Skip to content
DraconiticResearch
Search Sources API
203,234 studies31 sourcesUpdated 18 min ago
Peer-reviewedCC BY 4.0Cell Death & Disease

Tumor-derived annexin A1 drives lenvatinib resistance by regulating SOX2/STAT3/S100A6 feedback loop and M2 macrophage polarization in hepatocellular carcinoma

  • Catherine Yu Jia Gu1
  • Carmen Oi Ning Leung1
  • Rainbow Wing Hei Leung1
  • Wing Ki Chau1
  • Martina Mang Leng Lei1
  • Yi Tian Chen1
  • Sze Man Chan1
  • Gregory Kenneth Muliawan1
  • Yuan Gao2
  • Qian Qian Yu3
  • Ming Liu4,5
  • Xiao Qi Wu6
4 more authors
  • Jin Ding7
  • Xin Wang8
  • Stephanie Ma9,10
  • Terence Kin Wah Lee1,11
11 affiliations
  1. 1Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
  2. 2State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi’an, China
  3. 3Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
  4. 4Affiliated Cancer Hospital Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
  5. 5State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China
  6. 6Xi’an Boxin Zhida Biotechnology Co. Ltd, Xi’an, China
  7. 7Clinical Cancer Institute, Center for Translational Medicine, Naval Medical University, Shanghai, China
  8. 8Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China
  9. 9School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
  10. 10State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
  11. 11Research Institute for Future Food, The Hong Kong Polytechnic University, Hong Kong, China
Read full textPDFDOICite

Abstract

Lenvatinib has been approved by the FDA as a front-line treatment for advanced hepatocellular carcinoma (HCC), but its survival benefits are limited by acquired drug resistance. In this study, we investigate the mechanisms underlying lenvatinib resistance in HCC by establishing lenvatinib-resistant (LenR) patient-derived tumor xenograft (PDTX) and analyzing their genetic profiles via single-cell RNA sequencing (scRNA-seq). Through single-cell regulatory network inference and clustering (SCENIC) analysis, we find that Annexin A1 (ANXA1) is significantly enriched in LenR HCC clusters. Using knockdown and overexpression strategies, we demonstrate the critical role of ANXA1 in regulating cancer stemness-driven lenvatinib resistance. ANXA1 mediates resistance by regulating S100A6 expression, while its expression is regulated by SOX2 via promoter activation, forming a positive feedback loop with STAT3. Notably, we reveal that ANXA1 secreted from LenR HCC cells reshapes the tumor microenvironment (TME) by inducing M2 macrophage polarization via FPR2 binding and activation of ERK and NF-κB signaling, leading to decreased T cell infiltration. Targeting ANXA1 via an adeno-associated virus serotype 8 (AAV8) approach improves lenvatinib efficacy in our LenR Tp53KO/MycOE HCC mouse model, accompanied by the suppression of an immunosuppressive TME. In conclusion, HCC-derived ANXA1 regulates lenvatinib resistance both intrinsically and extrinsically. Targeting the SOX2/ANXA1/STAT3/S100A6 positive loop may provide a novel therapeutic strategy for HCC treatment.

Related

  1. Glycyrrhizic acid attenuates sepsis-induced acute lung injury by regulating macrophage M2 polarization via PRKCD
    Yikun Chen, Yucheng Liu, Jiayi Shen +4
    Journal of thoracic diseasePeer-reviewedCC BY-NC-NDFull textGeneral medicineEurope PMC
  2. HuR Confers Resistance of Hepatocellular Carcinoma to Lenvatinib by Inhibiting Ferroptosis
    Siren Feng, Fang Wang, Huayi Wu +7
    Journal of Cellular and Molecular MedicinePeer-reviewedCC BY 4.0Full textOncologyPMC
  3. Spermidine, a chondrocyte apoptotic metabolite, delays osteoarthritis by regulating macrophage M2c polarization.
    Jiajia Lu, Hongbiao Sun, Fan Zhang +7
    Journal of nanobiotechnologyPeer-reviewedCC BY-NC-NDFull textSystems & synthetic biologyGeneral medicineEurope PMCDOAJ
  4. Magnesium cantharidate suppresses hepatocellular carcinoma progression and modulates tumor-associated macrophage polarization: potential involvement of ERK1/2 signaling and de novo serine synthesis
    Zhenfu Chen, Liu Liu, Sali Li +4
    Frontiers in PharmacologyPeer-reviewedCC BY 4.0Pharmacology & toxicologyFrontiersCrossref
  5. MTA1 promotes hepatocellular carcinoma progression by remodeling the immune microenvironment and regulating drug resistance gene networks: an integrated multi-database analysis.
    Wen Jin, Liang Chen, Mei Yang +2
    Journal of gastrointestinal oncologyPeer-reviewedCC BY-NC-NDFull textOncologyEurope PMC

