Take Home Messages: Basic Science

1. Take Home Messages: Basic Science Rosalyn M. Adam, PhD Boston Children’s Hospital and Harvard Medical School

2. Basic Science Abstracts • 22 basic research sessions • Over 400 abstracts covering a range of topics: • GU cancers (~220 abstracts) • Physiology, pharmacology and lower urinary tract dysfunction (~100 abstracts) • BPH (~20 abstracts) • Stone disease (~20 abstracts) • Infertility (~40 abstracts) • Sexual function and dysfunction (~40 abstracts) • Other topics (~20 abstracts)

3. Key Themes • Molecular correlates of disease • Biomarkers • Functional and clinical implications • Novel model systems • Disease modeling to understand etiology • Identification of new therapeutic strategies • Contribution of microenvironment to disease • Cell and tissue interactions • Subcellular elements (cell free DNA, extracellular vesicle)

4. MP87-11: Intrinsic prostate cancer subtypes determined in diagnostic prostate biopsies of men with metastatic disease resemble castration-resistant prostate cancer metastases (Miller et al., Los Angeles, CA) • 37 gene signature identified 3 PCa subtypes of differing biology • When applied to two additional independent PCa cohorts the signature clustered new samples appropriately with the identified subtypes, suggesting potential prognostic utility • MP87-10: Genomic Analysis of a Longitudinal Series of Surgical Prostate Cancer Bone Metastases and Xenografts from the Same Patient Revealed Selection of a Progressively Therapy Resistant Metastatic Clone (Jamieson et al., San Diego, CA) • Tumor recurrence provides unique insights into biology of bone metastases • PDXs from primary and metastatic lesions are being used to interrogate biology underlying development of resistance and suggest alternative therapeutic interventions

5. PD04-12 & MP73-06: Drug Resistance Consequences of Tumor Heterogeneity in Metastatic Renal Cell Carcinoma using Ultra-Fast Patient Derived Xenografts and Multiregional Genomic Sequencing (Lowerison et al., London, ON) • Primary tumors and metastases from RCC engrafted on the CAM of chick embryos in 2 days • Readout of resistance based on phenotype as opposed to genotype • System can be used to guide drug selection • MP88-17: Patient Derived Xenografts of Upper Tract Urothelial Carcinoma: A Potential Tool for Personalized Medicine (Murray et al., Columbia, MO) • Cohort of stable PDX models and cell lines for UTUC that maintains the genetic characteristics of the primary tumor • Generation of these resources has utility for drug screening for personalized medicine

6. PD62-03: The Effect of Intrinsic Subtype on Response to Neoadjuvant Chemotherapy for Muscle Invasive Bladder Cancer (Metcalfe et al., Houston, TX) • Basal tumors in the absence of NAC are high risk • Basal tumors have a favorable response to NAC which results in an increased OS • MP34-01 (Seiler et al, Vancouver, BC), MP58-05 (Tregnago et al., Baltimore, MD) • MP44-05: Overexpression of immune co-stimulatory molecule B7-H4 is associated with poor survival in bladder urothelial carcinoma (Glaser et al., Chicago, IL) • B7-H4 is highly expressed in TCGA Subtype II (luminal), unlike PD-L1, which is highly expressed in Subtype IV (basal / claudin-low). • B7-H4 may be a promising target for immunotherapy, especially for patients who do not respond to PD-L1 therapy.

7. MP82-08: The potential of 2 microRNA clusters in elucidation of biological functions of signalling pathways regulated by microRNAs in underactive bladder (HashemiGheinani et al., Bern, Switzerland) • Analysis of bladder biopsies from urodynamically characterized patients with obstruction identified downregulated miRNA clusters in underactive bladder patients (MP26-01) • Functional characterization of these clusters (hsa-miR-199a-3p/hsa-miR-3120-3p and hsa-miR- 429/hsa-miR-200b-3p miRNA) could provide insights into loss of function in these patients • MP31-02: MicroRNA-132 Induces Bladder Hypertrophy and Bladder Overactivity Via Downregulation of Acetylcholinesterase (Kashyap et al., Pittsburgh, PA) • BO and bladder hypertrophy following exogenous overexpression of miR-132 in rodents demonstrates the potential pathological role of miR-132 in OAB • Enhanced detrusor strip contractility and NVCs in CMGs are consistent with the miR-132 mediated decrease of AChE and upregulation of Cx43, NGF and MCP-1 expression • Consider utility of specific miRNAs as biomarkers and determinants of disease

8. MP17-08: The identification of estrogen receptor gene networks in benign prostatic hyperplasia (Liu et al., Madison, WI) • RNAseq analysis of BPH-1 cells treated with a range of selective ER agonists identified differentially regulated genes depending on the pattern of ER activation • These genes and associated networks may provide novel biomarkers for study of BPH and associated LUT symptoms • MP17-18: Peri-prostatic Fat (PPF) Secretome in BPH Progression (Franco et al., Evanston, IL) • PPF harbors macrophages that release adipokines including and may contribute to tissue remodeling through elaboration of pro-inflammatory cytokines • PPF from obese versus lean patients displayed increased thickness, whereas PPF from lean patients lack inflammatory infiltrates

9. MP41-01: Extracellular Vesicles Regulate Glomerular VEGF Homeostasis in Chronic Kidney Disease (Perin et al., Los Angeles, CA) • AFSC derived EVs play important role in maintaining glomerular homeostasis of VEGF signaling • EVs attenuate elevated VEGF signaling and the pathologic sequelae in a mouse model of Alport syndrome and represent immune-privileged modulators of disease. • MP19-19: Patients with calcium stones and Randall’s plaque excrete distinct populations of micro RNA-containing urinary extracellular vesicles (Lieske et al., Rochester, MN) • Stone formers and those with high amounts of RP excrete distinct populations of miRNAs within urinary EVs. • Upregulated miRNAs contribute in calcification, cell proliferation, AKI, renal fibrosis, pro-apoptotic and pro-inflammatory pathways

10. MP41-05: Biofabricated Bone Marrow-derived Cell Patches Restore Structure and Function of Radiation-Injured Urinary Bladders in Rat (Minagawa et al., Japan) • Voiding interval and micturition volume in the patch-transplantation group were higher and residual volume was lower compared to control • Biofabricatedbone marrow-derived cell patches could reconstruct structures and improve bladder functions in the irradiated urinary bladders • PD70-04: Optogenetic Modulation of Bladder Function (Mickle et al., St. Louis, MO) • Bidirectional control of bladder function in rodent models can be induced by selective targeting of discrete populations of neurons with light of different wavelengths to control their activity • Restriction of opsin-based control switches to specific populations of bladder sensory fibers could lead to a better understanding of their role in bladder function and disease