Targeting EMT plasticity to prevent metastasis and chemoresistance development

The development of metastasis and resistance to conventional chemotherapy remain unresolved problems in cancer treatment. It is not deniable that EMT is closely involved in these processes. However, targeting EMT program in tumor cells could be a dilemma：1) EMT promoting factors (TGFb, EGF, FGFs, WNTs, etc) are redundant, and targeting them may not efficiently block EMT program in tumor cells; 2) Both EMT and its reverse process MET promote metastasis formation, which makes it a paradox of inhibiting EMT program while promoting MET as the same time. Targeting EMT plasticity other than E/M phenotype will provide us better approaches for metastasis and chemoresistance treatment. Our EMT lineage tracing models provide us unique opportunities to characterized the transitioning phase of EMT. In culture, the newborn post-EMT tumor cells are RFP+/GFP+, as their RFP gene had just been removed but the RFP protein still existed, and GFP was expressed due to the activation of EMT . Using single-cell RNA sequencing technology, we aimed to identify the specific pathways that were activated during the transitioning phase of EMT and MET, which will provide novel strategies of targeting EMT/MET simultaneously. Moreover, we have found that post-EMT tumor cells highly express pro-angiogenesis factors (Vegf, Pdgf, Cxcl12, etc) and lower their expression of MHC which may facilitate their escape from immune attacks. These findings provide clues that tumor cells may not only adapt to but also alter the microenvironment to facilitate the outgrowth of metastasis. Characterizing the reciprocal interactions between tumor cells (the “Seed”) and microenvironment (the Soil”) by using scRNA-seq and spatial transcriptome profiling techniques, especially, the EMT plasticity-related immune regulation will be an interesting field of our future studies.