of ITGA5 and PIGK in colorectal Cancer.

Discussion: We performed the first pan-cancer analysis of migrasomes and discovered that they play an important role in tumor development and immune escape. Our study provides new insights into the role of migrasomes in tumor prognosis and immunotherapy.

immune checkpoint inhibitors; migrasome; pan-cancer; scRNA-seq; tumor immunity; tumor microenvironment.