MAD2L1 Induces Tumor Progression through Influencing Multiple Immune Components: A Multi-Omics Analysis with Potential Inhibitor Prediction

Abstract

Mitotic arrest deficient 2 like 1 (MAD2L1) is a component of the mitotic spindle assembly checkpoint that prevents the onset of anaphase until all chromosomes are properly aligned at the metaphase plate, a process that confirms genomic stability. As several human cancers experience abnormal expression of such components, MAD2L1 has been studied in different human cancers owing to its oncogenic behavior. Here, we employed several omics-related tools to investigate the characteristics of MAD2L1 in a pan-cancer model of analysis, with a focus on its impact on the infiltration of multiple immune components in the tumor microenvironment as a mechanism allowing for tumor progression and poor patient survival. Our analysis revealed that MAD2L1 was significantly upregulated in several human tumors, and this upregulation was further confirmed at the protein level. In addition, a significant hypomethylation status of MAD2L1 was detected in multiple cancers compared with the corresponding controls. The consequences of this upregulation on tumor progression and clinical outcome were further assessed, where tumor stage, grade and metastasis were positively correlated with MAD2L1 overexpression in a panel of tumors. Moving to the immune interaction, our analysis demonstrated that MAD2L1 significantly increased the infiltration of the myeloid-derived suppressor cells (MDSCs) and reduced the infiltration of tumor-attacking natural killer (NK) cells. Furthermore, MAD2L1 expression positively correlated with the expression of exhaustion markers and immunosuppressive chemokines. Owing to its role in tumor progression, we detected MAD2L1 as a target for anticancer therapy, where high-throughput screening (HTS) was performed to identify possible inhibitors that could act as antitumor drugs. Our screening process identified nine FDA-approved drugs with favorable binding energies (>−7 kcal/mol) among the 3180 compounds examined. Meropenem, Glipizide and Dolutegravir were particularly promising candidates, showing distinctive interactions within the active pocket of MAD2L1. Here, we describe the stages and output of our multi-omics analysis with a drug screening assessment.