Notch signaling suppresses neuroendocrine differentiation and alters the immune microenvironment in advanced prostate cancer

Sep 21, 2026

Notch signaling suppresses neuroendocrine (NE) differentiation during progression of prostate cancer. The work shows downregulation of the Notch pathway as adenocarcinoma transitions to NE prostate cancer, where Notch activity is tumor-suppressive. In NE and Rb1/Trp53-deficient models, Notch activation drives phenotypic conversion toward a more indolent, non-NE state, increasing glandular features and luminal lineage markers. Corresponding immune changes include upregulation of MHC and type I IFN and immune cell infiltration. These findings connect Notch to lineage plasticity and shaping of the tumor microenvironment (TME).

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages17

Reading Time43 min

AccessFree to download

Introduction

Tumor phenotypic plasticity and NE prostate cancer

Lineage drivers and mechanisms

Tumor microenvironment crosstalk

DLL3 and Notch pathway background

The Journal of Clinical Investigation RESEAR CH ARTICLE Notch signaling suppresses neuroendocrine differentiation and alters the immune microenvironment in advanced prostate cancer Sheng-Yu Ku,1 Yanqing Wang,2 Maria Mica Garcia,1 Yasutaka Yamada,1 Kei Mizuno,1 Mark D. Long,3 Spencer Rosario,2,3 Meenalakshmi Chinnam,2 Majd Al Assaad,4 Loredana Puca,5 Min Jin Kim,1 Martin K. Bakht,1 Varadha Balaji Venkadakrishnan,1 Brian D. Robinson,4 Andrés M. Acosta,6 Kristine M. Wadosky,2 Juan Miguel Mosquera,4 David W. Goodrich,2,7 and Himisha Beltran1 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. 2Department of Pharmacology and Therapeutics and 3Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA. 4Department of Pathology and Laboratory Medicine and 5Department of Medicine, Weill Cornell Medicine, New York, New York, USA. 6Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA. 7Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA. Notch signaling can have either an oncogenic or tumor-suppressive function in cancer depending on the cancer type and cellular context. While Notch can be oncogenic in early prostate cancer, we identified significant downregulation of the Notch pathway during prostate cancer progression from adenocarcinoma to neuroendocrine (NE) prostate cancer, where it functions as a tumor suppressor. Activation of Notch in NE and Rb1/Trp53-deficient prostate cancer models led to phenotypic conversion toward a more indolent, non-NE state with glandular features and expression of luminal lineage markers. This was accompanied by upregulation of MHC and type I IFN and immune cell infiltration. Overall, these data support Notch signaling as a suppressor of NE differentiation in advanced prostate cancer and provide insights into how Notch signaling influences lineage plasticity and the tumor microenvironment (TME) . Introduction Phenotypic plasticity is a hallmark of cancer (1–3). In advanced prostate cancer, up to 15%–20% of patients develop resistance to androgen receptor–directed (AR-directed) therapies through conversion from an androgen-driven adenocarcinoma to an alternative lineage state such as neuroendocrine prostate cancer (NEPC)(4–6). NEPC does not depend on AR signaling, in part due to loss of AR expression. Prostate cancer lineage plasticity is dynamic, with a spectrum of phenotypes observed during the transition toward NEPC. The development of NEPC is facilitated by genomic loss of retinoblastoma 1 (RB1) and tumor protein P53 (TP53) (7, 8), downregulation of RE1 Silencing Transcription Factor (REST) (9), and dysregulation of epigenetic regulators and key transcription factors (8, 10–16). NEPC is increasingly recognized in the clin- Authorship note: SYK and YW are co–first authors and contributed equally to this work. DWG and HB jointly supervised this work. Conflict of interest: HB has served as consultant or advisory board member for Janssen, Astellas, Astra Zeneca, Merck, Pfizer, Amgen, Bayer, Oncorus, Loxo Oncology, Daicchi Sankyo, Novartis, and Harpoon and has received research funding (to institution) from Janssen, AbbVie/Stemcentrx, Bristol Myers Squibb, Circle Pharma, Daiichi Sankyo, and Novartis. DWG has received research funding from Celgene/Bristol Meyers Squibb. LP is an employee of Loxo Oncology at Lilly; this work was completed prior to her employment at Loxo Oncology, she is acting on her own, and these endeavors are not in any manner affiliated with Loxo Oncology at Lilly. Copyright: © 2024, Ku et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. Submitted: August 28, 2023; Accepted: July 10, 2024; Published: July 18, 2024. Reference information: J Clin Invest. 2024;134(17):e175217. [https://doi.org/10.1172/JCI175217](https://doi.org/10.1172

FAQs

What happens to Notch signaling during prostate cancer progression to NE prostate cancer?

The Notch pathway is significantly downregulated during progression from adenocarcinoma to neuroendocrine prostate cancer, where it functions as a tumor suppressor.

How does activating Notch affect NE and Rb1/Trp53-deficient prostate cancer models?

Notch activation induces phenotypic conversion toward a more indolent, non-NE state with glandular features and increased expression of luminal lineage markers.

What immune microenvironment changes accompany Notch-mediated effects?

Activation is accompanied by upregulation of MHC and type I IFN and increased immune cell infiltration.

Sep 21, 2026

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