2. Academic Validation
  3. IGF2BP2 stabilized by USP7 promotes cancer-associated fibroblast activation and attenuates gemcitabine sensitivity in PDAC

IGF2BP2 stabilized by USP7 promotes cancer-associated fibroblast activation and attenuates gemcitabine sensitivity in PDAC

  • Cell Rep. 2025 Nov 25;44(11):116476. doi: 10.1016/j.celrep.2025.116476.
Fujing Ge 1,  Hongdao Zhu 1,  Xiangning Liu 1,  Yuekang Li 1,  Runqiu Guo 2,  Chenming Zeng 2,  Tao Yuan 1,  Liu Yang 3,  Xin Dong 4,  Yulian Wu 4,  Renhua Gai 5,  Ronggui Hu 4,  Tianhua Zhou 6,  Qiaojun He 7,  Hong Zhu 8,  Bo Yang 9
Affiliations

Affiliations

  • 1 Institute of Pharmacology & Toxicology, Zhejiang Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
  • 2 Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, China.
  • 3 Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, Hangzhou, China.
  • 4 The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 5 Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
  • 6 Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China.
  • 7 Institute of Pharmacology & Toxicology, Zhejiang Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China; The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 8 Institute of Pharmacology & Toxicology, Zhejiang Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China; The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Electronic address: [email protected].
  • 9 Institute of Pharmacology & Toxicology, Zhejiang Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China; School of Medicine, Hangzhou City University, Hangzhou, China. Electronic address: [email protected].
PMID: 41201091 DOI: 10.1016/j.celrep.2025.116476
Abstract

N6-Methyladenosine (m6A) modification is a prevalent alteration in RNA, influencing stability, localization, and translation. The m6A reader IGF2BP2 stabilizes various mRNA transcripts of oncogenic proteins and has been extensively implicated in various tumors. Intriguingly, in pancreatic ductal adenocarcinoma (PDAC), IGF2BP2 maintains its protein stability despite the elevated autophagic activity, suggesting the existence of regulatory mechanisms that counteract IGF2BP2 degradation in PDAC. Herein, we explore the crosstalk between m6A modification and protein homeostasis, particularly the protein stability of IGF2BP2 under excessive activation of autophagic flux. Mechanistically, we show that Deubiquitinase USP7 acts on IGF2BP2, which enhances the stability of IGF2BP2 by reversing its K33-linked polyubiquitin chains, thereby preventing its degradation via the autophagy-lysosome pathway. Accumulated IGF2BP2 stabilizes PDGFA mRNA, activating myofibroblastic cancer-associated fibroblasts (myCAFs) through PDGFR interaction, which promotes resistance to gemcitabine. These findings uncover the USP7/IGF2BP2/PDGFA axis as a critical regulatory pathway in PDAC progression and chemoresistance.

Keywords

CP: Cancer; N(6)-methyladenosine; PDGFR; cancer-associated fibroblasts; deubiquitinase; pancreatic ductal adenocarcinoma.

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