Abstract 2871: Hypermetastatic stem-like cells from 'cancer of unknown primary' (CUP) model multi-organ dissemination and unveil liability to MEK inhibition

• Published in: Cancer research (Chicago, Ill.) Vol. 81; no. 13_Supplement; p. 2871
• Main Authors: Verginelli, Federica, Pisacane, Alberto, Gambardella, Gennaro, D'Ambrosio, Antonio, Candiello, Ermes, Ferrio, Marco, Panero, Mara, Casorzo, Laura, Benvenuti, Silvia, Cascardi, Eliano, Senetta, Rebecca, Geuna, Elena, Ballabio, Andrea, Montemurro, Filippo, Sapino, Anna, Comoglio, Paolo M., Boccaccio, Carla
• Format: Journal Article
• Language: English
• Published: 01.07.2021
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2021-2871

Abstract Cancers of Unknown Primary (CUPs), featuring metastatic dissemination in the absence of a primary tumor, anatomically or histologically recognizable through a standardized work-up, are a fatal disease and still a biological enigma. Here, we propose CUPs as a distinct, yet unrecognized, pathological entity originating from stem-like cells endowed with unique properties, irrespective of their different genetic backgrounds. These cells were isolated and long-term propagated in vitro in highly stringent conditions as ‘agnospheres', and serially transplanted in vivo, displaying an extremely high tumorigenic potential and reproducing the undifferentiated histology of the original tumors. Early after subcutaneous engraftment, agnospheres recapitulated the CUP clinical presentation, as they spontaneously and quickly disseminated, establishing widespread metastases and retracing the whole metastatic cascade. Agnospheres invariably displayed cell-autonomous proliferation and self-renewal, mostly relying on unrestrained activation of the MAP kinase/MYC axis. This feature conferred sensitivity to MEK inhibitors, which induced apoptosis in vitro and impaired in vivo growth and dissemination. We generated and validated a transcriptional signature that, applied to original tumors, predicts eligibility to MEK inhibition in 75% of CUP patients. Altogether, these findings shed light on CUP biology, unveiling an opportunity for a targeted therapeutic intervention and, concomitantly, provide a novel in vivo model, suitable for assessing molecular determinants of the metastatic cascade. Citation Format: 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, Carla Boccaccio. Hypermetastatic stem-like cells from 'cancer of unknown primary' (CUP) model multi-organ dissemination and unveil liability to MEK inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2871.