Targeting Wnt signalling through LINC02418: insights from CRISPR screens

Abstract

Colorectal cancer (CRC) remains highly challenging due to its complexity, high mortality rate and resistance to therapies. The development and progression of CRC are driven by complex interactions between genetic mutations and disruptions in epigenetic regulation.1 Among critical pathways involved, Wnt/β-catenin signalling plays a pivotal role by driving uncontrolled cell proliferation and maintaining cancer stem cell-like behaviour.2 Mutations in the APC gene frequently result in the hyperactivation of β-catenin-mediated transcriptional programmes3 (online supplemental figure 1A). While Wnt signalling represents a promising therapeutic target, its crucial role in normal tissue homeostasis complicates intervention, often leading to on-target toxicities.2 To address these challenges, in Gut, Schwarzmueller et al 4 applied cutting-edge RNA-based screening tools, including Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) interference (CRISPRi) and Global Run-On Sequencing (GRO-seq), to identify tumour-specific vulnerabilities in CRC. Previous studies identified LINC02418 as an oncogenic regulator in CRC, acting primarily as a competing endogenous RNA (ceRNA).5 For instance, LINC02418 modulates oncogenic pathways by sponging miR-3619–5 p, thereby influencing the expression of targets such as MELK and contributing to tumour progression.6 While these findings highlight its role in CRC biology, Schwarzmueller et al provide evidence that LINC02418 is regulated, at least in part, by the Wnt/β-catenin pathway. This connection not only enhances our understanding of LINC02418’s function but also underscores its potential as a tumour-specific vulnerability, to selectively target CRC cells while sparing normal tissues. ### Supplementary data [gutjnl-2024-334266supp001.pdf] RNA-based therapies have become a transformative approach in oncology due to their capacity to target pathways previously considered to be undruggable.7 A significant benefit is their adaptability in addressing both traditional protein-coding genes (through their mRNA) and regulatory non-protein-coding RNAs like long non-coding RNA (lncRNAs), which, with their regulatory roles and tissue-specific expression, are valuable therapeutic targets in cancers with dysregulated gene expression.8 Although …