Targeting USP7 identifies a metastasis-competent state within bone marrow-resident melanoma CTCs

Systemic metastasis is the major cause of death from melanoma, the most lethal form of skin cancer. Although most melanoma patients exhibit a substantial gap between onset of primary and metastatic tumors, signaling mechanisms implicated in the period of metastatic latency remain unclear. We hypothesized that melanoma circulating tumor cells (CTCs) home to and reside in the bone marrow (BM) during the asymptomatic phase of disease progression. Using a strategy to deplete normal cell lineages (Lin-neg), we isolated CTC-enriched cell populations from blood of metastatic melanoma patients, verified by the presence of putative CTCs characterized by melanoma-specific biomarkers and upregulated gene transcripts involved in cell survival and pro-development functions. Implantation of Lin-neg population in NSG mice (CTC-derived xenografts, i.e. CDXs), and subsequent transcriptomic analysis of ex vivo bone marrow-resident tumor cells (BMRTC) vs. CTC identified protein ubiquitination as a significant regulatory pathway of BMRTC signaling. Selective inhibition of USP7, a key deubiquinating enzyme, arrested BMRTC in BM locales and decreased systemic micro-metastasis. This study provides first time evidence that the asymptomatic progression of metastatic melanoma can be recapitulated in vivo using patient-isolated CTC. Furthermore, these results suggest that USP7 inhibitors warrant further investigation as a strategy to prevent progression to overt clinical metastasis.

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