HOXD11-NMDAR signaling drives neuroendocrine prostate cancer and enables potential therapeutic intervention as a target of memantine

  • Cell Rep. 2026 May 26;45(5):117330. doi: 10.1016/j.celrep.2026.117330.
Tiange Wu  1 ,  Song Tan  1 ,  Likai Mao  1 ,  Ruixin Zhang  1 ,  Enyao Huang  1 ,  Can Wang  2 ,  Hao Lin  3 ,  Hui Wang  4 ,  Xiaolin Wang  5 ,  Shengrong Chen  1 ,  Haowen Lu  1 ,  Caichen Luo  6 ,  Yurui Chen  1 ,  Yifei Cheng  1 ,  Tianyi Xia  7 ,  Xiangyu Yan  8 ,  Ziqi Zhu  1 ,  Zonghao You  1 ,  Yunlai Zhi  4 ,  Xiejunhao Zheng  1 ,  Tian Gao  1 ,  Fan Shi  1 ,  Zhan Chen  9 ,  Congbin Fan  10 ,  Fei Zhong  11 ,  Rong Na  12 ,  Ming Chen  1 ,  Gao-Jun Teng  13 ,  Yini Zhu  14 ,  Wenchao Li  15 ,  Bin Xu  16
Affiliations
  • 1. Department of Urology, Zhongda Hospital, Southeast University, Nanjing 210009, China; Surgical Research Center, Institute of Urology, Medical School of Southeast University, Nanjing 210009, China.
  • 2. Department of Urology, Zhongda Hospital, Southeast University, Nanjing 210009, China; Surgical Research Center, Institute of Urology, Medical School of Southeast University, Nanjing 210009, China. Electronic address: [email protected].
  • 3. Department of Clinical Science and Research, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China.
  • 4. Department of Urology, The First People's Hospital of Lianyungang, Lianyungang 222001, China.
  • 5. Department of Urology, Nantong Tumor Hospital, Nantong 226006, China.
  • 6. Surgical Research Center, Institute of Urology, Medical School of Southeast University, Nanjing 210009, China.
  • 7. Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology (Southeast University), Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, China.
  • 8. China Pharmaceutical University, Nanjing 211198, China.
  • 9. Department of Urology, Nantong First People's Hospital, School of Medicine, Southeast University, Nantong 226001, China.
  • 10. Department of Urology, Nantong Rugao Hospital of Traditional Chinese Medicine, Nantong 226500, China.
  • 11. Basic Medicine Research and Innovation Center of Ministry of Education, Zhongda Hospital, National Innovation Platform for Integration of Medical Engineering Education (NMEE) (Southeast University), State Key Laboratory of Digital Medical Engineering, Southeast University, Nanjing 210009, China.
  • 12. Department of Surgery, LKS School of Medicine, The University of Hong Kong, Hong Kong 999077, China.
  • 13. Center of Interventional Radiology and Vascular Surgery, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, China; Basic Medicine Research and Innovation Center of Ministry of Education, Zhongda Hospital, National Innovation Platform for Integration of Medical Engineering Education (NMEE) (Southeast University), State Key Laboratory of Digital Medical Engineering, Southeast University, Nanjing 210009, China. Electronic address: [email protected].
  • 14. Department of Microbiology and Immunology, Medical School of Southeast University, Nanjing 210009, China; Department of Urology, Nantong First People's Hospital, School of Medicine, Southeast University, Nantong 226001, China. Electronic address: [email protected].
  • 15. Department of Urology, Zhongda Hospital, Southeast University, Nanjing 210009, China; Surgical Research Center, Institute of Urology, Medical School of Southeast University, Nanjing 210009, China. Electronic address: [email protected].
  • 16. Department of Urology, Zhongda Hospital, Southeast University, Nanjing 210009, China; Surgical Research Center, Institute of Urology, Medical School of Southeast University, Nanjing 210009, China; Basic Medicine Research and Innovation Center of Ministry of Education, Zhongda Hospital, National Innovation Platform for Integration of Medical Engineering Education (NMEE) (Southeast University), State Key Laboratory of Digital Medical Engineering, Southeast University, Nanjing 210009, China. Electronic address: [email protected].
PMID: 42126948 DOI: 10.1016/j.celrep.2026.117330
Abstract

Prostate Cancer resistance to androgen deprivation therapy often involves neuroendocrine transformation. Using single-cell RNA Sequencing of transgenic adenocarcinoma of the mouse prostate (TRAMP) mice across pathological stages (early adenocarcinoma to late neuroendocrine prostate Cancer [NEPC]), we find an early neuroendocrine-initiating cluster marked by elevated HOXD11, conserved in human NEPC. Genetic suppression of HOXD11 blocks neuroendocrine differentiation and restores Androgen Receptor (AR) signaling. Mechanistically, HOXD11 directly activates FOXA2 and N-methyl-D-aspartate receptor (NMDAR) subunits (GRIN1/GRIN3A), pathways upregulated in NEPC and linked to poor prognosis. Pharmacological NMDAR inhibition with memantine suppresses NEPC progression preclinically. Notably, a preliminary clinical observation in one evaluable patient with chemotherapy-failed NEPC shows radiographic regression of primary and metastatic lesions after memantine treatment. These findings establish HOXD11 as a driver of neuroendocrine transformation and support further investigation of memantine as a candidate therapeutic strategy for NEPC.

Keywords
CP: cancer; CP: neuroscience; HOXD11; NEPC; NMDARs; drug repurposing; lineage plasticity; memantine; neuroendocrine prostate cancer.
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