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.
Highlights
Tumour lineage plasticity is an emerging hallmark of aggressive tumours
We find that a series of cancer testis antigens (CTAs) are significantly activated in GDF1overexpressing tumour cells, and this process might be mediated through inhibition of the epigenetic modulator Lysine specific demethylase 1 (LSD1)
The upregulation of growth and differentiation factor 1 (GDF1) was further confirmed in The Cancer Genome Atlas (TCGA) database LIHC project, which included 373 hepatocellular carcinoma (HCC) patients and 50 paratumor liver tissues (Fig. 1b)
Summary
Tumour cells usually hijack developmental signalling pathways to gain cellular plasticity and evade therapeutic targeting. Clinical high-grade tumours usually show phenotypic resemblance to their ancestral cells and hijack developmental signalling pathways to gain lineage plasticity[6]. Cancer cells of hepatic origins and bile duct epithelial origins can switch identities upon activation of certain developmental signalling pathways and hamper effective therapeutic targeting of HCC13,14. Many factors can affect the effectiveness of immune checkpoint inhibitor therapy, including tumour mutation burden (TMB), programmed cell death-ligand 1 (PD-L1) expression, T-cell infiltration, and human leucocyte antigen (HLA) diversity[16]. The mechanisms underlying the effects of cancer stemness and tumour plasticity on the immune therapeutic response are still unclear
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