MAP2-mediated integrin dysregulation reprograms cancer cell plasticity to drive liver cancer cell transition to a mesenchymal and stemness state in hepatocellular carcinoma

Targeting tumor cell plasticity is central to overcome drug resistance and metastasis. Through lineage-tracing and lineage-ablation studies, our team has previously shown hepatocellular carcinoma (HCC) cells marked by CD133 to represent a functional subset displaying dedifferentiated status with stemness traits, yet there are limited therapies effective for eradicating such resilient cell populations. Here, we explore the therapeutic potential of repurposing an existing drug estramustine phosphate (EMP) for targeting HCC plasticity through inhibiting MAP2, a gene uniquely enriched in CD133+ ‘HCC’ stemness subset but not in CD133+ ‘normal’ regenerative cells. MAP2 is transcriptionally activated by H3K27Ac and its upregulation correlates with aggressive clinical features. Mechanistically, MAP2 sustains tumor plasticity and transition to a mesenchymal state through inducing filamentous actin polymerization and YAP activation, which subsequently disrupts integrin-mediated cell adhesions. Our research offers a promising opportunity for drug repurposing using EMP in combination with sorafenib to target HCC at its stemness roots.