Growth differentiation factor 1-induced tumour plasticity provides a therapeutic window for immunotherapy in Hepatocellular Carcinoma

Tumour lineage plasticity is an emerging hallmark of aggressive tumours. Tumour cells usually hijack developmental signaling pathways to gain cellular plasticity and evade therapeutic targeting. In the present study, the secreted protein growth and differentiation factor 1 (GDF1) was found to be closely associated with poor tumour differentiation. Overexpression of GDF1 suppressed cell proliferation but strongly enhanced tumour dissemination and metastasis. Ectopic expression of GDF1 induced the dedifferentiation of hepatocellular carcinoma (HCC) cells into their ancestral lineages and reactivated a broad panel of cancer testis antigens (CTAs), which further stimulated the immunogenicity of HCC cells to immune-based therapies. Mechanistic studies revealed that GDF1 functioned through the Anaplastic lymphoma kinase 7 (ALK7)-Mothers against decapentaplegic homolog 2/3 (SMAD2/3) signaling cascade and suppressed 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.