2. Academic Validation
  3. Neurogenic inducers inhibit the proliferation of pancreatic cancer by promoting tumor cell transdifferentiation

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

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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