Cite

BibTeXRIS
BibTeX
@article{gu2026tumorderived,
  title = {{Tumor-derived annexin A1 drives lenvatinib resistance by regulating SOX2/STAT3/S100A6 feedback loop and M2 macrophage polarization in hepatocellular carcinoma}},
  author = {Catherine Yu Jia Gu and Carmen Oi Ning Leung and Rainbow Wing Hei Leung and Wing Ki Chau and Martina Mang Leng Lei and Yi Tian Chen and Sze Man Chan and Gregory Kenneth Muliawan and Yuan Gao and Qian Qian Yu and Ming Liu and Xiao Qi Wu and Jin Ding and Xin Wang and Stephanie Ma and Terence Kin Wah Lee},
  journal = {Cell Death \& Disease},
  year = {2026},
  month = jul,
  doi = {10.1038/s41419-026-09118-w},
  url = {https://doi.org/10.1038/s41419-026-09118-w},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Tumor-derived annexin A1 drives lenvatinib resistance by regulating SOX2/STAT3/S100A6 feedback loop and M2 macrophage polarization in hepatocellular carcinoma
AU  - Catherine Yu Jia Gu
AU  - Carmen Oi Ning Leung
AU  - Rainbow Wing Hei Leung
AU  - Wing Ki Chau
AU  - Martina Mang Leng Lei
AU  - Yi Tian Chen
AU  - Sze Man Chan
AU  - Gregory Kenneth Muliawan
AU  - Yuan Gao
AU  - Qian Qian Yu
AU  - Ming Liu
AU  - Xiao Qi Wu
AU  - Jin Ding
AU  - Xin Wang
AU  - Stephanie Ma
AU  - Terence Kin Wah Lee
PY  - 2026
DA  - 2026/07/29
JO  - Cell Death & Disease
DO  - 10.1038/s41419-026-09118-w
UR  - https://doi.org/10.1038/s41419-026-09118-w
AB  - Lenvatinib has been approved by the FDA as a front-line treatment for advanced hepatocellular carcinoma (HCC), but its survival benefits are limited by acquired drug resistance. In this study, we investigate the mechanisms underlying lenvatinib resistance in HCC by establishing lenvatinib-resistant (LenR) patient-derived tumor xenograft (PDTX) and analyzing their genetic profiles via single-cell RNA sequencing (scRNA-seq). Through single-cell regulatory network inference and clustering (SCENIC) analysis, we find that Annexin A1 (ANXA1) is significantly enriched in LenR HCC clusters. Using knockdown and overexpression strategies, we demonstrate the critical role of ANXA1 in regulating cancer stemness-driven lenvatinib resistance. ANXA1 mediates resistance by regulating S100A6 expression, while its expression is regulated by SOX2 via promoter activation, forming a positive feedback loop with STAT3. Notably, we reveal that ANXA1 secreted from LenR HCC cells reshapes the tumor microenvironment (TME) by inducing M2 macrophage polarization via FPR2 binding and activation of ERK and NF-κB signaling, leading to decreased T cell infiltration. Targeting ANXA1 via an adeno-associated virus serotype 8 (AAV8) approach improves lenvatinib efficacy in our LenR Tp53KO/MycOE HCC mouse model, accompanied by the suppression of an immunosuppressive TME. In conclusion, HCC-derived ANXA1 regulates lenvatinib resistance both intrinsically and extrinsically. Targeting the SOX2/ANXA1/STAT3/S100A6 positive loop may provide a novel therapeutic strategy for HCC treatment.
SN  - 2041-4889
ER  -