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

• Published in: Nature communications Vol. 12; no. 1; pp. 7142 - 14
• Main Authors: Cheng, Wei, Li, Hao-Long, Xi, Shao-Yan, Zhang, Xiao-Feng, Zhu, Yun, Le Xing, Mo, Yan-Xuan, Li, Mei-Mei, Kong, Fan-En, Zhu, Wen-Jie, Chen, Xiao-Gang, Cui, Hui-Qing, Cao, Zhi-Ming, Gong, Yuan-Feng, Tang, Yun-Qiang, Zhang, Yan, Guan, Xin-Yuan, Ma, Ning-Fang, Liu, Ming
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.12.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 38/109; 42/89; 49/91; 59/5; 692/4028/67/1504/1610/4029; 692/4028/67/580; 692/4028/67/71; Activin; Antigens; Biomarkers; Cancer; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - therapy; Cell Differentiation; Cell Line, Tumor; Cell Plasticity - drug effects; Cell Proliferation; Ectopic expression; Epigenetics; Growth differentiation factor 1; Growth Differentiation Factor 1 - metabolism; Growth Differentiation Factor 1 - pharmacology; Hepatocellular carcinoma; Homology; Humanities and Social Sciences; Humans; Immune checkpoint inhibitors; Immunogenicity; Immunotherapy; Kinases; Liver cancer; Liver Neoplasms - metabolism; Lysine; Male; Metastases; multidisciplinary; Plastic foam; Plastic properties; Plasticity; Science; Science (multidisciplinary); Signal Transduction; Signaling; Smad2 protein; Smad2 Protein - metabolism; Smad3 Protein - metabolism; Testicular Neoplasms - metabolism; Therapeutic targets; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-27525-9

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. Poorly differentiated hepatocellular carcinoma (HCC) is an aggressive disease with poor prognosis. Here the authors show that GDF1, a member of the TGF-β superfamily, is highly expressed in high-grade poorly differentiated HCC and is associated with tumor plasticity, and that GDF1-induced reexpression of cancer testis antigens could render tumors sensitive to immune checkpoint inhibition.