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

Federica Verginelli, Alberto Pisacane, Gennaro Gambardella, Antonio D’Ambrosio, Ermes Candiello, Marco Ferrio, Mara Panero, Laura Casorzo, Silvia Benvenuti, Eliano Cascardi, Rebecca Senetta, Elena Geuna, Andrea Ballabio, Filippo Montemurro, Anna Sapino, Paolo M. Comoglio and Carla Boccaccio ()
Additional contact information
Federica Verginelli: Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS
Alberto Pisacane: Unit of Pathology, Candiolo Cancer Institute, FPO-IRCCS
Gennaro Gambardella: Telethon Institute of Genetics and Medicine (TIGEM)
Antonio D’Ambrosio: Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS
Ermes Candiello: Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS
Marco Ferrio: Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS
Mara Panero: Unit of Pathology, Candiolo Cancer Institute, FPO-IRCCS
Laura Casorzo: Unit of Pathology, Candiolo Cancer Institute, FPO-IRCCS
Silvia Benvenuti: Laboratory of Exploratory Research and Molecular Cancer Therapy, Candiolo Cancer Institute, FPO-IRCCS
Eliano Cascardi: Unit of Pathology, Candiolo Cancer Institute, FPO-IRCCS
Rebecca Senetta: Unit of Pathology, Candiolo Cancer Institute, FPO-IRCCS
Elena Geuna: Multidisciplinary Oncology Outpatient Clinic, Candiolo Cancer Institute, FPO-IRCCS
Andrea Ballabio: Telethon Institute of Genetics and Medicine (TIGEM)
Filippo Montemurro: Multidisciplinary Oncology Outpatient Clinic, Candiolo Cancer Institute, FPO-IRCCS
Anna Sapino: Unit of Pathology, Candiolo Cancer Institute, FPO-IRCCS
Paolo M. Comoglio: Laboratory of Exploratory Research and Molecular Cancer Therapy, Candiolo Cancer Institute, FPO-IRCCS
Carla Boccaccio: Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22643-w

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