The plasticity of cancer cell invasion represents substantial hindrance for effective anti-metastatic therapy. To better understand the cancer cells' plasticity, we performed complex transcriptomic and proteomic profiling of HT1080 fibrosarcoma cells undergoing mesenchymal-amoeboid transition (MAT). As amoeboid migratory phenotype can fully manifest only in 3D conditions, all experiments were performed with 3D collagen-based cultures. Two previously described approaches to induce MAT were used: doxycycline-inducible constitutively active RhoA expression and dasatinib treatment. RNA sequencing was performed with ribo-depleted total RNA. Protein samples were analysed with tandem mass tag (TMT)-based mass spectrometry. The data provide unprecedented insight into transcriptome and proteome changes accompanying MAT in true 3D conditions.