Photo Credit: Elena Merkulova

The following is a summary of “Exosome-transmitted LUCAT1 promotes stemness transformation and chemoresistance in bladder cancer by binding to IGF2BP2,” published in the March 2025 issue of the Journal of Experimental & Clinical Cancer Research by Zhan et al.

Chemotherapy resistance remains a significant challenge in the clinical management of bladder cancer (BC), often leading to treatment failure and disease progression. The development of reliable preclinical models that accurately replicate the tumor microenvironment and drug response is crucial for understanding the underlying mechanisms of chemoresistance. Among these, cancer organoid models have emerged as powerful tools, faithfully recapitulating the biological characteristics of tumors and simulating drug resistance phenomena observed in patients. Recent evidence suggests that cancer stem cells (CSCs) contribute significantly to chemotherapy resistance by maintaining tumor heterogeneity and promoting cell survival under cytotoxic stress. 

Additionally, exosomes—extracellular vesicles responsible for intercellular communication—have been implicated in regulating various tumorigenic processes, including the acquisition of chemoresistance. However, the specific role of exosome-mediated long non-coding RNAs (lncRNAs) in BC drug resistance remains largely unexplored. In this study, investigators established cancer organoid models derived from urothelial carcinoma specimens to investigate the molecular mechanisms underlying BC chemoresistance. RNA sequencing (RNA-seq) was performed to identify lncRNAs associated with chemotherapy resistance. The findings revealed that chemotherapy enriches stem-like cell populations within BC, with a significant upregulation of Lung Cancer Associated Transcript 1 (LUCAT1) in chemotherapy-resistant organoids. Elevated LUCAT1 expression correlated with poor chemotherapy response in patients with BC. 

Functional assays demonstrated that LUCAT1 enhances chemoresistance by promoting the stemness phenotype of BC cells both in vitro and in vivo. Furthermore, researchers identified that exosomes derived from bladder CSCs facilitate chemoresistance by transferring LUCAT1 to recipient BC cells, thereby reinforcing stem-like properties and drug resistance. Mechanistically, LUCAT1 was found to stabilize the mRNA of High Mobility Group AT-Hook 1 (HMGA1) by interacting with Insulin-like Growth Factor 2 mRNA-binding Protein 2 (IGF2BP2) in an N6-methyladenosine (m6A)-dependent manner, leading to enhanced HMGA1 expression and subsequent activation of stemness-associated pathways. 

These findings highlight the pivotal role of exosome-mediated LUCAT1 transfer in BC chemoresistance and suggest that targeting LUCAT1 may offer a promising therapeutic strategy for overcoming drug resistance. Moreover, LUCAT1 holds potential as both a predictive biomarker for chemotherapy response and a molecular target for precision therapy in BC. Further research is warranted to explore the clinical applications of these findings and develop effective interventions aimed at disrupting LUCAT1-mediated resistance mechanisms.

Source: jeccr.biomedcentral.com/articles/10.1186/s13046-025-03330-w