1. Cancer of unknown primary stem-like cells model multi-organ metastasis and unveil liability to MEK inhibition
- Author
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Mara Panero, Antonio D'Ambrosio, Marco Ferrio, Andrea Ballabio, Alberto Pisacane, Elena Geuna, Laura Casorzo, Carla Boccaccio, Gennaro Gambardella, Ermes Candiello, Eliano Cascardi, Filippo Montemurro, Paolo M. Comoglio, Federica Verginelli, Rebecca Senetta, Anna Sapino, Silvia Benvenuti, Verginelli, F., Pisacane, A., Gambardella, G., D'Ambrosio, A., Candiello, E., Ferrio, M., Panero, M., Casorzo, L., Benvenuti, S., Cascardi, E., Senetta, R., Geuna, E., Ballabio, A., Montemurro, F., Sapino, A., Comoglio, P. M., and Boccaccio, C.
- Subjects
0301 basic medicine ,Male ,Cellular pathology ,genetic structures ,Carcinogenesis ,General Physics and Astronomy ,Mice, SCID ,Metastasis ,Transcriptome ,Mice ,0302 clinical medicine ,Mice, Inbred NOD ,Tumor Cells, Cultured ,Neoplasm Metastasis ,Carcinogenesi ,Multidisciplinary ,Cancer stem cells ,Phenotype ,Primary tumor ,Gene Expression Regulation, Neoplastic ,Neoplasm Metastasi ,030220 oncology & carcinogenesis ,Neoplastic Stem Cells ,Heterografts ,Heterograft ,Human ,Science ,Biology ,Malignancy ,General Biochemistry, Genetics and Molecular Biology ,Article ,Cancer of unknown primary ,03 medical and health sciences ,Targeted therapies ,Cancer stem cell ,In vivo ,Spheroids, Cellular ,medicine ,Animals ,Humans ,Cancer models ,Animal ,General Chemistry ,medicine.disease ,Disease Models, Animal ,030104 developmental biology ,Cancer research ,Neoplasms, Unknown Primary ,sense organs ,Neoplastic Stem Cell ,Neoplasm Transplantation - 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 peculiar and shared properties. These cells can be isolated in vitro (agnospheres) and propagated in vivo by serial transplantation, displaying high tumorigenicity. After subcutaneous engraftment, agnospheres recapitulate the CUP phenotype, by spontaneously and quickly disseminating, and forming widespread established metastases. Regardless of different genetic backgrounds, agnospheres invariably display 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., Cancer of unknown primary (CUP) is a mysterious malignancy featuring metastatic dissemination in the absence of a recognizable primary tumor. By characterizing CUP cancer stem cells we show that self-sustained long-term propagation and sensitivity to MEK inhibition are CUP common features.
- Published
- 2021