Cathy Lee Mendelsohn, PhD

Our research focuses on understanding normal and abnormal biology of the urothelium, a water-tight epithelial barrier lining the urinary outflow tract that protects against infection. The urothelium is nearly quiescent, but can rapidly undergo regeneration in response to injury from urinary tract infection or exposure to chemicals. Chronic injury or inflammation however, induces a shift from a urothelial differentiation program to a basal/squamous differentiation program generating an epithelium similar to skin. Our studies have used mouse models to identify major transcriptional and epigenetic regulators of urothelial differentiation both in the healthy urothelium and in bladder cancer, including nuclear receptors (Pparg, retinoids) and chromatin remodeling genes.

Bladder cancers can be divided into distinct classes; Basal/Squamous tumors tend to be invasive, and are immune infiltrated, while luminal/papillary tumors tend to be less invasive, are exophytic, and have low levels of immune infiltration. Pparg, a transcription factor belonging to the nuclear receptor superfamily promotes urothelial/luminal differentiation and suppresses basal/squamous differentiation. At present, most patients with high-grade Basal/squamous tumors undergo cystectomy, while lower grade papillary tumors can be resected by TURBT, but often regrow, and can become invasive. Deficiency in retinoids has long been known to induce squamous differentiation in a number of epithelial including the urothelium. We find that Pparg regulates urothelial differentiation at least in part, by up-regulating retinoid signaling and Kdm6a, a chromatin modifier required for retinoid signaling.

Most recently, our studies have investigated the efficacy of a 2-drug treatment consisting of rosiglitazone, a synthetic Pparg agonist, and trametinib, a MEK/ERK inhibitor. Using a mouse model of basal/squamous muscle invasive bladder cancer, we show that either drug alone can restrict tumor growth, while the 2-drug combination induces tumor cell death within 7 days of treatment. Furthermore, the epithelium of rosiglitazone/trametinib treated mice undergoes a switch from basal/squamous differentiation which promotes tumor formation to urothelial differentiation; restoring endogenous cell types and functions, which are important for bladder stretch and physiology.  An important goal, is translating these preclinical findings into a clinical study which is currently underway.