IBCN 2017: Bladder Cancer Models

Lisbon, Portugal (UroToday.com) Mullenders from Hubrecht Institute/Royal Netherlands Academy of Arts and Sciences and University Medical Centre Utrecht, Utrecht, The Netherlands presented his work regarding urothelial organoids. Healthy and malignant urothelial tissue was procured from bladder cancer patients. Using prior published methods for organoid cultures in breast and pancreas they created organoid cultures in 60% of all tissue samples. Organoids from both tumor and normal bladder tissue contained both basal and superficial cells. Presence of tumor cells in our organoid culture through various methods: either TP53 mutation, FGFR3 mutation, growth factor independent growth or abnormal karyotype. Based on pathological assessment we found that the majority of bladder cancer samples present were urothelial carcinomas complemented with small cell and squamous tumors at low frequency. Future applications of human bladder cancer organoids include drug screening, molecular studies and potential for personalized medicine for the treatment of bladder cancer.

Joshua Meeks from Northwestern University, Chicago, IL presented ‘A Mouse Model for Carcinogen-induced Bladder Cancer Recapitulates the Epigenetic Signature and the Machinery of the Human Disease’. Objective: Developing innovative cancer therapeutics relies on the availability of genetic models that replicate the genetic foundation of human disease. It is currently unknown whether the N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) mouse model also features the same genetic alterations found in human tumors and how well it mimics human MIBC at the molecular level. The authors analyzed the mutational landscape of the BBN model by whole exome sequencing (WES) followed by a bioinformatic comparison to human MIBC using genomic data from The Cancer Genome Atlas and other repositories. BBN tumors had a high mutation burden with a wide spectrum of non-synonymous variants. Analysis of mutational signatures on the BBN genomes identified a DNA mutation profile that is closely related to a mutagenesis pattern recently characterized in nucleotide excision repair-deficient human bladder tumors, and might be related to the exposure to the carcinogen and the early steps of tumorigenesis. BBN tumors had frequent mutations in Trp53 (80%), and the epigenetic master regulators MLL4 (Kmt2d) (70%), and MLL3 (Kmt2c) (90%), which are commonly observed in human MIBC. A closer inspection revealed that many of these variants corresponded to cancer hotspot mutations in the human ortholog genes, thus supporting a role as driver mutations. These data support the biological rationale for the use of the BBN mouse model in studies of bladder cancer progression and drug discovery. It should be noted the model was performed in male mice and it remains to be determined gender effect when extrapolating these data.

Speaker(s): Mullenders from Hubrecht Institute; Joshua Meeks, Northwestern University, Chicago, IL

Written by: Stephen B. Williams, M.D., Associate Professor, Division of Urology, The University of Texas Medical Branch, Galveston, TX. and Ashish M. Kamat, M.D. Professor, Department of Urology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX., at the International Bladder Cancer Network - October 21, 2017- Lisbon, Portugal

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