期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 215, 期 7, 页码 1891-1912出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20171385
关键词
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资金
- Cancer Research UK (CRUK) Clinician Scientist Fellowship [C14094/A16485]
- CRUK [C44943/A22536]
- Stand Up to Cancer [SU2C-AACR-DT1213]
- Wellcome Trust [102696]
- New York Stem Cell Foundation
- KWF (Dutch Cancer Society) [UVA2014-7245]
- Maurits en Anna de Kock Stichting [2015-2]
- Worldwide Cancer Research [14-1164]
- Maag Lever Darm Stichting [MLDS-CDG 14-03]
- European Research Council [ERG-StG 638193]
- ZonMW [Vidi 016.156.308]
- CRUK
Cellular dormancy and heterogeneity in cell cycle length provide important explanations for treatment failure after adjuvant therapy with S-phase cytotoxics in colorectal cancer (CRC), yet the molecular control of the dormant versus cycling state remains unknown. We sought to understand the molecular features of dormant CRC cells to facilitate rationale identification of compounds to target both dormant and cycling tumor cells. Unexpectedly, we demonstrate that dormant CRC cells are differentiated, yet retain clonogenic capacity. Mouse organoid drug screening identifies that itraconazole generates spheroid collapse and loss of dormancy. Human CRC cell dormancy and tumor growth can also be perturbed by itraconazole, which is found to inhibit Wnt signaling through noncanonical hedgehog signaling. Preclinical validation shows itraconazole to be effective in multiple assays through Wnt inhibition, causing both cycling and dormant cells to switch to global senescence. These data provide preclinical evidence to support an early phase trial of itraconazole in CRC.
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