Temporal evolution reveals bifurcated lineages in aggressive neuroendocrine small cell prostate cancer trans-differentiation

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

doi:10.1016/j.ccell.2023.10.009

Temporal evolution reveals bifurcated lineages in aggressive neuroendocrine small cell prostate cancer trans-differentiation

Cancer Cell. 2023 Dec 11;41(12):2066-2082.e9. doi: 10.1016/j.ccell.2023.10.009. Epub 2023 Nov 22.

Authors

Chia-Chun Chen¹, Wendy Tran², Kai Song³, Tyler Sugimoto², Matthew B Obusan², Liang Wang², Katherine M Sheu², Donghui Cheng⁴, Lisa Ta¹, Grigor Varuzhanyan², Arthur Huang¹, Runzhe Xu⁵, Yuanhong Zeng¹, Amirreza Borujerdpur¹, Nicholas A Bayley¹, Miyako Noguchi², Zhiyuan Mao¹, Colm Morrissey⁶, Eva Corey⁶, Peter S Nelson⁷, Yue Zhao⁸, Jiaoti Huang⁹, Jung Wook Park⁹, Owen N Witte¹⁰, Thomas G Graeber¹¹

Affiliations

¹ Department of Molecular and Medical Pharmacology, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
² Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, CA, USA.
³ Department of Bioengineering, UCLA, Los Angeles, CA, USA.
⁴ Eli and Edythe Broad Stem Cell Research Center, UCLA, Los Angeles, CA, USA.
⁵ Department of Biological Chemistry, UCLA, Los Angeles, CA, USA.
⁶ Department of Urology, University of Washington School of Medicine, Seattle, WA, USA.
⁷ Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, WA, USA; Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.
⁸ Department of Pathology, Duke University School of Medicine, Durham, NC, USA; Department of Pathology, College of Basic Medical Sciences and the First Hospital, China Medical University, Shenyang, China.
⁹ Department of Pathology, Duke University School of Medicine, Durham, NC, USA.
¹⁰ Department of Molecular and Medical Pharmacology, University of California Los Angeles (UCLA), Los Angeles, CA, USA; Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, CA, USA; Eli and Edythe Broad Stem Cell Research Center, UCLA, Los Angeles, CA, USA; Molecular Biology Institute, UCLA, Los Angeles, CA, USA; Parker Institute for Cancer Immunotherapy, UCLA, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA. Electronic address: owenwitte@mednet.ucla.edu.
¹¹ Department of Molecular and Medical Pharmacology, University of California Los Angeles (UCLA), Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA; Crump Institute for Molecular Imaging, UCLA, Los Angeles, CA, USA; California NanoSystems Institute, UCLA, Los Angeles, CA, USA; Metabolomics Center, UCLA, Los Angeles, CA, USA. Electronic address: tgraeber@mednet.ucla.edu.

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.

Keywords: ASCL1; ASCL2; POU2F3, TFAP4; cancer; lineage plasticity; neuroendocrine; prostate; small cell; stem-like; trans-differentiation.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Basic Helix-Loop-Helix Transcription Factors / genetics
Basic Helix-Loop-Helix Transcription Factors / metabolism
Carcinoma, Small Cell* / genetics
Cell Line, Tumor
Cell Transdifferentiation / genetics
Gene Expression Regulation, Neoplastic
Humans
Lung Neoplasms* / genetics
Male
Prostatic Neoplasms* / genetics
Prostatic Neoplasms* / pathology
Small Cell Lung Carcinoma* / genetics
Transcription Factors / genetics

Substances

Transcription Factors
Basic Helix-Loop-Helix Transcription Factors
ASCL2 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding