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Cancer of Unknown Primary stem-like cells model multi-organ metastasis and unveil liability to MEK inhibition

ABSTRACT: Cancers of Unknown Primary (CUPs), featuring metastatic dissemination in the absence of a primary tumor, are a biological enigma and a fatal disease. We propose that CUPs are a distinct, yet unrecognized, pathological entity originating from stem-like cells endowed with distinguished properties. These cells can be isolated in vitro (agnospheres) and propagated in vivo by serial transplantation, displaying a high tumor-initiating cell frequency. After subcutaneous engraftment, agnospheres recapitulated the CUP phenotype, by spontaneously and quickly disseminating, and forming widespread established metastases. Regardless of different genetic backgrounds, agnospheres invariably displayed cell-autonomous proliferation and self-renewal, mostly relying on unrestrained activation of the MAP kinase/MYC axis, which confers sensitivity to MEK inhibitors in vitro and in vivo. Such sensitivity is associated with a transcriptomic signature predicting that more than 70% of CUP patients could be eligible to MEK inhibition. These data shed light on CUP biology and unveil an opportunity for therapeutic intervention.

ORGANISM(S): Homo sapiens

PROVIDER: GSE167473 | GEO | 2021/02/25

REPOSITORIES: GEO

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