PhD candidate The University of Hong Kong HONG KONG, Hong Kong
Abstract: Integrins are adhesion molecules that mediate mechanical and chemical signal transduction for supporting cell survival and proliferation. Dysregulated integrin signaling empower tumor cells with abilities to drive cancer cell plasticity, including stemness, epithelial plasticity, metastatic reactivation and resistance to therapies. However, the interplay of cancer cell plasticity and integrin signaling in hepatocellular carcinoma (HCC) remains poorly understood. Through lineage-tracing and lineage-ablation studies, our team has previously shown HCC cells genetically marked by Prom1/CD133 to represent an important functional subset in HCC tumors, displaying a dedifferentiated status with stem cell traits. In this study, transcriptome profiling revealed specific downregulation of integrin signaling in ‘HCC’ CD133+ cells isolated from NRAS+AKT protooncogenes-driven HCC, but not epithelial-specific ‘normal’ CD133+ cells isolated from the regenerating liver. One of the most differentially upregulated genes identified in the CD133+ HCC cell profiling, MAP2, demonstrated the ability to suppress integrin expression. MAP2 overexpression is frequently observed in HCC, and correlated with aggressive clinical features. Functionally, MAP2 promoted cancer stemness and proliferation, and conferred resistance to sorafenib. Mechanistically, MAP2-induced F-actin polymerization activates YAP, which transcriptionally suppresses expression of integrin α genes to ablate integrin β1-mediated cell adhesion. Pharmacological inhibition of MAP2 using Estramustine Phosphate (EMP), which is reported to inhibit the interaction of MAP2 with actin filaments, attained a synergistic effect in suppressing tumor initiation and growth of HCC cell lines, HCC patient-derived organoids and NRAS+AKT protooncogenes-driven HCC mouse model when used in combination with sorafenib. In summary, our findings reveal the pivotal functional role and clinical significance of MAP2 in mediating cancer cell plasticity to drive HCC, and that MAP2 inhibition represents a potential novel therapy for the disease targeted at its stemness roots.
