Bladder cancer variants share aggressive features including a CA125+ cell state and targetable TM4SF1 expression

Area of Science:

• Oncology
• Cancer Biology
• Molecular Pathology

Background:

• Histologic variant (HV) subtypes of bladder cancer are aggressive and treatment-resistant compared to conventional urothelial carcinoma (UC).
• The molecular and transcriptional underpinnings of HV bladder cancer's distinct biology remain largely uncharacterized.

Purpose of the Study:

• To identify unique transcriptional programs driving the aggressive phenotype of histologic variant bladder cancers.
• To explore potential therapeutic targets within these identified programs.

Main Methods:

• Single-cell RNA sequencing was employed to analyze tumor cell states in histologic variants.
• Expression analysis focused on specific genes including MUC16, MUC4, KRT24, and TM4SF1.
• Chimeric antigen receptor (CAR) T cell therapy was evaluated against TM4SF1 in vitro and in vivo.

Main Results:

• A distinct tumor cell state characterized by MUC16, MUC4, and KRT24 expression was identified in HVs.
• This cell state is associated with metastatic potential, predicted chemotherapy resistance, and poor patient survival.
• Enriched expression of TM4SF1 was observed in HV tumor cells.
• TM4SF1-targeted CAR T cells demonstrated specific anti-cancer activity.

Conclusions:

• Histologic variants of bladder cancer possess unique cellular states linked to poor prognosis and therapeutic resistance.
• TM4SF1 represents a promising therapeutic target for treating aggressive histologic variant bladder cancers.