| Literature DB >> 32656539 |
Harihar Basnet1, Yasemin Kaygusuz1,2, Ashley M Laughney1,3, Karuna Ganesh1,4,5, Lan He1, Roshan Sharma6,7,8, Kevin P O'Rourke1,9, Vincent P Reuter10, Yun-Han Huang1,2,9, Mesruh Turkekul11, Ekrem Emrah Er1,12, Ignas Masilionis6, Katia Manova-Todorova11, Martin R Weiser13, Leonard B Saltz4, Julio Garcia-Aguilar13, Richard Koche10, Scott W Lowe1, Dana Pe'er6, Jinru Shia14, Joan Massagué15.
Abstract
Metastasis-initiating cells with stem-like properties drive cancer lethality, yet their origins and relationship to primary-tumor-initiating stem cells are not known. We show that L1CAM+ cells in human colorectal cancer (CRC) have metastasis-initiating capacity, and we define their relationship to tissue regeneration. L1CAM is not expressed in the homeostatic intestinal epithelium, but is induced and required for epithelial regeneration following colitis and in CRC organoid growth. By using human tissues and mouse models, we show that L1CAM is dispensable for adenoma initiation but required for orthotopic carcinoma propagation, liver metastatic colonization and chemoresistance. L1CAMhigh cells partially overlap with LGR5high stem-like cells in human CRC organoids. Disruption of intercellular epithelial contacts causes E-cadherin-REST transcriptional derepression of L1CAM, switching chemoresistant CRC progenitors from an L1CAMlow to an L1CAMhigh state. Thus, L1CAM dependency emerges in regenerative intestinal cells when epithelial integrity is lost, a phenotype of wound healing deployed in metastasis-initiating cells.Entities:
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Year: 2020 PMID： 32656539 PMCID： PMC7351134 DOI： 10.1038/s43018-019-0006-x
Source DB: PubMed Journal: Nat Cancer ISSN： 2662-1347