EMT Dysregulation Promotes the Most Aggressive Variant of Sarcomatoid Bladder Cancer - Expert Commentary

Sarcomatoid urothelial bladder cancer (SARC) is an aggressive histological variant of bladder cancer. It is associated with early distant metastasis and poor survival rates. Understanding the molecular characteristics of SARC will lead to improved clinical outcomes.
A new article published by Guo et al. in Cell Reports studied the molecular basis for the aggressive nature of SARC. The authors included 28 SARC cases and 84 conventional urothelial carcinomas (UC) in the analysis, using 408 muscle-invasive bladder cancers from the Cancer Genome Atlas (TCGA) cohort as a reference.

It was found that SARC showed a distinct mutational signature with a significantly higher frequency in TP53, PIK3CA, and RB1 mutations in comparison to conventional UC. Expression analysis revealed that SARC is characterized by a low mRNA expression levels of the luminal genes. This suggests that SARC likely evolves from a UC basal subtype precursor. Additional molecular analysis revealed that SARC can be further subdivided into epithelial-basal and mesenchymal 'double-negative' subtypes.

The investigators conclude that SARCs are characterized by an epithelial-mesenchymal transition (EMT) permissive state. Complete EMT is seen in the clinically aggressive mesenchymal subtype. Interestingly, half of SARCs exhibited an expression signature associated with immune cell infiltration and a significant increase of CD8+ cytotoxic lymphocytes.

This important study describes the molecular features of SARCs. Understanding the defining characteristics of each bladder cancer histologic variant is required for the development of effective therapeutic strategies.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York

Reference:

1. Guo, Charles C., Tadeusz Majewski, Li Zhang, Hui Yao, Jolanta Bondaruk, Yan Wang, Shizhen Zhang et al. "Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer." Cell reports 27, no. 6 (2019): 1781-1793.

Read the Abstract

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