Temporal Evolution Reveals Bifurcated Lineages in Aggressive Neuroendocrine Small Cell Prostate Cancer Trans-differentiation

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2023 Nov 23

PMID 37995683

Authors

Chia-Chun Chen

Wendy Tran

Kai Song

Tyler Sugimoto

Matthew B Obusan

Liang Wang

Katherine M Sheu

Donghui Cheng

Lisa Ta

Grigor Varuzhanyan

Arthur Huang

Runzhe Xu

Yuanhong Zeng

Amirreza Borujerdpur

Nicholas A Bayley

Miyako Noguchi

Zhiyuan Mao

Colm Morrissey

Eva Corey

Peter S Nelson

Yue Zhao

Jiaoti Huang

Jung Wook Park

Owen N Witte

Thomas G Graeber

Affiliations

Soon will be listed here.

Abstract

Trans-differentiation from an adenocarcinoma to a small cell neuroendocrine state is associated with therapy resistance in multiple cancer types. To gain insight into the underlying molecular events of the trans-differentiation, we perform a multi-omics time course analysis of a pan-small cell neuroendocrine cancer model (termed PARCB), a forward genetic transformation using human prostate basal cells and identify a shared developmental, arc-like, and entropy-high trajectory among all transformation model replicates. Further mapping with single cell resolution reveals two distinct lineages defined by mutually exclusive expression of ASCL1 or ASCL2. Temporal regulation by groups of transcription factors across developmental stages reveals that cellular reprogramming precedes the induction of neuronal programs. TFAP4 and ASCL1/2 feedback are identified as potential regulators of ASCL1 and ASCL2 expression. Our study provides temporal transcriptional patterns and uncovers pan-tissue parallels between prostate and lung cancers, as well as connections to normal neuroendocrine cell states.

Citing Articles

Emerging Therapeutic Targets of Neuroendocrine Prostate Cancer.

Zhu X, Ding C, Aggarwal R Curr Oncol Rep. 2025; .

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SOX2 control activation of dormant prostate cancer cells in bone metastases by promoting CCNE2 gene expression.

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Meta-analyses of mouse and human prostate single-cell transcriptomes reveal widespread epithelial plasticity in tissue regression, regeneration, and cancer.

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