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A pre-existing population of ZEB2+ quiescent cells with stemness and mesenchymal features dictate chemoresistance in colorectal cancer.

Journal of experimental & clinical cancer research : CR (2020-01-09)
Federica Francescangeli, Paola Contavalli, Maria Laura De Angelis, Silvia Careccia, Michele Signore, Tobias Longin Haas, Federico Salaris, Marta Baiocchi, Alessandra Boe, Alessandro Giuliani, Olga Tcheremenskaia, Alfredo Pagliuca, Ombretta Guardiola, Gabriella Minchiotti, Lidia Colace, Antonio Ciardi, Vito D'Andrea, Filippo La Torre, JanPaul Medema, Ruggero De Maria, Ann Zeuner

Quiescent/slow cycling cells have been identified in several tumors and correlated with therapy resistance. However, the features of chemoresistant populations and the molecular factors linking quiescence to chemoresistance are largely unknown. A population of chemoresistant quiescent/slow cycling cells was isolated through PKH26 staining (which allows to separate cells on the basis of their proliferation rate) from colorectal cancer (CRC) xenografts and subjected to global gene expression and pathway activation analyses. Factors expressed by the quiescent/slow cycling population were analyzed through lentiviral overexpression approaches for their ability to induce a dormant chemoresistant state both in vitro and in mouse xenografts. The correlation between quiescence-associated factors, CRC consensus molecular subtype and cancer prognosis was analyzed in large patient datasets. Untreated colorectal tumors contain a population of quiescent/slow cycling cells with stem cell features (quiescent cancer stem cells, QCSCs) characterized by a predetermined mesenchymal-like chemoresistant phenotype. QCSCs expressed increased levels of ZEB2, a transcription factor involved in stem cell plasticity and epithelial-mesenchymal transition (EMT), and of antiapototic factors pCRAF and pASK1. ZEB2 overexpression upregulated pCRAF/pASK1 levels resulting in increased chemoresistance, enrichment of cells with stemness/EMT traits and proliferative slowdown of tumor xenografts. In parallel, chemotherapy treatment of tumor xenografts induced the prevalence of QCSCs with a stemness/EMT phenotype and activation of the ZEB2/pCRAF/pASK1 axis, resulting in a chemotherapy-unresponsive state. In CRC patients, increased ZEB2 levels correlated with worse relapse-free survival and were strongly associated to the consensus molecular subtype 4 (CMS4) characterized by dismal prognosis, decreased proliferative rates and upregulation of EMT genes. These results show that chemotherapy-naive tumors contain a cell population characterized by a coordinated program of chemoresistance, quiescence, stemness and EMT. Such population becomes prevalent upon drug treatment and is responsible for chemotherapy resistance, thus representing a key target for more effective therapeutic approaches.

Product Number
Product Description

Triton X-100, laboratory grade
PKH26 Red Fluorescent Cell Linker Kit for General Cell Membrane Labeling, Distributed for Phanos Technologies
Etoposide, synthetic, 98.0-105.0%, powder
Monoclonal Anti-β-Actin antibody produced in mouse, clone AC-74, ascites fluid
Hematoxylin Solution, Mayer′s
Irinotecan hydrochloride, topoisomerase inhibitor
Eosin Y solution, aqueous
MISSION® esiRNA, targeting human ZEB2