Identification of Lineage-specific Transcriptional Factor-defined Molecular Subtypes in Small Cell Bladder Cancer.

ASCL1 Lineage-specific transcriptional factor NEUROD1 POU2F3 Small cell bladder cancer Subtypes

Journal

European urology
ISSN: 1873-7560
Titre abrégé: Eur Urol
Pays: Switzerland
ID NLM: 7512719

Informations de publication

Date de publication:
27 Jun 2023
Historique:
received: 16 11 2022
revised: 27 04 2023
accepted: 17 05 2023
medline: 29 6 2023
pubmed: 29 6 2023
entrez: 28 6 2023
Statut: aheadofprint

Résumé

Small cell/neuroendocrine bladder cancers (SCBCs) are rare and highly aggressive tumors that are associated with poor clinical outcomes. We discovered that lineage-specific transcription factors (ASCL1, NEUROD1, and POU2F3) defined three SCBC molecular subtypes that resemble well-characterized subtypes in small cell lung cancer. The subtypes expressed various levels of neuroendocrine (NE) markers and distinct downstream transcriptional targets. Specifically, the ASCL1 and NEUROD1 subtypes had high NE marker expression and were enriched with different downstream regulators of the NE phenotype (FOXA2 and HES6, respectively). ASCL1 was also associated with the expression of delta-like ligands that control oncogenic Notch signaling. POU2F3, a master regulator of the NE low subtype, targeted TRPM5, SOX9, and CHAT. We also observed an inverse association between NE marker expression and immune signatures associated with sensitivity to immune checkpoint blockade, and the ASCL1 subtype had distinct targets for clinically available antibody-drug conjugates. These findings provide new insight into molecular heterogeneity in SCBCs with implications for the development of new treatment regimens. PATIENT SUMMARY: We investigated the levels of different proteins in a specific type of bladder cancer (small cell/neuroendocrine; SCBC). We could identify three distinct subtypes of SCBC with similarity to small cell/neuroendocrine cancers in other tissues. The results may help in identifying new treatment approaches for this type of bladder cancer.

Identifiants

DOI: 10.1016/j.eururo.2023.05.023 PMID: 37380560
pubmed: 37380560
pii: S0302-2838(23)02830-0
doi: 10.1016/j.eururo.2023.05.023
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Auteurs

Mingxiao Feng (M)

Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Greenberg Bladder Cancer Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA.

Andres Matoso (A)

Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Greenberg Bladder Cancer Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.

Gabriel Epstein (G)

Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Greenberg Bladder Cancer Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA.

Megan Fong (M)

Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Greenberg Bladder Cancer Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA.

Yong Hyun Park (YH)

Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Department of Urology, St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea.

Andrew Gabrielson (A)

Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Greenberg Bladder Cancer Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA.

Sunil Patel (S)

Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Greenberg Bladder Cancer Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA.

Bagdan Czerniak (B)

University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Eva Compérat (E)

Department of Pathology, Medical University Vienna, General Hospital, Vienna, Austria.

Jeannie Hoffman-Censits (J)

Greenberg Bladder Cancer Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA.

Max Kates (M)

Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Greenberg Bladder Cancer Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA.

Seungchan Kim (S)

Center for Computational Systems Biology, Department of Electrical and Computer Engineering, Roy G. Perry College of Engineering, Prairie View A&M University, Prairie View, TX, USA.

David McConkey (D)

Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Greenberg Bladder Cancer Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA.

Woonyoung Choi (W)

Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Greenberg Bladder Cancer Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA. Electronic address: wchoi16@jhmi.edu.

Classifications MeSH