Exosome-transmitted LUCAT1 promotes stemness transformation and chemoresistance in bladder cancer by binding to IGF2BP2

Abstract The chemotherapy resistance is an awkward challenge in management of bladder cancer (BC). Cancer organoid model is an effective preclinical tumor model that could faithfully represent clinical manifestations and simulate the biological processes of chemoresistance. Recent studies have revealed that cancer stem cells (CSCs) play a significant role in the development of chemoresistance in cancer. Exosomes act as essential intercellular messengers and participate in controlling the conversion of distinct cell characteristics, including chemoresistance. However, the role of exosome-transmitted lncRNAs in bladder cancer chemoresistance has rarely been reported. In this study, cancer organoid models were developed from urothelial carcinomas to explore the pathophysiology mechanism of BC chemoresistance, and RNA-seq was performed to screen for lncRNAs involved in chemoresistance of BC. We found chemotherapy enriches stem-like cells in BC, and significant upregulation of Lung Cancer Associated Transcript 1 (LUCAT1) occurs in chemotherapy-resistant organoids and correlated with chemotherapy response. Further experimental results demonstrated that LUCAT1 promotes chemoresistance in bladder cancer by enhancing the stemness phenotype of BC cells in vivo and in vitro. Moreover, exosomes derived from bladder cancer stem cells can enhance the stemness phenotype and chemoresistance of BC cells by delivering LUCAT1. Mechanistically, LUCAT1 could significantly enhance the mRNA stability of HMGA1 via binding to IGF2BP2 in an m6A-dependent manner. The study demonstrates an important role for exosome-transmitted LUCAT1 in chemoresistance and LUCAT1 has the potential to function as both a diagnostic biomarker and therapeutic target for BC.