2. Academic Validation
  3. Growth differentiation factor 1-induced tumour plasticity provides a therapeutic window for immunotherapy in hepatocellular carcinoma

Growth differentiation factor 1-induced tumour plasticity provides a therapeutic window for immunotherapy in hepatocellular carcinoma

  • Nat Commun. 2021 Dec 8;12(1):7142. doi: 10.1038/s41467-021-27525-9.
Wei Cheng 1 2,  Hao-Long Li 1 2,  Shao-Yan Xi 3,  Xiao-Feng Zhang 1 2,  Yun Zhu 4,  Le Xing 1 2,  Yan-Xuan Mo 1 2,  Mei-Mei Li 1 2,  Fan-En Kong 1 2,  Wen-Jie Zhu 1 2,  Xiao-Gang Chen 1 2,  Hui-Qing Cui 1 2,  Zhi-Ming Cao 1 2,  Yuan-Feng Gong 1 2,  Yun-Qiang Tang 1 2,  Yan Zhang 4,  Xin-Yuan Guan 5,  Ning-Fang Ma 1 2,  Ming Liu 6 7
Affiliations

Affiliations

  • 1 Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, 510095, China.
  • 2 Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Science, Guangzhou Medical University, Guangzhou, 511436, China.
  • 3 State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 4 Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
  • 5 Department of Clinical Oncology, State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China.
  • 6 Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, 510095, China. [email protected].
  • 7 Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Science, Guangzhou Medical University, Guangzhou, 511436, China. [email protected].
PMID: 34880251 DOI: 10.1038/s41467-021-27525-9
Abstract

Tumour lineage plasticity is an emerging hallmark of aggressive tumours. Tumour cells usually hijack developmental signalling pathways to gain cellular plasticity and evade therapeutic targeting. In the present study, the secreted protein growth and differentiation factor 1 (GDF1) is found to be closely associated with poor tumour differentiation. Overexpression of GDF1 suppresses cell proliferation but strongly enhances tumour dissemination and metastasis. Ectopic expression of GDF1 can induce the dedifferentiation of hepatocellular carcinoma (HCC) cells into their ancestral lineages and reactivate a broad panel of Cancer testis antigens (CTAs), which further stimulate the immunogenicity of HCC cells to immune-based therapies. Mechanistic studies reveal that GDF1 functions through the Activin receptor-like kinase 7 (ALK7)-Mothers against decapentaplegic homolog 2/3 (SMAD2/3) signalling cascade and suppresses the epigenetic regulator Lysine specific demethylase 1 (LSD1) to boost CTA expression. GDF1-induced tumour lineage plasticity might be an Achilles heel for HCC immunotherapy. Inhibition of LSD1 based on GDF1 biomarker prescreening might widen the therapeutic window for immune checkpoint inhibitors in the clinic.

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