IBCN 2018: RBM10: A New Bladder Tumor Suppressor Gene Involved in Alternative Splicing
Rotterdam, The Netherlands (UroToday.com) Whole-genome and -exome sequencing studies have recently uncovered a novel putative tumor suppressor gene, RBM10, which is mutated in 2-5% of bladder tumors as well as in lung adenocarcinoma, colon, and pancreatic cancer. RBM10 maps to the X chromosome; approximately 30% of the somatic mutations in tumors predict a premature stop codon and lead to loss of protein expression. RBM10 encodes an RNA-binding protein that modulates alternative splicing of genes involved in cell growth, proliferation, and apoptosis (i.e. NUMB, CREBBP, FAS, BCL-X). Ana M Maldonado-Barragán and team Identified the mechanisms by which RBM10 inactivation contributes to bladder cancer. They have previously established new conditional RBM10 knockout mouse models to investigate the role of RBM10 in homeostasis and carcinogenesis. For in vitro studies, bladder organoids from Rbm10lox/lox; UbCreERT2; Rosa26mTmG mice we derived to elucidate RBM10 role in the urothelial. Mouse data will be complemented by IHC analysis and RNA-Sequencing results from human bladder tumor biopsies and human-bladder tumor-derived organoids. They found the loss of RBM10 expression is observed across all bladder tumor stages and grades, suggesting that it is an early event in tumor progression. Ubiquitous RBM10 inactivation in adult mice appears well tolerated, indicating that it is not absolutely required for tissue homeostasis. They are now characterizing the effects of RBM10 inactivation in mouse bladder organoids by assessing proliferation, differentiation, as well as growth factor dependency. The organoids will also allow analyzing the effects of RBM10 depletion on RNA splicing and will be combined with those from wild-type and RBM10-null human bladder tumors.
In conclusion, these studies will provide an understanding of the mechanisms through which RBM10 contributes to disease and pave the way to identify therapies for RBM10-mutant tumors.
Presented by: Ana M Maldonado-Barragán, National Center of Cancer Research, Spain
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