GALNT6 drives lenvatinib resistance in hepatocellular carcinoma through autophagy and cancer-associated fibroblast activation

  • Cell Oncol (Dordr). 2024 Dec;47(6):2439-2460. doi: 10.1007/s13402-024-01032-7.
Peiling Zhang  #  1  2 ,  Shiping Chen  #  1  2 ,  Jialiang Cai  #  1  2 ,  Lina Song  1  2 ,  Bing Quan  1  2 ,  Jinglei Wan  1 ,  Guiqi Zhu  1  3  4 ,  Biao Wang  5 ,  Yi Yang  5 ,  Zhengjun Zhou  1  2 ,  Tao Li  6 ,  Zhi Dai  7  8
Affiliations
  • 1. Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
  • 2. Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, 200032, China.
  • 3. Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 4. Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China.
  • 5. Departments of Radiation Oncology Zhongshan Hospital, Fudan University, Shanghai, China.
  • 6. Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. [email protected].
  • 7. Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. [email protected].
  • 8. Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, 200032, China. [email protected].
  • # Contributed equally.
PMID: 39718738 DOI: 10.1007/s13402-024-01032-7
Abstract

Background: Hepatocellular carcinoma (HCC) remains a significant global health challenge with limited treatment options. Lenvatinib, a tyrosine kinase inhibitor, has shown promise but is often undermined by the development of drug resistance.

Methods: Utilizing high-throughput Sequencing, we investigated the molecular mechanisms underlying lenvatinib resistance in HCC cells, with a focus on metabolic pathways. Key genes, including GALNT6, were validated through quantitative Real-Time PCR. The effects of GALNT6 knockdown on lenvatinib sensitivity were examined in vitro and in vivo. O-GalNAc glycosylation was assessed using Vicia Villosa Lectin. Immune cell infiltration and interactions were analyzed in the TCGA-LIHC cohort, with further validation by Western blotting and immunohistochemistry.

Results: Our findings indicate that lenvatinib resistance in HCC is driven by the mucin-type O-glycosylation pathway, with GALNT6 playing a critical role. Knockdown of GALNT6 led to reduced O-GalNAc glycosylation, including the modification of LAPTM5, resulting in decreased LAPTM5 activity and Autophagy inhibition. Additionally, GALNT6 silencing disrupted the PDGFA-PDGFRB axis, impairing the activation of cancer-associated fibroblasts (CAFs) and reducing their secretion of SPP1, which collectively diminished lenvatinib resistance.

Conclusions: GALNT6 is integral to the resistance mechanisms against lenvatinib in HCC by modulating Autophagy and CAF activation. Targeting GALNT6 offers a promising strategy to enhance lenvatinib efficacy and improve therapeutic outcomes in HCC.

Keywords
CAFs; GALNT6; LAPTM5; Lenvatinib resistance; Mucin-type O-glycosylation.
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