Despite recent advances in therapy, liver metastasis from melanoma is still associated with poor prognosis.,Although targeting the mTOR signaling pathway exerts potent anti-tumor activity, little is known about specific mTORC2 inhibition regarding liver metastasis.,Using the novel mTORC2 specific inhibitor JR-AB2-011, we show significantly reduced migration and invasion capacity by impaired activation of MMP2 in melanoma cells.,In addition, blockade of mTORC2 induces cell death by non-apoptotic pathways and reduces tumor cell proliferation rate dose-dependently.,Furthermore, a significant reduction of liver metastasis was detected in a syngeneic murine metastasis model upon therapy with JR-AB2-011 as determined by in vivo imaging and necropsy.,Hence, our study for the first time highlights the impact of the pharmacological blockade of mTORC2 as a potent novel anti-cancer approach for liver metastasis from melanoma.
Despite recent advances in melanoma treatment, metastasis and resistance to therapy remain serious clinical challenges.,NME1 is a metastasis suppressor, a class of proteins which inhibits metastatic spread of cancer cells without impact on growth of the primary tumor.,We have identified a rare subpopulation of cells with markedly reduced expression of NME1 (NME1LOW) in human melanoma cell lines.,To enable isolation of viable NME1LOW cells for phenotypic analysis by fluorescence-activated cell sorting (FACS), a CRISPR-Cas9-mediated approach was used to attach an EGFP coding module to the C-terminus of the endogenous NME1 gene in melanoma cell lines.,NME1LOW cells displayed enhanced collective invasion in vitro when implanted as 3D aggregates in Matrigel.,NME1LOW cells were also highly metastatic to lung and liver when xenografted subcutaneously in immune-deficient NSG mice.,RNA-seq analysis revealed that NME1LOW cells express elevated levels of genes associated with tumor aggressiveness, as well as with morphogenesis of tissues of neural crest-like origin (melanocytes and neurons, bone and heart tissues; GO: 0009653).,The highly malignant NME1LOW variant of melanoma cells has potential to provide novel therapeutic targets and molecular markers for improved clinical management of patients with advanced melanoma.