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

Wei Cheng, Hao-Long Li, Shao-Yan Xi, Xiao-Feng Zhang, Yun Zhu, Le Xing, Yan-Xuan Mo, Mei-Mei Li, Fan-En Kong, Wen-Jie Zhu, Xiao-Gang Chen, Hui-Qing Cui, Zhi-Ming Cao, Yuan-Feng Gong, Yun-Qiang Tang, Yan Zhang, Xin-Yuan Guan, Ning-Fang Ma and Ming Liu ()
Additional contact information
Wei Cheng: Affiliated Cancer Hospital and Institute of Guangzhou Medical University
Hao-Long Li: Affiliated Cancer Hospital and Institute of Guangzhou Medical University
Shao-Yan Xi: Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center
Xiao-Feng Zhang: Affiliated Cancer Hospital and Institute of Guangzhou Medical University
Yun Zhu: Guangzhou Women and Children’s Medical Center, Guangzhou Medical University
Le Xing: Affiliated Cancer Hospital and Institute of Guangzhou Medical University
Yan-Xuan Mo: Affiliated Cancer Hospital and Institute of Guangzhou Medical University
Mei-Mei Li: Affiliated Cancer Hospital and Institute of Guangzhou Medical University
Fan-En Kong: Affiliated Cancer Hospital and Institute of Guangzhou Medical University
Wen-Jie Zhu: Affiliated Cancer Hospital and Institute of Guangzhou Medical University
Xiao-Gang Chen: Affiliated Cancer Hospital and Institute of Guangzhou Medical University
Hui-Qing Cui: Affiliated Cancer Hospital and Institute of Guangzhou Medical University
Zhi-Ming Cao: Affiliated Cancer Hospital and Institute of Guangzhou Medical University
Yuan-Feng Gong: Affiliated Cancer Hospital and Institute of Guangzhou Medical University
Yun-Qiang Tang: Affiliated Cancer Hospital and Institute of Guangzhou Medical University
Yan Zhang: Guangzhou Women and Children’s Medical Center, Guangzhou Medical University
Xin-Yuan Guan: The University of Hong Kong
Ning-Fang Ma: Affiliated Cancer Hospital and Institute of Guangzhou Medical University
Ming Liu: Affiliated Cancer Hospital and Institute of Guangzhou Medical University

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-27525-9

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