The following is a summary of “Circulating tumor cell clustering modulates RNA splicing and polyadenylation to facilitate metastasis,” published in the February 2024 issue of Oncology by Wu et al.

Circulating tumor cell (CTC) clusters have been identified as potent mediators of metastasis, exhibiting markedly higher metastatic potential compared to their single CTC counterparts. Despite this recognition, the underlying mechanisms governing this phenomenon remain poorly understood, particularly regarding the role of posttranscriptional RNA regulation within CTC clusters. In this study, researchers undertook a comprehensive comparative analysis of alternative splicing (AS) and alternative polyadenylation (APA) profiles between single CTCs and CTC clusters. 

The investigation identified several AS events in both single CTCs and CTC clusters, with approximately 20% demonstrating differential regulation between the two cell types. The study group pinpointed SRSF6 as a pivotal regulator contributing to the altered AS profiles observed in CTC clusters, thereby enhancing their malignant potential. Additionally, their analysis revealed a global elongation of 3′ untranslated regions (UTRs) in CTC clusters relative to single CTCs, primarily orchestrated by core APA factors such as PPP1CA. 

This elongation of 3′ UTRs facilitated cell cycle progression in CTC clusters and conferred increased resistance to oxidative stress. Importantly, the study group identified a higher proportion of H2AFY mRNA with long 3′ UTRs in CTC clusters, a modification associated with enhanced mRNA stability and translation activity due to AU-rich elements (AREs). Consequently, this alteration promoted cell proliferation and invasion, facilitating metastatic tumor establishment and rapid growth mediated by CTC clusters. Overall, the findings shed light on the intricate mechanisms underlying CTC cluster metastasis, offering valuable insights into potential therapeutic targets for impeding metastatic dissemination in cancer.

Source: sciencedirect.com/science/article/abs/pii/S0304383524001502