L1CAM defines the regenerative origin of metastasis-initiating cells in colorectal cancer

Karuna Ganesh, Harihar Basnet, Yasemin Kaygusuz, Ashley M. Laughney, Lan He, Roshan Sharma, Kevin P. O’Rourke, Vincent P. Reuter, Yun Han Huang, Mesruh Turkekul, Ekrem Emrah Er, Ignas Masilionis, Katia Manova-Todorova, Martin R. Weiser, Leonard B. Saltz, Julio Garcia-Aguilar, Richard Koche, Scott W. Lowe, Dana Pe’er, Jinru ShiaJoan Massagué

Research output: Contribution to journalArticlepeer-review

148 Scopus citations

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.

Original languageEnglish
Pages (from-to)28-45
Number of pages18
JournalNature cancer
Volume1
Issue number1
DOIs
StatePublished - Jan 1 2020
Externally publishedYes

Funding

FundersFunder number
National Cancer InstituteR01CA182551
National Cancer Institute

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