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, two major obstacles in eradicating cancer. Through lineage-tracing and lineage-ablation studies, our team has previously shown hepatocellular carcinoma (HCC) cells marked by prominin-1 (CD133) to represent a functional subset displaying dedifferentiated status with stemness traits, yet there are limited therapies effective for eradicating such resilient cell populations. To address this unmet clinical need, we explore the therapeutic potential of repurposing an existing drug estramustine phosphate (EMP) for targeting HCC plasticity through inhibiting microtubule associated protein 2 (MAP2), a gene uniquely enriched in CD133+ ‘HCC' stemness subset but not in CD133+ ‘normal' regenerative cells. MAP2 is transcriptionally activated by p300-driven histone 3 lysine 27 acetylation, and its upregulation is associated with aggressive clinical features. Functional characterization demonstrates that MAP2 confers tumor-initiating and migratory abilities to HCC cells both in vitro and in vivo, and enables cells to resist cell apoptosis upon sorafenib treatment. Comparative transcriptome profiling and pathway analysis by Gene Set Enrichment Analysis and Gene Ontology identifies a pan-deficiency of integrin alpha expressions and depletion of integrin-directed adhesion pathways upon MAP2 overexpression. Mechanistically, MAP2 sustains tumor plasticity and transition to a mesenchymal phenotype through inducing filamentous actin polymerization and activation of yes-associated protein (YAP), which subsequently disrupts integrin-mediated cell adhesion behaviors on type I collagen. Of note, pharmacological inhibition of MAP2 effectively sensitizes HCC to targeted therapy sorafenib in HCC cells lines, patients-derived organoids and immunocompetent HCC mice model. Collectively, our research offers a promising opportunity for drug repurposing using EMP in combination with sorafenib to target HCC at its stemness roots.