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

Abstract

IntroductionThe 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.MethodsGene 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.ResultsPIGK 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.DiscussionWe 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.

Cervical cancer immune infiltration microenvironment identification, construction of immune scores, assisting patient prognosis and immunotherapy

“…IL1B can also enhance the signal transduction of CTLA4, and targeting the IL1B-CTLA4 axis can effectively inhibit the occurrence of metastatic and recurrent colon cancer (69). ITGA5 is a crucial immunotherapy predictive target that is thought to be crucial in the incidence and progression of many cancers (70)(71)(72). CST7 is associated with activation of CD4T and CD8T cells in liver cancer (73).…”

Immunotherapy and Cancer: The Multi-Omics Perspective

“…In a recent study, Qin and his group used the TIDE, showing that enhanced TIDE scores correlate to a higher expression of migrasomes—a novel, identified, large vesicle containing chemokines, cytokines, and growth factors able to promote tumor metastasis and immune escape, reducing the response to ICI. Additionally, the researchers also evaluated ESTIMATE scores of migrasomes in different tumors, finding out that patients treated with immunotherapy had higher scores, which correlates with a better prognosis [ 18 ].…”

“…Furthermore, an exploratory analysis using RNA seq observed a correlation between the T-cell-inflamed gene expression profile (TcellinfGEP) with the Objective Response Rate (ORR) and Progression-Free Survival (PFS), specifically for pembrolizumab. The UMIN000025947 study (phase I/II) investigated a combined treatment (nivolumab, paclitaxel, and ramucirumab) used after the first line along with a phase II trial held by the Arbeitsgemeinschaft Internistische Onkologie (AIO), highlighting the CPS’s prognostic value in predicting the ICI response [ 18 ]. Similarly, the MAHOGANY study explored the combination of margetuximab (anti-HER2) and pembrolizumab (anti-PD-1), confirming the role of CPS as a predictive score [ 48 ].…”

A Review of the Roles of Specialized Extracellular Vesicles, Migrasomes, and Exosomes in Normal Cell Physiology and Disease

“…TSPAN4 is abundant in the migrasome membrane and is one of the most effective tetraspanins for migrasome induction [46], stabilizing the migrasome structure and acting as a migrasome marker [6,60]. The expressionof APPROVED GALLEY PROOF migrasome-related genes such as pigk, itgb1, and tspan4 are significantly up-regulated in a variety of tumor types [61][62][63]. Moreover, expression levels of multiple migrasome-related genes were associated with a poorer prognosis and drug sensitivity [61].…”

“…The expressionof APPROVED GALLEY PROOF migrasome-related genes such as pigk, itgb1, and tspan4 are significantly up-regulated in a variety of tumor types [61][62][63]. Moreover, expression levels of multiple migrasome-related genes were associated with a poorer prognosis and drug sensitivity [61]. Using single-cell sequencing analysis, Yue Zheng et al showed that the migrasome-related gene tspan4 was highly correlated with the atherosclerosis regression-associated macrophages, intraplaque hemorrhage, and ruptured plaques [62].…”