Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer

SUMMARYThe sarcomatoid variant of urothelial bladder cancer (SARC) displays a high propensity for distant metastasis and is associated with short survival. We report a comprehensive genomic analysis of 28 cases of SARCs and 84 cases of conventional urothelial carcinomas (UCs), with the TCGA cohort of 408 muscle-invasive bladder cancers serving as the reference. SARCs showed a distinct mutational landscape with enrichment ofTP53, RB1, and PIK3CAmutations. They were related to the basal molecular subtype of conventional UCs and could be divided into epithelial/basal and more clinically aggressive mesenchymal subsets based on TP63 and its target genes expression levels. Other analyses revealed that SARCs are driven by downregulation of homotypic adherence genes and dysregulation of cell cycle and EMT networks, and nearly half exhibited a heavily infiltrated immune phenotype. Our observations have important implications for prognostication and the development of more effective therapies for this highly lethal variant of bladder cancer.

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Sarcopenia as a Predictive Factor for Response to Upfront Cisplatin-Based Chemotherapy in Patients with Muscle-Invasive Urothelial Bladder Cancer

Urologia Internationalis ◽

10.1159/000489013 ◽

2018 ◽

Vol 101 (2) ◽

pp. 197-200 ◽

Cited By ~ 1

Author(s):

◽

Andrea Mari ◽

David D’Andrea ◽

Shoji Kimura ◽

Irene Resch ◽

...

Keyword(s):

Bladder Cancer ◽

Predictive Factor ◽

Urothelial Bladder Cancer ◽

Urothelial Bladder ◽

Muscle Invasive

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Revisiting Histone Deacetylases in Human Tumorigenesis: The Paradigm of Urothelial Bladder Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms20061291 ◽

2019 ◽

Vol 20 (6) ◽

pp. 1291 ◽

Cited By ~ 14

Author(s):

Aikaterini Giannopoulou ◽

Athanassios Velentzas ◽

Eumorphia Konstantakou ◽

Margaritis Avgeris ◽

Stamatia Katarachia ◽

...

Keyword(s):

Bladder Cancer ◽

Urinary Bladder ◽

Histone Deacetylases ◽

Strong Association ◽

Hdac Inhibitors ◽

Urinary Bladder Cancer ◽

Molecular Heterogeneity ◽

Urothelial Bladder Cancer ◽

Urothelial Bladder ◽

Muscle Invasive

Urinary bladder cancer is a common malignancy, being characterized by substantial patient mortality and management cost. Its high somatic-mutation frequency and molecular heterogeneity usually renders tumors refractory to the applied regimens. Hitherto, methotrexate-vinblastine-adriamycin-cisplatin and gemcitabine-cisplatin represent the backbone of systemic chemotherapy. However, despite the initial chemosensitivity, the majority of treated patients will eventually develop chemoresistance, which severely reduces their survival expectancy. Since chromatin regulation genes are more frequently mutated in muscle-invasive bladder cancer, as compared to other epithelial tumors, targeted therapies against chromatin aberrations in chemoresistant clones may prove beneficial for the disease. “Acetyl-chromatin” homeostasis is regulated by the opposing functions of histone acetyltransferases (HATs) and histone deacetylases (HDACs). The HDAC/SIRT (super-)family contains 18 members, which are divided in five classes, with each family member being differentially expressed in normal urinary bladder tissues. Since a strong association between irregular HDAC expression/activity and tumorigenesis has been previously demonstrated, we herein attempt to review the accumulated published evidences that implicate HDACs/SIRTs as critical regulators in urothelial bladder cancer. Moreover, the most extensively investigated HDAC inhibitors (HDACis) are also analyzed, and the respective clinical trials are also described. Interestingly, it seems that HDACis should be preferably used in drug-combination therapeutic schemes, including radiation.

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