Neurogenic inducers inhibit the proliferation of pancreatic cancer by promoting tumor cell transdifferentiation

  • J Exp Clin Cancer Res. 2025 Nov 12;44(1):304. doi: 10.1186/s13046-025-03563-9.
Duancheng Guo  #  1  2  3 ,  Saimeng Shi  #  4  5  6  7 ,  Longyun Ye  #  4  5  6  7 ,  Mengdi Yang  #  5  8 ,  Wenxia Peng  5  8 ,  Jianhui Yang  4  5  6  7 ,  Ji Xu  9 ,  Qinglin Fei  4  5  6  7 ,  Hao Li  10 ,  Kaizhou Jin  11  12  13  14 ,  Xichun Hu  15  16 ,  Weiding Wu  17  18  19  20
Affiliations
  • 1. Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. [email protected].
  • 2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. [email protected].
  • 3. State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China. [email protected].
  • 4. Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
  • 5. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
  • 6. Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China.
  • 7. Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
  • 8. Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
  • 9. Department of Oncology and Hematology, Zhoupu Hospital, Pudong New Area, Shanghai, 201318, China.
  • 10. State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China. [email protected].
  • 11. Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. [email protected].
  • 12. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. [email protected].
  • 13. Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China. [email protected].
  • 14. Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China. [email protected].
  • 15. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. [email protected].
  • 16. Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. [email protected].
  • 17. Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. [email protected].
  • 18. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. [email protected].
  • 19. Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China. [email protected].
  • 20. Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China. [email protected].
  • # Contributed equally.
PMID: 41225636 DOI: 10.1186/s13046-025-03563-9
Abstract

Background: Tumor cell differentiation is a critical determinant of malignancy and clinical treatment selection. Pancreatic ductal adenocarcinoma (PDAC), a poorly differentiated and highly aggressive tumor, has a poor prognosis, whereas well-differentiated tumors often correlate with better outcomes. The mechanisms underlying differentiation and its therapeutic potential remain unclear.

Objectives: This study aims to investigate whether inducing transdifferentiation in pancreatic Cancer cells can reduce malignancy, focusing on the role of the transcription factor NeuroD1 and its regulatory pathways.

Methods: We analyzed single-cell RNA-seq data from the GEO database to identify differentiation-associated genes. NeuroD1 was overexpressed in PDAC cells to assess its effects on transdifferentiation and proliferation. Drug screening and molecular docking were performed to identify differentiation-inducing compounds. RNA Sequencing, coimmunoprecipitation, and mass spectrometry were used to identify NeuroD1-interacting proteins. Cell/patient-derived xenograft mouse models are utilized for in vivo experiments and compound efficacy testing.

Results: Highly differentiated tumor cells exhibited elevated NeuroD1 expression. NeuroD1 overexpression promoted neuronal transdifferentiation and suppressed proliferation. Neuropathiazol, a neurogenic inducer, was found to bind MET and upregulate NeuroD1 via the PI3K/Akt pathway, enhancing transdifferentiation and inhibiting tumor growth. Neurog3 was identified as a functional partner of NeuroD1.

Conclusion: Our findings demonstrate that pancreatic Cancer cells can be induced to transdifferentiate through NeuroD1 activation or pharmacological induction, suggesting a potential therapeutic strategy to mitigate malignancy by reprogramming tumor cells into less aggressive states.

Keywords
Differentiation therapy; NeuroD1; Neurogenic inducers; Pancreatic cancer; Transdifferentiation.
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