journal contribution
posted on 2025-09-02, 07:25 authored by Yong-Ding Wu, Xiao-Xiao Huang, Hao-Xiang Zhang, Yu Pan, Cheng-Ke Xie, Ge Li, Cai-Feng Lin, Xin-Quan Lin, Zhi-Yuan Li, Yin-Hao Chen, Jian-Fei Hu, Hong-Yi Lin, Shun-Cang Zhu, Zu-Wei Wang, Yi-Feng Tian, Qiao-Wei Li, Cheng-Yu Liao, Shi Chen <p>Supplementary Fig. S1 The cell marker for cell type definition and the flowchart of PDOX model construction.</p>
Funding
The Fujian Research and Training Grants for Young and Middle-aged Leaders in Healthcare 10
The Fujian Province Science and Technology Innovation Joint Fund Project
The National Natural Science Foundation of China
The Major Scientific Research Project of Young and Middle-aged people of Fujian Provincial Health Commission
The Provincial Hospital Affiliated with Fuzhou University National Science Foundation Talent Cultivation Program
The medical Innovation Project of Fujian Provincial Health Commission
History
ARTICLE ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies. PDAC is characterized by prominent necrotic foci within the tumor and a high propensity for distant liver metastasis, leading to a poor prognosis. In this study, using patient-derived organoid models, single-cell RNA sequencing, and multiplex immunofluorescence staining of samples from patients with PDAC, in vivo TGFβ1 conditional knockout mouse models, and 3D in vitro models, we discovered that the formation of intratumoral necrotic foci in pancreatic cancer is closely associated with liver metastatic events. This process was triggered by the deficiency of the long noncoding RNA TRAF3IP2-AS1 that induced necroptosis, which was accompanied by an immunosuppressive microenvironment. Mechanistically, TRAF3IP2-AS1 blocked necroptosis by reducing the mRNA stability of MLKL through competitively binding to IGF2BP2. Loss of TRAF3IP2-AS1 also promoted necroptosis by promoting RIPK3 phosphorylation via interference with the ubiquitination of the phosphatase PPM1B that dephosphorylates RIPK3. Additionally, TRAF3IP2-AS1 deficiency promoted the release of TGFβ1 from tumor cells, which induced an M2-like immunosuppressive phenotype and the release of more TGFβ1. The elevated production of TGFβ1 created a feedback loop that promoted the transcription of TRAF3IP2-AS1 in tumor cells to balance necroptosis. Overall, these findings identify TRAF3IP2-AS1 as a key regulator of necroptosis and the formation of an immunosuppressive microenvironment in PDAC, providing potential therapeutic targets for treating liver metastasis in patients with pancreatic cancer.
TRAF3IP2-AS1 deficiency drives necroptosis in pancreatic cancer cells to engender a prometastatic immunosuppressive niche mediated by TGFβ1 production, providing mechanistic understanding of necroptosis and therapeutic strategies for treating liver metastasis.
