BCAN TT 2022: NRF2 Activation Promotes a Basal-like Phenotype but a Fitness Disadvantage in Normal Urothelium

(UroToday.com) Dr. Yuki Kita, MD, PhD, is a Medical Oncology Fellow at the University of North Carolina in Chapel Hill, NC. He is the recipient of the 2020 BCAN Young Investigator Award for his research focused on the role of NRF2 in bladder urothelial differentiation. NRF2 is a tumor suppressor through cellular regulation of oxidative stress- detoxifying ROS, drugs and toxins. Activating mutations in NRF2 are common in bladder cancer, present in 7% of TCGA tumors.


The investigators evaluated the downstream effects of conditional Nrf2 mutation (Nrf2E79Q) in a cre-inducible mouse model. In the N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) mouse model of basal-subtype MIBC tumorigenesis, wildtype (WT) and Nrf2 mutant mice developed bladder tumors at the same rate. Additionally, cells expressing mutant Nrf2 were selected during BBN model carcinogenesis.

Organoids were generated from normal and BBN Nrf2E79Q mutants. Fluorescent IHC indicated that Nrf mutation results in suppressed Ki67 and reduced proliferation in normal urothelial organoids, suggesting a survival disadvantage. The investigators then used single cell RNAseq to molecularly subtype epithelial cells in Nrf2E79Q activated normal urothelium. Nrf2E79Q activation was associated with a higher proportion of basal cells and ultimately inhibited the differentiation of urothelial organoids. Additionally, expression of mutant Nrf2 in in vitro cell culture models results in upregulation of the basal marker KRT5.

The authors identified a crucial role of NRF2 in normal urothelial differentiation. The mechanism by which NRF2 promotes a fitness disadvantage remains unclear as these data were largely descriptive, but this may be related to a reduction in oxidative stress. As a potent tumor suppressor, these data suggest a possible chemo-preventative role for drugs that active NRF2, but this needs to be balanced with the reduced proliferative capacity conferred in the normal urothelium by NRF2.

Presented by: Dr. Yuki Kita, MD, PhD is a Medical Oncology Fellow at the University of North Carolina in Chapel Hill, NC

Written by: Patrick Hensley, MD, Urologic Oncologist at the University of Kentucky (@pjhensley11) with Ashish Kamat, MD, Urologic Oncologist at MD Anderson Cancer Center (@UroDocAsh) during the 2022 Bladder Cancer Advocacy Network Think Tank (#BCANTT22) Wednesday Aug 3 – Friday Aug 5, 2022 

References:

  1. Bowman BM, Montgomery SA, Schrank TP, Simon JM, Ptacek TS, Tamir TY, Mulvaney KM, Weir SJ, Nguyen TT, Murphy RM, Makowski L, Hayes DN, Chen XL, Randell SH, Weissman BE, Major MB. A conditional mouse expressing an activating mutation in NRF2 displays hyperplasia of the upper gastrointestinal tract and decreased white adipose tissue. J Pathol. 2020 Oct;252(2):125-137. doi: 10.1002/path.5504. Epub 2020 Aug 29. PMID: 32619021; PMCID: PMC7511428.
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