Stem-like cells from Cancer of Unknown Primary are endowed with distinctive hypermetastatic properties and unveil liability to MEK inhibition

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 unique properties. These cells can be isolated in vitro (agnospheres) and propagated in vivo by serial transplantation, displaying exceptionally high tumorigenicity. After subcutaneous engraftment, agnospheres recapitulated the CUP phenotype, by showing the ability to spontaneously and quickly disseminate, and form 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 75% of CUP patients could be eligible to MEK inhibition. These data shed light on CUP biology and unveil an opportunity for therapeutic intervention.