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

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.

• Authors: 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, Ming Liu
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 7142 (12 08 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 34880251 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• GDF1 protein, human
• Growth Differentiation Factor 1
• SMAD2 protein, human
• SMAD3 protein, human
• Smad2 Protein
• Smad3 Protein

Topics

• Carcinoma, Hepatocellular (genetics, metabolism, pathology, therapy)
• Cell Differentiation
• Cell Line, Tumor
• Cell Plasticity (drug effects)
• Cell Proliferation
• Growth Differentiation Factor 1 (metabolism, pharmacology)
• Humans
• Immunotherapy
• Liver Neoplasms (metabolism)
• Male
• Signal Transduction
• Smad2 Protein (metabolism)
• Smad3 Protein (metabolism)
• Testicular Neoplasms (metabolism)