GSE167473
Cancer of Unknown Primary stem-like cells model multi-organ metastasis 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 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. Overall design: Transcriptional characterization of CUP stem-like cells and CUP tissues