The Seizure-related Homolog (SEZ6) Family in Cancer: Emerging Biomarkers and Therapeutic Targets

Abstract:

Cancer is a global burden, contributing to about 20 million incident cases and around 10 million mortalities in 2022. Metastasis, or secondary tumor formation, is the prevalent cause of most mortalities. Metastasis and resistance to therapy are major contributors to cancer-related mortality. Expression shifts of cytoplasmic, nuclear, cell-surface, and transmembrane proteins play an important role in tumor progression and therapeutic targeting. This review summarizes the family of SEZ6 proteins, which are single-transmembrane proteins. The family comprises Seizure-related 6 homolog (SEZ6), SEZ6-like (SEZ6L), and SEZ6-like 2 (SEZ6L2) proteins. These proteins are studied for their primary roles in synaptic connectivity, signal transduction, protein interactions, and the mediation of neurodevelopmental and psychiatric disorders. However, the SEZ6 family proteins have also been identified as emerging biomarkers and therapeutic targets across various cancers. Recent studies have shown that SEZ6L2 and SEZ6L, not SEZ6, are involved in complement regulation, which can lead to tumor escape and modulation of the tumor microenvironment. This review summarises the multifaceted roles of SEZ6 family members in modulating the complement system, their expression patterns, prognostic relevance, and the proposed molecular mechanisms underlying tumor aggressiveness, migration, and other malignant phenotypes. This study also discusses the recent advances in SEZ6-targeted ADCs, biomarker-driven patient selection, and future opportunities for cancer biology.